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.].

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.

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.

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.

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.

Patient Preferences for Device-Aided Treatments Indicated for Advanced Parkinson Disease.

BACKGROUND: Effective treatment for advanced Parkinson disease (PD) uncontrolled with oral medication includes device-aided therapies such as deep brain stimulation (DBS) and continuous levodopa-carbidopa infusion to the duodenum via a portable pump. OBJECTIVE: Our objective was to quantify patient preferences for attributes of these device-aided treatments. METHODS: We administered a Web-enabled survey to 401 patients in the United States. A discrete-choice experiment (DCE) was used to evaluate patients' willingness to accept tradeoffs among efficacy, tolerability, and convenience of alternative treatments. DCE data were analyzed using random-parameters logit. Best-worst scaling (BWS) was used to elicit the relative importance of device-specific attributes. Conditional logit was used to analyze the BWS data. We tested for differences in preferences among subgroups of patients. RESULTS: Improving ability to think clearly was twice as important as a 6-hour-per-day improvement in control of movement symptoms. After controlling for efficacy, treatment delivered via portable infusion pump was preferred over DBS, and both devices were preferred to oral therapy with poor symptom control. Patients were most concerned about device attributes relating to risk of stroke, difficulty thinking, and neurosurgery. Avoiding surgery to insert a wire in the brain was more important than avoiding surgery to insert a tube into the small intestine. Some differences in preferences among subgroups were statistically, but not qualitatively, significant. CONCLUSIONS: This study clarifies the patient perspective in therapeutic choices for advanced PD. These findings may help improve communication between patients and providers and also provide evidence on patient preferences to inform regulatory and access decisions.

Thromboprophylaxis With Heparin During Orthotopic Liver Transplantation: Comparison of Hepcon HMS Plus and Anti-Xa Assays for Low-Range Heparin.

OBJECTIVES: The purpose of this study was to compare the agreement between two heparin assays, Hepcon HMS plus/Kaolin-ACT and Anti-Xa, and their predictive power in detecting circulating heparin levels post-reperfusion of the liver graft when compared with thromboelastogram (TEG) r time ratio in patients undergoing orthotopic liver transplantation (OLT). DESIGN: Prospective, observational cohort study design. SETTING: Single center, university hospital. PARTICIPANTS: Thirty-eight consecutive adults who had undergone liver transplant. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Paired arterial blood samples were collected before surgical incision, 5 minutes after administration of an average dose of 2,054±771 units of intravenous unfractionated heparin before caval cross-clamping, 5 minutes after portal reperfusion, 5 minutes after hepatic artery reperfusion, and 1 hour after hepatic artery reperfusion. The observations that heparin assay measurements were within the predetermined limits of agreement, strongly suggested the two heparin assays (Hepcon HMS plus and Anti-Xa assay) are interchangeable during prophylactic heparin dose therapy during OLT. Post-reperfusion, receiver operating characteristic curve analysis revealed high accuracy in measuring circulating heparin levels with both Anti-Xa and Hepcon HMS assays when compared with the TEG r time ratio assay. CONCLUSIONS: The point-of-care Hepcon HMS plus/Kaolin-ACT (activated clotting time) assay appeared to be a reliable alternative to the more expensive and laboratory-required Anti-Xa assay in monitoring the response to intravenous heparin in patients undergoing OLT.

Epsilon-Aminocaproic Acid Has No Association With Thromboembolic Complications, Renal Failure, or Mortality After Liver Transplantation.

OBJECTIVES: To examine the role of epsilon-aminocaproic acid (EACA) administered after reperfusion of the donor liver in the incidences of thromboembolic events and acute kidney injury within 30 days after orthotopic liver transplantation. One-year survival rates between the EACA-treated and EACA-nontreated groups also were examined. DESIGN: Retrospective, observational, cohort study design. SETTING: Single-center, university hospital. PARTICIPANTS: The study included 708 adult liver transplantations performed from 2008 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EACA administration was not associated with incidences of intracardiac thrombosis/pulmonary embolism (1.3%) or intraoperative death (0.6%). Logistic regression (n = 708) revealed 2 independent risk factors associated with myocardial ischemia (age and pre-transplant vasopressor use) and 8 risk factors associated with the need for post-transplant dialysis (age, female sex, redo orthotopic liver transplantation, preoperative sodium level, pre-transplant acute kidney injury or dialysis, platelet transfusion, and re-exploration within the first week after transplant); EACA was not identified as a risk factor for either outcome. One-year survival rates were similar between groups: 92% in EACA-treated group versus 93% in the EACA-nontreated group. CONCLUSIONS: The antifibrinolytic, EACA, was not associated with an increased incidence of thromboembolic complications or postoperative acute kidney injury, and it did not alter 1-year survival after liver transplantation.

The 1964 Surgeon General's report and Americans' beliefs about smoking.

Half a century ago, on January 11, 1964, the U.S. Surgeon General's office released a landmark report on the health consequences of smoking. That report received massive media attention and triggered a steadily growing number of federal, state, and local restrictions on the advertising, sale, and use of cigarettes. Little is known about the report's impact on American public opinion because all the timely public opinion polls that measured the report's impact were privately commissioned by the tobacco industry and were not made publicly available. A review of these polls shows that the 1964 Surgeon General's report had a large and immediate effect on Americans' beliefs that cigarettes were a cause of lung cancer and of heart disease. However, the report had less impact on public preferences for government action or on smoking rates.

"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.

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.

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.

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.

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.

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.

Content validity and test-retest reliability of Patient Perception of Intensity of Urgency Scale (PPIUS) for overactive bladder.

BACKGROUND: The Patient Perception of Intensity of Urgency Scale (PPIUS) is a patient-reported outcome instrument intended to measure the intensity of urgency associated with each urinary or incontinence episode. The objectives of this study were to assess the content validity, test-retest reliability, and acclimation effect of the PPIUS in overactive bladder (OAB) patients. METHODS: Patients undergoing treatment for OAB were recruited to participate in a non-interventional study by completing a three-day micturition diary including the PPIUS for three consecutive weeks. Following completion of the three-week study, participants from two select sites also completed a cognitive interview to assess their comprehension of the PPIUS. RESULTS: Thirty-nine participants successfully completed the three-week test-retest study; twelve of these participants completed the cognitive interview. Test-retest reliability was high based on intra-class correlation coefficient of 0.95. Among stable patients, the difference between the mean ratings of any two weeks was non-significant. Among the twelve interview participants, nine found it simple to choose a PPIUS rating for each of their micturition episodes and most found the urgency rating definitions consistent with their urgency experiences. CONCLUSIONS: The results demonstrated content validity based on qualitative interviews, and excellent test-retest reliability among stable patients. In addition, no acclimation effect was observed among stable patients. These findings support the use of the PPIUS as a reliable measure of urgency in both clinical trial and real life settings. The validity of PPIUS could be further established with future studies investigating the relationship between discretely graded urgency and incontinence continuum.

Supplementing retention through crown/preparation modification: an in vitro study.

STATEMENT OF PROBLEM: The best treatment for a crown that has come loose but has appropriate marginal fit and form is not clear. PURPOSE: This study was designed to determine whether the retention of such crowns can be increased without remaking the crown or by extensively modifying the tooth preparation. MATERIAL AND METHODS: Ninety cast metal complete crowns, divided into 9 groups of 10, were fabricated to be slightly loose in their internal adaptation to metal dies with an optimal tooth preparation. Horizontal grooves were formed around the circumference of the internal crown surface and the external surface of the metal die, the control being the unaltered crown and die. The crowns were cemented with resin-modified glass ionomer cement and then subjected to a tensile force until they were dislodged. The data were subjected to a 2-way ANOVA to determine the significance of the differences between crowns and dies, and 2 t tests were then used to compare each crown/die combination to the control (α=.05). RESULTS: The mean retention was significantly higher when 1 horizontal groove was placed inside the crowns (P<.001) and was even higher when 2 grooves were placed inside the crowns (P<.001). Placing 1 or 2 grooves in the metal die or in both the crown and die was not significantly more retentive than placing grooves only in the crown. CONCLUSIONS: Placing 1 or 2 horizontal circumferential grooves into the internal surface increased the retention of metal complete crowns made for optimal tooth preparations. Grooves placed into the crown were as effective as or more effective than grooves placed into the tooth / die.

Injury prevention and recreational all-terrain vehicle use: the impact of helmet use in West Virginia.

UNLABELLED: All-terrain vehicles (ATVs) are a popular source of outdoor activity in the United States, particularly in West Virginia. During the period of time from 1999 to 2007, deaths associated with ATVs in West Virginia increased by 28%. Helmet use among bicycle and motorcycle riders has been shown to decrease morbidity and mortality following trauma. METHODS: We performed a retrospective observational study to compare injury patterns, hospital course, and resource utilization of non-helmeted and helmeted riders involved in ATV accidents using data from the West Virginia Trauma Center System. Descriptive statistics were calculated for all study variables and comparisons were made between helmeted and non-helmeted riders. RESULTS: In 2010, there were 1,059 patients aged 18 and over with traumas resulting from ATV accidents within the System. Riders involved in ATV trauma occurring on farms and streets were significantly more likely to be non-helmeted, while those using ATVs for recreational purposes were more likely to be helmeted. Non-helmeted riders were significantly more likely to arrive to the hospital via helicopter than helmeted riders, and were less likely to be discharged home from the ED compared to helmeted riders. Non-helmeted riders sustained significantly more head, neck, soft tissue injuries, concussions, intracranial hemorrhages, facial fractures, skull fractures, and thoracic spine fractures than helmeted riders. DISCUSSION: The findings of the current study support previous studies documenting that helmet use is protective against intracranial injury and other injuries of the head and neck. ATV use continues to be a significant contribution to trauma morbidity and mortality in West Virginia. CONCLUSION: Efforts that focus on increased helmet use have the potential to significantly reduce morbidity and mortality following ATV trauma. Enforcement of the current West Virginia ATV Law should be encouraged. Legislation expanding the mandatory use of safety equipment and rider training should be enacted in West Virginia.

Coronin 2A regulates a subset of focal-adhesion-turnover events through the cofilin pathway.

Coronins are conserved F-actin-binding proteins that are important for motility and actin dynamics. Unlike type I coronins, coronin 2A localizes to stress fibers and some focal adhesions, and is excluded from the leading edge. Depletion of coronin 2A in MTLn3 cells decreases cell motility and turnover of focal adhesions. Surprisingly, none of the pathways known to regulate focal-adhesion turnover are affected by depletion of coronin 2A. Depletion of coronin 2A does, however, increase phospho-cofilin, suggesting that misregulation of cofilin might affect adhesion dynamics. Slingshot-1L, a cofilin-activating phosphatase, localizes to focal adhesions and interacts with coronin 2A. Depletion of coronin 2A reduces cofilin activity at focal adhesions, as measured by barbed-end density and actin FRAP. In both fixed cells and live cells, cofilin localizes to the proximal end of some focal adhesions. Although expression of wild-type cofilin in coronin-2A-depleted cells has no major effect on focal-adhesion dynamics, expression of an active mutant of cofilin bypasses the defects in cell motility and focal-adhesion disassembly. These results implicate both coronin 2A and cofilin as factors that can regulate a subset of focal-adhesion-turnover events.