Managing STEMIs without a Catheterization Lab: A Simulated Scenario to Improve Emergency Clinician Recognition and Execution of Thrombolysis in the Setting of Rural STEMI Management.

Audience: The targeted audience for this simulation is Emergency Medicine (EM) residents. Medical students, advanced practice providers, and staff physicians could all also find educational merit in this scenario. Background: Cardiovascular disease is the leading cause of death in the United States according to the CDC.1 Coronary artery disease caused 375,000 deaths 2021 alone, and about 5% of all adult patients have a prior history of coronary artery disease.2 Furthermore, chest pain itself is a common chief complaint encountered in the ED, with nearly 8 million visits annually occurring throughout the United States, with 10-20% of those patients ultimately being diagnosed with an acute coronary syndrome3, including ST-elevation myocardial infarction (STEMI). Given this, it is essential that EM residents are well prepared to care for all patients presenting with chest pain, regardless of the acute care or emergency setting.Throughout their training, most EM residents typically learn and evaluate patients at a large tertiary or quaternary medical center with 24-hour catheterization laboratory availability. For patients presenting with electrocardiogram (EKG) findings consistent with STEMI, the standard of care is for the patient to undergo cardiac catheterization and stent placement within 90 minutes of arrival. Unfortunately, only half of patients living in rural areas have a cardiac catheterization-capable facility available to them within a 60-minute driving radius, making it difficult for those patients to undergo cardiac catheterization within the desired time frame.4 These patients remain candidates for thrombolytic therapy, but given infrequent opportunities to learn about and deploy thrombolytic agents during residency training, graduating EM residents may be unfamiliar with indications, dosing, and contraindications before they begin practice. Furthermore, the recent EM workforce data suggests that although there may be an oversupply of 8,000 emergency physicians by 2030, robust practice opportunities for emergency physicians remain in rural settings.5 Although historically EM graduates have not selected rural areas for practice, with only approximately 8% of emergency physicians practicing in rural areas,6 it is likely that given the opportunities present and perceived saturation in many non-rural settings, more EM graduates will pursue practice in a rural setting. With these changing practice dynamics in mind, this simulation provides the opportunity for residents and medical students to experience the management of a STEMI in the rural setting, with a focus upon the indications, contraindications, dosing, and disposition of a patient receiving thrombolytics. Educational Objectives: By the end of this simulation, learners will be able to:Diagnose ST elevation myocardial infarction accurately and initiate thrombolysis in the rural setting without timely access to cardiac catheterization.Engage the simulated patient in a shared decision-making conversation, clearly outlying the benefits and risks of thrombolysis.Identify the indications and contraindications for thrombolysis in ST elevation myocardial infarction.Arrange for transfer to a tertiary care center following completion of thrombolysis. Educational Methods: This scenario is a simulated encounter in a rural emergency department setting requiring the diagnosis of a STEMI, a discussion with the patient regarding the risks and benefits of thrombolysis prior to administration, administration of thrombolysis, and transfer of patient to a higher level of care. Research Methods: The educational content of this simulation as a teaching instrument was evaluated by the learner utilizing an internally developed survey after case completion. This survey was reviewed for precision of language and assessment of learning objectives by our simulation faculty and other members of our West Virginia University Emergency Medicine Department of Medical Education. The learner was asked to specify any prior experience with rural STEMI management as well as quantify via a five-point Likert Scale, where 1 = very uncomfortable and 5 = very comfortable, their level of comfort with thrombolysis before and after the scenario as well as their comfort with having a shared decision-making conversation with patients with regards to thrombolysis. Learners were also asked to rank the helpfulness of this simulation in preparing them for administering thrombolytics for STEMI in a rural setting on a five-point Likert scale, where 1 = not helpful and 5 =very helpful. An open response section was also provided to allow learners the opportunity to comment directly on any aspect of the simulation. Results: Data was collected anonymously from 16 PGY1-3 resident learners via surveys with a 100% response rate. Overall, the feedback received regarding the simulation was positive. There was a low average comfort level with administering thrombolytics and having a shared decision-making conversation regarding administering thrombolytics. There was a high average rating of the helpfulness of this simulation in preparing residents for this conversation as well as managing STEMIs in a rural setting. Subjective comments regarding the simulation were universally positive. Discussion: The management of STEMI in the rural emergency department differs significantly from the environment in which many EM residents train. As a leading cause of death in the United States, STEMI management is a vital component of EM resident education. Although the concept of thrombolysis in the rural setting is discussed, the opportunity for real-world experience in its execution is often limited despite many graduates ultimately working in rural emergency departments. This simulation sought to provide a realistic patient encounter to promote familiarity and comfort in the identification, patient discussion and execution of thrombolysis in the treatment of a STEMI. The educational content was shown to be effective via learner survey completion.

Site-directed cation ordering in chabazite-type AlxGa1-xPO4-34 frameworks revealed by NMR crystallography.

We report the first synthesis of the mixed-metal chabazite-type AlxGa1-xPO4-34(mim) solid solution, containing 1-methylimidazolium, mim, as structure directing agent (SDA), from the parent mixed-metal oxide solid solution, γ-(AlxGa1-x)2O3. This hitherto unreported family of materials exhibits complex disorder, arising from the possible distributions of cations over available sites, the orientation of the SDA and the presence of variable amounts of water, which provides a prototype for understanding structural subtleties in nanoporous materials. In the as-made forms of the phosphate frameworks, there are three crystallographically distinct metal sites: two tetrahedral MO4 and one octahedral MO4F2 (M = Al, Ga). A combination of solid-state NMR spectroscopy and periodic DFT calculations reveals that the octahedral site is preferentially occupied by Al and the tetrahedral sites by Ga, leading to a non-random distribution of cations within the framework. Upon calcination to the AlxGa1-xPO4-34 framework, all metal sites are tetrahedral and crystallographically equivalent in the average R3̄ symmetry. The cation distribution was explored by 31P solid-state NMR spectroscopy, and it is shown that the non-random distribution demonstrated to exist in the as-made materials would be expected to give remarkably similar patterns of peak intensities to a random distribution owing to the change in average symmetry in the calcined materials.

Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial.

BACKGROUND: Chimeric antigen receptor T-cell therapy idecabtagene vicleucel (ide-cel) showed significantly improved progression-free survival compared with standard regimens in adults with relapsed and refractory multiple myeloma who had received two to four previous regimens in the ongoing phase 3 KarMMa-3 trial (NCT03651128). This study analysed patient-reported outcomes (PROs), a KarMMa-3 secondary endpoint. METHODS: In the randomised, open-label, phase 3 KarMMa-3 trial, 386 patients in hospitals (≥18 years of age, with measurable disease and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who had received two to four previous regimens-including an immunomodulatory agent, a proteasome inhibitor, and daratumumab-and had documented disease progression after receiving their last dose of the last therapy) were randomly assigned to ide-cel (n=254) or standard regimens (daratumumab, pomalidomide, and dexamethasone; daratumumab, bortezomib, and dexamethasone; ixazomib, lenalidomide, and dexamethasone; carfilzomib and dexamethasone; or elotuzumab, pomalidomide, and dexamethasone; n=132). Patients were expected to complete the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life C30 Questionnaire (QLQ-C30), Multiple Myeloma Module (QLQ-MY20), EQ 5 dimensions (EQ-5D), and EQ-5D visual analogue scale (VAS) at baseline and follow-up timepoints (data cutoff April 18, 2022). PROs included nine prespecified primary domains: EORTC QLQ-C30 GHS-quality of life (QoL), physical functioning, cognitive functioning, fatigue, and pain; QLQ-MY20 disease symptoms and side effects of treatment; and five-level EQ-5D (EQ-5D-5L) index score and EQ-5D visual VAS. Differences in overall least-squares mean changes from baseline to month 20 were analysed using post-hoc constrained longitudinal data analysis. Time to confirmed improvement or deterioration from baseline was analysed using Cox proportional hazard models. FINDINGS: Patients were randomly assigned between May 6, 2019, and April 8, 2022. Overall, the median age was 63 years (IQR 55-68); 151 (39%) patients were female; and 250 (65%) patients were White, 36 (9%) Black or African American, 19 (5%) Hispanic or Latino, 12 (3%) Asian, and seven (2%) of other race. The median follow-up was 18·6 months (IQR 14·0-26·4). PRO compliance was higher than 75% throughout. Overall least-squares mean changes from baseline favoured ide-cel with Hedges' g effect sizes from 0·3 to 0·7 for most domains. Patients in the ide-cel group showed statistically significant and clinically meaningful improvements across the primary PRO domains of interest, with the exception of QLQ-MY20 disease symptoms, side effects of treatment, and EQ-5D-5L index score, which showed improvement across assessment visits but did not exceed the within-group minimally important difference thresholds. The ide-cel group had shorter times to clinically meaningful improvement than the standard regimens group in QLQ-C30 domains except in role functioning, diarrhoea, and financial difficulties; in QLQ-MY20 domains except body image; and in EQ-5D-VAS. INTERPRETATION: Ide-cel offers improved health-related quality of life compared with standard regimens for patients with relapsed and refractory multiple myeloma after previous lines of therapy. The PRO data highlight the extended QoL benefits of a one-time infusion with ide-cel compared with continuous treatment with standard regimens in the treatment of triple-class exposed patients with relapsed and refractory multiple myeloma. FUNDING: 2seventy bio and Celgene, a Bristol Myers Squibb Company.

Cognition and saccadic eye movement performance are impaired in chronic rhinosinusitis.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) can experience cognitive dysfunction. The literature on this topic mostly reflects patient-reported measurements. Our goal was to assess cognitive function in patients with CRS using objective measures, including saccadic eye movements-a behavioral response reflecting cognitive and sensory information integration that is often compromised in conditions with impaired cognition. METHODS: Participants (N = 24 with CRS, N = 23 non-CRS healthy controls) enrolled from rhinology clinic underwent sinonasal evaluation, quality of life assessment (Sino-nasal Outcome Test 22 [SNOT-22]), and cognitive assessment with the Neuro-QOL Cognitive Function-Short Form, the Montreal Cognitive Assessment (MoCA), and recording of eye movements using video-oculography. RESULTS: Participants with CRS were more likely to report cognitive dysfunction (Neuro-QOL; 45.8% vs. 8.7%; p = 0.005) and demonstrate mild or greater cognitive impairment (MoCA; 41.7% vs. 8.7%; p = 0.005) than controls. Additionally, participants with CRS performed worse on the MoCA overall and within the executive functioning and memory domains (all p < 0.05) and on the anti-saccade (p = 0.014) and delay saccade (p = 0.044) eye movement tasks. Poorer performance on the MoCA (r = -0.422; p = 0.003) and the anti-saccade (r = -0.347; p = 0.017) and delay saccade (r = -0.419; p = 0.004) eye movement tasks correlated with worse CRS severity according to SNOT-22 scores. CONCLUSION: This study is the first to utilize objective eye movement assessments in addition to researcher-administered cognitive testing in patients with CRS. These patients demonstrated a high prevalence of cognitive dysfunction, most notably within executive functioning and memory domains, with the degree of dysfunction correlating with the severity of CRS.

Rapid Prototyping of Thermoplastic Microfluidic 3D Cell Culture Devices by Creating Regional Hydrophilicity Discrepancy.

Microfluidic 3D cell culture devices that enable the recapitulation of key aspects of organ structures and functions in vivo represent a promising preclinical platform to improve translational success during drug discovery. Essential to these engineered devices is the spatial patterning of cells from different tissue types within a confined microenvironment. Traditional fabrication strategies lack the scalability, cost-effectiveness, and rapid prototyping capabilities required for industrial applications, especially for processes involving thermoplastic materials. Here, an approach to pattern fluid guides inside microchannels is introduced by establishing differential hydrophilicity using pressure-sensitive adhesives as masks and a subsequent selective coating with a biocompatible polymer. Optimal coating conditions are identified using polyvinylpyrrolidone, which resulted in rapid and consistent hydrogel flow in both the open-chip prototype and the fully bonded device containing additional features for medium perfusion. The suitability of the device for dynamic 3D cell culture is tested by growing human hepatocytes in the device under controlled fluid flow for a 14-day period. Additionally, the study demonstrated the potential of using the device for pharmaceutical high-throughput screening applications, such as predicting drug-induced liver injury. The approach offers a facile strategy of rapid prototyping thermoplastic microfluidic organ chips with varying geometries, microstructures, and substrate materials.

"What we talk about is creating a probability": Exploring the interaction between the anticipation and decision-making processes of professional bowlers and batters in Twenty20 cricket.

Expert performers in time constrained sports use a range of information sources to facilitate anticipatory and decision-making processes. However, research has often focused on responders such as batters, goalkeepers, defenders, and returners of serve, and failed to capture the complex interaction between opponents, where responders can also manipulate probabilities in their favour. This investigation aimed to explore the interaction between top order batters and fast or medium paced bowlers in cricket and the information they use to inform their anticipatory and decision-making skills in Twenty20 competition. Eleven professional cricketers were interviewed (8 batters and 3 bowlers) using semi-structured questions and scenarios from Twenty20 matches. An inductive and deductive thematic analysis was conducted using the overarching themes of Situation Awareness (SA) and Option Awareness (OA). Within SA, the sub-themes identified related to information sources used by bowlers and batters (i.e., stable contextual information, dynamic contextual information, kinematic information). Within OA, the sub-themes identified highlighted how cricketers use these information sources to understand the options available and the likelihood of success associated with each option (e.g., risk and reward, personal strengths). A sub-theme of 'responder manipulation' was also identified within OA to provide insight into how batters and bowlers interact in a cat-and-mouse like manner to generate options that manipulate one another throughout the competition. A schematic has been developed based on the study findings to illustrate the complex interaction between the anticipation and decision-making processes of professional top order batters and fast or medium paced bowlers in Twenty20 cricket.

Postmarketing Reporting of Paxlovid-Related Dysgeusia: A Real-World Pharmacovigilance Study.

OBJECTIVE: A novel COVID-19 therapeutic, nirmatrelvir/ritonavir (Paxlovid), is commonly associated with reports of dysgeusia. The Food and Drug Administration Adverse Event Reporting System (FAERS) database was used to determine the real-world reporting of Paxlovid-associated dysgeusia (PAD), identify associated factors, and describe the relative reporting rates of dysgeusia for Paxlovid compared to other COVID-19 therapeutics (OCT), ritonavir alone, and other protease inhibitors (OPI). STUDY DESIGN: Observational retrospective. SETTING: Tertiary academic medical center. METHODS: We collected patient and adverse event characteristics reported in the FAERS database between January 1968 and September 2022. Disproportionality analyses were used to compare the reporting of PAD to dysgeusia reported for OCT, ritonavir, and OPI. RESULTS: 345,229 adverse events were included in the present study. Dysgeusia was a frequently reported Paxlovid-associated adverse event (17.5%) and was associated with nonserious COVID-19 infection (reporting odds ratio [ROR] 1.4; 95% confidence interval [CI] 1.2, 1.7) and female sex (ROR = 1.7; 95% CI 1.6, 1.9). Paxlovid was more likely to be associated with the reporting of dysgeusia compared to OCT (ROR 305.4; 95% CI 164.1, 568.5), ritonavir (ROR 28.0; 95% CI 24.1, 32.7), and OPI (ROR 49.0; 95% CI 42.8, 56.1). CONCLUSION: Dysgeusia is much more likely to be reported by patients receiving Paxlovid than those receiving OCT, ritonavir alone, or OPI. These findings suggest a potential mechanism of dysgeusia that causes distorted taste out of proportion to the background effects of COVID-19 infection and specific to nirmatrelvir. Future studies are needed to determine the underlying pathophysiology and long-term clinical implications for patients who report dysgeusia with Paxlovid.

The Importance of Contact Zones for Distinguishing Interspecific from Intraspecific Geographic Variation.

With limited sampling, geographic variation within a single species can be difficult to distinguish from interspecific variation, confounding our ability to draw accurate species boundaries. We argue that thorough sampling and analysis of contact zones between putative taxa can determine if assortative mating or selection against hybrids exists (supporting the presence of two distinct species), or alternatively if mating is random among genotypes and admixture among adjacent populations is gradual and continuous (supporting geographic variation within a single species). Here, we test two alternative hypotheses for two pairs of named taxa at contact zones within the American milksnake (Lampropeltis triangulum) complex. A prior morphological analysis found areas of gradual intergradation among named taxa, and concluded that the taxa represented geographical races of a single polytypic species. In contrast, a subsequent analysis of gene sequence data, but with limited sampling near the contact zones, hypothesized distinct boundaries between species at the contact zones. At the contact zone between proposed species L. triangulum and Lampropeltis gentilis, we examined a $\sim$700 km-wide transect across the states of Kansas and Missouri, with thorough sampling and reduced-representation genomic-level sequencing, to test the two opposing taxonomic hypotheses. Our transect analyses included examinations of population structure, fixed differences, cline-fitting, and an admixture index analysis. These analyses all supported a gradual and continuous geographic cline across a broad intergrade zone between two geographic forms of L. triangulum, thus providing strong support for a single species in this region (and no support for the recognition of L. gentilis as a distinct species). At a second contact zone between proposed species L. triangulum and Lampropeltis elapsoides (but variously treated as species or subspecies by different researchers) in Kentucky and Tennessee, we re-evaluated morphological data. In this case, the contact zone analysis indicated sympatry and reproductive isolation of the two taxa, and thus strongly supported L. triangulum and L. elapsoides as distinct species. We conclude that detailed studies of contact zones, based on either genetic or morphological data, are essential for distinguishing intraspecific from interspecific variation in the case of widely and continuously distributed taxa. [Contact zones; speciation; species concepts; species delimitation; taxonomy.].

Structured expert elicitation to inform long-term survival extrapolations using alternative parametric distributions: a case study of CAR T therapy for relapsed/ refractory multiple myeloma.

BACKGROUND: Our aim was to extend traditional parametric models used to extrapolate survival in cost-effectiveness analyses (CEAs) by integrating individual-level patient data (IPD) from a clinical trial with estimates from experts regarding long-term survival. This was illustrated using a case study evaluating survival of patients with triple-class exposed relapsed/refractory multiple myeloma treated with the chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel, bb2121) in KarMMa (a phase 2, single-arm trial). METHODS: The distribution of patients expected to be alive at 3, 5, and 10 years given the observed survival from KarMMa (13.3 months of follow-up) was elicited from 6 experts using the SHeffield ELicitation Framework. Quantities of interest were elicited from each expert individually, which informed the consensus elicitation including all experts. Estimates for each time point were assumed to follow a truncated normal distribution. These distributions were incorporated into survival models, which constrained the expected survival based on standard survival distributions informed by IPD from KarMMa. RESULTS: Models for ide-cel that combined KarMMa data with expert opinion were more consistent in terms of survival as well as mean survival at 10 years (survival point estimates under different parametric models were 29-33% at 3 years, 5-17% at 5 years, and 0-6% at 10 years) versus models with KarMMa data alone (11-39% at 3 years, 0-25% at 5 years, and 0-11% at 10 years). CONCLUSION: This case study demonstrates a transparent approach to integrate IPD from trials with expert opinion using traditional parametric distributions to ensure long-term survival extrapolations are clinically plausible.

What is the effectiveness of radiofrequency ablation in the management of patients with spinal metastases? A systematic review and meta-analysis.

PURPOSE: Spinal metastases are indicative of progressive cancer which can lead to vertebral body fractures and spinal cord compression. Radiofrequency ablation (RFA) treatment is infrequently used in patients with refractory pain. The aim of this systematic review is to determine the clinical efficacy of RFA, with the scope of using it as front-line management of spinal metastases. METHODS: Electronic databases were searched (to July 2020) for studies evaluating RFA treatment for spinal metastases in adults. Measured outcomes were pain (primary), disability, health-related quality of life (HRQOL), complications, tumour control and mortality. Study inclusion, data extraction and risk of bias using the ROBIN-I tool were assessed. Meta-analysis was conducted for pooled results with homogeneity, and narrative synthesis was conducted otherwise. RESULTS: 15 studies were included. RFA reduces pain scores at 3-5 weeks [standardised mean difference (SMD 2.24, 95% confidence intervals (CI) 1.55-2.93], 3-4 months (SMD 3.00, 95% CI 1.11-4.90) and 5-6 months (SMD 3.54, 95% CI 1.96-5.11). RFA is effective in reducing disability/improving HRQOL in the short-term but longer-term efficacy remains unclear. 13.2% cases reported local tumour control failure (2.5 months-5 year follow-up) whereas mortality was 23.6% (follow-up of up to 1 year). CONCLUSION: Low quality evidence has proven RFA to be safe and effective in reducing pain and disability, especially in the short-term. RFA may be routinely implemented in all cases involving refractory pain or radiotherapy-resistant tumours but controlled trials are required to compare the efficacy of RFA to current frontline treatments. PROSPERO protocol registration number: CRD42020202377.

Fluoxetine and environmental enrichment similarly reverse chronic social stress-related depression- and anxiety-like behavior, but have differential effects on amygdala gene expression.

The adverse effects of stress on brain and behavior have long been known and well-studied, with abundant evidence linking stress to, among other things, mood and anxiety disorders. Likewise, many have investigated potential treatments for stress-related mood and anxiety phenotypes and demonstrated good response to standard antidepressant medications like selective serotonin reuptake inhibitors (SSRIs), as well as environmental manipulations like exercise or enrichment. However, the extent to which stress and various treatments act on overlapping pathways in the brain is less well understood. Here, we used a widely studied social defeat stress paradigm to induce a robust depression- and anxiety-like phenotype and chronic corticosterone elevation that persisted for at least 4 weeks in wild type male mice. When mice were treated with either the SSRI fluoxetine or an enriched environment, both led to similar behavioral recovery from social defeat. We then focused on the amygdala and assessed the effects of social defeat, fluoxetine, and enrichment on 168 genes broadly related to synaptic plasticity or oxidative stress. We found 24 differentially expressed genes in response to social defeat stress. Interestingly, fluoxetine led to broad normalization of the stress-induced expression pattern while enrichment led to expression changes in a separate set of genes. Together, this study provides additional insight into the chronic effects of social defeat stress on behavior and gene expression in the amygdala. The findings also suggest that, for a subset of genes assessed, fluoxetine and environmental enrichment have strikingly divergent effects on expression in the amygdala, despite leading to similar behavioral outcomes.

Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models.

BACKGROUNDS & AIMS: Fluoropyrimidine c (5-fluorouracil [5FU]) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant, and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor. METHODS: We designed, generated, and characterized 5FU-incorporated systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (EGFR)-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo. RESULTS: 5FU-EGFR aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging showed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. The 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell lines. Biweekly treatment with 5FU-EGFR aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-KrasG12D/+;LSL-Trp53flox/+;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1nu), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up. CONCLUSIONS: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids and, therefore, represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into cancer cell-targeting aptamers as the delivery platform.

How mitonuclear discordance and geographic variation have confounded species boundaries in a widely studied snake.

As DNA sequencing technologies and methods for delimiting species with genomic data become more accessible and numerous, researchers have more tools than ever to investigate questions in systematics and phylogeography. However, easy access to sophisticated computational tools is not without its drawbacks. Choosing the right approach for one's question can be challenging when presented with multitudinous options, some of which fail to distinguish between species and intraspecific population structure. Here, we employ a methodology that emphasizes intensive geographic sampling, particularly at contact zones between populations, with a focus on differentiating intraspecific genetic clusters from species in the Pantherophis guttatus complex, a group of North American ratsnakes. Using a mitochondrial marker as well as ddRADseq data, we find evidence of mitonuclear discordance which has contributed to historical confusion about the relationships within this group. Additionally, we identify geographically and genetically structured populations within the species Pantherophis emoryi that are congruent with previously described morphological variation. Importantly, we find that these structured populations within P. emoryi are highly admixed throughout the range of the species and show no evidence of any reproductive isolation. Our data support a revision of the taxonomy of this group, and we recognize two species within the complex and three subspecies within P. emoryi. This study illustrates the importance of thorough sampling of contact zones and consideration of gene flow when delimiting species in widespread complexes containing parapatric lineages.

Evaluating West Virginia's Emergency Medicine Workforce: A Longitudinal Observational Study.

Objective Although the urban emergency workforce is well studied, rural departments are less understood. This study seeks to further define the landscape of rural healthcare and expand on previous studies of the West Virginia (WV) workforce. Methods During the second quarter of 2019, surveys were sent via email to medical directors' professional IDs as anonymous survey links. Hard copies were also sent to directors at their hospital addresses. Responses were aggregated with hospitals stratified based on annual census and rural classification. Data was interpreted through descriptive analysis. Results Surveys were sent to 53 departments with a 55% response rate. Of the responding hospitals, 15 of 29 were identified as rural. The average state-wide annual hospital census was 29,500 visits with board-certified emergency medicine (EM)-trained physicians covering 67% of shifts. Rural departments have a smaller census and less specialized coverage. Full-time physicians are found to have the strongest ties to WV, with 65% attending medical school, residency, or growing up in the state. Conclusion Board-certified EM-trained physicians provide some level of coverage in most emergency departments in WV but remain underrepresented in rural locations. This specialized coverage has increased by 20% in the last 15 years. Additionally, a majority of hospitals have access to basic consulting services (surgery and primary care); however, other specialists are rare in rural WV.

Nonsteroidal Anti-inflammatory Drugs and Cardiovascular Risk in American Football.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with adverse cardiovascular outcomes and reportedly overused in American-style football (ASF). However, assessment of ASF NSAID use in the context of cardiovascular risk has not been performed. We sought to characterize NSAID use patterns and the association with cardiovascular risk in a diverse cohort of high school and collegiate ASF athletes. METHODS: A total of 226 ASF athletes, 60 endurance athletes, and 63 nonathletic controls were studied pre- and postseason with echocardiography, vascular applanation tonometry, and clinical data assessment. Qualitative NSAID use throughout the season was recorded at postseason. RESULTS: ASF athletes gained weight (Δ0.86 ± 3.9 kg, P < 0.001), increased systolic blood pressure (SBP, Δ3.1 ± 12 mm Hg, P < 0.001) and pulse wave velocity (Δ0.2 ± 0.6 m·s, P < 0.001), and decreased E' (Δ-1.4 ± 2.8 cm·s, P < 0.001) across one athletic season. Seventy-seven percent (n = 173) of ASF athletes reported that sport-specific NSAID use began in middle school. ASF NSAID use was more frequent with "weekly" (n = 42.19%) and "daily" (n = 32.14%) use compared with endurance athletes (P < 0.001) and controls (P = 0.02). ASF NSAID use increased in parallel with postseason SBP and weights. "Daily" ASF NSAID users demonstrated the highest postseason SBP (137 ± 13 vs 128 ± 13 mm Hg, P = 0.002) and weight (109.0 ± 18.6 vs 95.8 ± 20.5 kg, P = 0.002) compared with "never/rare" users. Adjusting for player position, SBP, pulse wave velocity, and E', increased weight (odds ratio = 1.04, 95% confidence interval = 1.0-1.08, P = 0.037) was associated with more frequent NSAID use. CONCLUSIONS: Habitual NSAID use commonly begins during adolescence, before full physical maturation, and is associated with cardiovascular risk, particularly increased weight, in ASF athletes. NSAID use frequency should be considered when risk stratifying high-risk ASF athletes.

The Social Value of Improvement in Activities of Daily Living among the Advanced Parkinson's Disease Population.

OBJECTIVES: Quantify the value of functional status (FS) improvements consistent in magnitude with improvements due to levodopa-carbidopa intestinal gel (LCIG) treatment, among the advanced Parkinson's disease (APD) population. METHODS: The Health Economic Medical Innovation Simulation (THEMIS), a microsimulation that estimates future health conditions and medical spending, was used to quantify the health and cost burden of disability among the APD population, and the value of quality-adjusted life-years gained from FS improvement due to LCIG treatment compared to standard of care (SoC). A US-representative Parkinson's disease (PD)-comparable cohort was constructed in THEMIS based on observed PD patient characteristics in a nationally representative dataset. APD was defined from the literature and clinical expert input. The PD and APD cohorts were followed from 2010 over their remaining lifetimes. All individuals were ages 65 and over at the start of the simulation. To estimate the value of FS improvement due to LCIG treatment, decreases in activities of daily living (ADL) limitations caused by LCIG treatment were calculated using data from a randomized, controlled, double-blind, double-dummy clinical trial and applied to the APD population in THEMIS. RESULTS: Total burden of disability associated with APD was $17.7 billion (B). From clinical trial data, LCIG treatment versus SoC lowers the odds of difficulties in walking, dressing, and bathing by 76%, 42% and 39%, respectively. Among the APD population, these reductions generated $2.6B in value to patients and cost savings to payers. The added value was 15% of the burden of disability associated with APD and offsets 15% of the cost of LCIG treatment. CONCLUSIONS: FS improvements, consistent with improvements due to LCIG treatment, in the APD population created health benefits and reduced healthcare costs in the US.

The effect of functional status impairment on nursing home admission risk among patients with advanced Parkinson's disease.

Aims: To estimate the relationship between functional status (FS) impairment and nursing home admission (NHA) risk in Parkinson's disease (PD) patients, and quantify the effect of advanced PD (APD) treatment on NHA risk relative to standard of care (SoC).Materials and methods: PD patients were identified in the Medicare Current Beneficiary Survey (MCBS) (1992-2010). A working definition based on the literature and clinical expert input determined APD status. A logit model estimated the relationship between FS impairment and NHA risk. The effect of levodopa-carbidopa intestinal gel (LCIG) on NHA risk relative to SoC was simulated using clinical trial data (control: optimized oral levodopa-carbidopa IR, ClinicalTrials.gov NCT00660387 and NCT0357994).Results: Non-advanced PD and APD significantly increased NHA risk when controlling for demographics (p < 0.01). APD status was no longer significant after controlling for FS limitations, implying that FS limitations explain the increased NHA risk in APD patients. Reduced impairment in FS in patients with APD treated with LCIG reduced risk of NHA by 13.5% relative to SoC.Limitations: This study applies clinical trial results to real-world data. LCIG treatment might have a different effect on NHA risk for the nationally representative population than the effect measured in the trial. Both data sources employ different instruments to measure FS, instrument wording and study follow-up differed, which might bias our estimates. Finally, there lacks consensus on a definition of APD. The prevalence of APD in this study is high, perhaps due to the specific definition used.Conclusions: Patients with APD experience a higher risk in NHA than those with non-advanced disease. This increased risk in NHA in patients with APD is explained by greater limitations in FS. The relative reduction in risk of NHA for the APD population treated with LCIG is quantitatively similar to doubling Medicaid home care services.

The long-term direct and indirect economic burden among Parkinson's disease caregivers in the United States.

BACKGROUND: Parkinson's disease is a progressive, disabling neurodegenerative disorder associated with significant economic burden for patients and caregivers. The objective of this study was to compare the direct and indirect economic burden of Parkinson's patients' caregivers with demographically matched controls in the United States, in the 5 years after first diagnosis of Parkinson's disease. METHODS: Policyholders (18-64 years old) linked to a Parkinson's disease patient (≥2 diagnoses of Parkinson's disease; first diagnosis is the index date) from January 1, 1998 to March 31, 2014, were selected from a private-insurer claims database and categorized as Parkinson's caregivers. Eligible Parkinson's caregivers were matched 1:5 to policyholders with a non-Parkinson's dependent (controls). Multivariable regression adjusted for baseline characteristics estimated direct costs (all-cause insurer cost [medical and prescription] and comorbidity-related medical costs; patient out-of-pocket costs) and indirect costs (disability and medically related absenteeism costs). Income progression was also compared between cohorts. RESULTS: A total of 1211 eligible Parkinson's caregivers (mean age, 56 years; 54% female) were matched to 6055 controls. In adjusted analyses, Parkinson's caregivers incurred significantly higher year 1 total all-cause insurer costs ($8999 vs $7117) and medical costs ($7081 vs $5568) (both P < 0.01) and higher prescription costs (range for years 1-5, $2506-2573 vs $1405-$1687) and total out-of-pocket costs ($1259-1585 vs $902-$1192) in years 1-5 (all P < 0.01). Parkinson's caregivers had significantly higher adjusted indirect costs in years 1-3 (range for years 1-3, $2054-$2464 vs $1681-$1857; all P < 0.05) and higher cumulative income loss over 5 years ($5967 vs $2634 by year 5; P for interaction = 0.03). CONCLUSIONS: Parkinson's caregivers exhibited higher direct and indirect costs and greater income loss compared with matched controls. © 2018 International Parkinson and Movement Disorder Society © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson's disease: a multi-country Delphi-panel approach.

BACKGROUND: Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care. OBJECTIVES: To reach consensus among movement disorder specialists regarding key patient characteristics indicating transition to APD and guiding appropriate use of device-aided therapies in the management of PD symptoms. METHODS: A Delphi-panel approach was utilized to synthesize opinions of movement disorder specialists and build consensus. RESULTS: A panel was comprised of movement disorder specialists from 10 European countries with extensive experience of treating PD patients (mean =24.8 ± 7.2 years). Consensus on indicators of suspected APD and eligibility for device-aided therapies were based on motor symptoms, non-motor symptoms, and functional impairments. Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, ≥1 h of troublesome dyskinesia/day, ≥2 h "off" symptoms/day, and ≥5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living. Patients with good levodopa response, good cognition, and <70 years of age were deemed as good candidates for all three device-aided therapies. Patients with troublesome dyskinesia were considered good candidates for both levodopa-carbidopa intestinal gel and Deep Brain Stimulation (DBS). PD patients with levodopa-resistant tremor were considered good candidates for DBS. CONCLUSION: Identifying patients progressing to APD and suitable for device-aided therapies will enable general neurologists to assess the need for referral to movement disorder specialists and improve the quality of care and patient outcomes.