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Masters runners are an increasing proportion of the running community. The most significant musculoskeletal changes in runners occur after the age of 50 in addition to changes in injury rates and types, the most common being Achilles tendinopathy (AT). Previous evidence has suggested similarities between risk factors for AT and age-related changes that are focused at the hip and the ankle during the propulsive stage of running. The purpose of this study was to investigate biomechanical and peak torque association to AT in masters runners. Thirty-two masters runners over age 50 with AT (60.31 ± 8.37, n = 16) and without (59.94 ± 4.95 n = 16) were included. 3D motion capture and force plates were used to assess running biomechanics. A motor-driven dynamometer was used to assess isokinetic peak torque production. No significant differences in running biomechanics were found between masters runners with and without AT. Hip peak isokinetic torque production was found to be significantly less in masters runners with AT, but no significant differences in ankle plantarflexion peak isokinetic torque production were found. Masters runners with AT may be able to adapt their running biomechanics and muscular torque production during submaximal running efforts.
Masters runners with Achilles tendinopathy do not demonstrate differences in peak hip extension moments during the stance phase of running during submaximal efforts compared to healthy masters runners.Masters runners with Achilles tendinopathy do not demonstrate differences in peak ankle plantarflexion moments during the stance phase of running during submaximal efforts compared to healthy masters runners.Masters runners with Achilles tendinopathy do not demonstrate differences in peak ankle plantarflexion concentric or eccentric isokinetic torque compared to healthy masters runners.Masters runners with Achilles tendinopathy demonstrate differences in peak hip extension concentric and eccentric isokinetic torque compared to healthy masters runners.
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INTRODUCTION: This study was aimed at investigating changes in insulin requirements and glycemic outcomes in adults with type 1 diabetes (T1D) using Control IQ (Tandem Diabetes) automated insulin delivery system (AID) over 8 months of tirzepatide treatment. METHODS: In this single-center, observational study, we collected demographic, A1c, weight, sensor glucose, and insulin dose data for adults with T1D who were using AID and initiated tirzepatide adjunct therapy for clinical indications (n = 11, median age 37, 64% female and mean body mass index of 39.6 kg/m2). Data were compared from baseline and over 8 months. RESULTS: Within 2 months of tirzepatide treatment, there were significant reductions in total daily insulin [median (IQR) 73.9 (47.6-95.8) to 51.7 (46.7-66.8) units/day, p < 0.001], basal insulin [47 (28.2-51.8) to 32.4 (25.5-46.3) units/day, p < 0.001], and bolus insulin [31.4 (19.9-38.3) to 17.9 (14.9-22.2) units/day, p < 0.001] requirements. Insulin dose reduction from 2 to 8 months was modest. The frequency of user-initiated boluses did not differ throughout the study. Despite reductions in total insulin requirement, time in range (70-180 mg/dl) increased by 7%, A1c reduced by 0.5%, weight reduced by 9%, without increase in time below 70 mg/dl. CONCLUSIONS: This pilot study provides clinical guidance on insulin titration for adults with T1D who may initiate tirzepatide therapy. Based on the findings of this study, we recommend reducing 25% of total daily insulin dose at tirzepatide initiation in adults with T1D using AID with baseline A1c of less than 7.5%. Higher doses of tirzepatide were associated with greater weight loss, however, the reduction in insulin requirement was minimal.
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Simulation-based mastery learning is a powerful educational paradigm that leads to high levels of performance through a combination of strict standards, deliberate practice, formative feedback, and rigorous assessment. Successful mastery learning curricula often require well-designed checklists that produce reliable data that contribute to valid decisions. The following twelve tips are intended to help educators create defensible and effective clinical skills checklists for use in mastery learning curricula. These tips focus on defining the scope of a checklist using established principles of curriculum development, crafting the checklist based on a literature review and expert input, revising and testing the checklist, and recruiting judges to set a minimum passing standard. While this article has a particular focus on mastery learning, with the exception of the tips related to standard setting, the general principles discussed apply to the development of any clinical skills checklist.
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BACKGROUND: Once weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) have been shown to improve glycemic outcomes and cause significant weight loss. However, 9% to 27% of individuals have little or no response to these drugs. In this article, we investigated the efficacy of GLP-1 RA therapy among adults with type 1 diabetes and obesity likely related to genetic mutations compared with obesity likely unrelated to genetic mutations. METHODS: In this retrospective study, we compared body weight and glycated hemoglobin (HbA1c) change with the use of GLP-1 RA therapy (including a dual agonist, Tirzepatide) over six months among adults with type 1 diabetes and obesity likely (n = 11, median age 39.5 years with a median BMI of 43.0 kg/m2) versus unlikely related to genetic mutation(s) (n = 15, median age 45.8 years with a median BMI of 38.7 kg/m2). RESULTS: Six months of GLP-1 RA treatment resulted in a numerically lower reduction of weight (-5.75 ± 9.46 kg vs -8.65 ± 9.36 kg, P = .44) and HbA1c (-0.28 ± 0.96% vs -0.43 ± 0.57%, P = .64) among individuals with obesity likely versus unlikely related to a genetic mutation(s), respectively. Fewer individuals with genetic obesity met goal weight loss ≥5% or HbA1c decrease ≥0.4% than did individuals with obesity unlikely related to a genetic cause (36.4% vs 80.0%, P = .04). CONCLUSIONS: The weight loss and glycemic lowering effects of GLP-1 RA therapy may be decreased in people with type 1 diabetes and obesity likely related to genetic causes. Further research is needed to understand GLP-1 RA mechanisms via energy regulating genes.
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BACKGROUND: Physical abuse is a major public health concern and a leading cause of morbidity and mortality in infants. Clinical decision tools derived from trauma registries can facilitate timely risk-stratification. The Trauma Quality Improvement Program (TQIP) database does not report age for children <1 year who are at highest risk for abuse. We report a method to capture these infants despite the missing age. METHODS: Patients ≤17 years were identified from TQIP (2017-2019). The primary outcomes included injuries resulting from confirmed or suspected child abuse captured by diagnosis codes or report/investigation of physical abuse, or different caregiver at discharge available in TQIP. We used two methods to select infants within TQIP. In the first, World Health Organization (WHO) growth standards for stature or length-for-age and weight-for-age were selected to capture children younger than 1 year. In the second, a K-means machine learning algorithm was used to cluster patients by weight and height. We compared outcome and injury data with and without patients <1 year. RESULTS: Using the WHO growth standard 19,916 children <1 year were identified. A total of 20,513 patients had a report of physical abuse filed, and 9393 were infants <1 year. Increased age-adjusted odds ratios [95% CI] were seen for fractures of the upper limb (1.28 [1.22-1.34]), vertebrae (1.89 [1.68-2.13]), ribs (5.2 [4.8-5.63]), and spinal cord (3.39 [2.85-4.02]) and head injuries (1.55 [1.5-1.6]) with infants included. CONCLUSIONS: In a nationwide trauma registry, WHO growth standards can be used to capture patients under one year who are more adversely impacted by maltreatment. TYPE OF STUDY: Retrospective, Cross-sectional. LEVEL OF EVIDENCE: Level III, Diagnostic.
Subject(s)
Child Abuse , Registries , Wounds and Injuries , Humans , Infant , Child Abuse/diagnosis , Child Abuse/statistics & numerical data , Male , Female , Child, Preschool , Wounds and Injuries/epidemiology , Wounds and Injuries/etiology , Quality Improvement , Risk Assessment/methods , Infant, Newborn , Child , Retrospective Studies , Machine Learning , AdolescentABSTRACT
Letters of recommendation (LORs) are an essential component of a career in medicine. The process for obtaining certain letters, particularly those associated with scheduled periods of professional transition, often is governed by established institutional or specialty norms. The process of requesting LORs in more common scenarios-local or national awards, committee assignments, and leadership positions-many times is less clearly defined, however. Despite the important role that LORs play in professional development, the published literature on how to solicit a recommendation is limited, creating challenges for both those requesting LORs ("applicants") and the letter writers. This perspective piece offers insight on how to best identify and communicate with a potential writer. These suggestions are derived from the limited relevant literature and from the authors' experience both with requesting letters themselves and writing letters as leaders in undergraduate and graduate medical education. The goal is to reduce ambiguity for applicants and ensure that writers receive the information necessary to provide an informed and effective recommendation.
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Internship and Residency , Medicine , Humans , Education, Medical, Graduate , Writing , Personnel SelectionABSTRACT
ABSTRACT: Glycophorin A (GPA), a red blood cell (RBC) surface glycoprotein, can maintain peripheral blood leukocyte quiescence through interaction with a sialic acid-binding Ig-like lectin (Siglec-9). Under inflammatory conditions such as sickle cell disease (SCD), the GPA of RBCs undergo structural changes that affect this interaction. Peripheral blood samples from patients with SCD before and after RBC transfusions were probed for neutrophil and monocyte activation markers and analyzed by fluorescence-activated cell sorting (FACS). RBCs were purified and tested by FACS for Siglec-9 binding and GPA expression, and incubated with cultured endothelial cells to evaluate their effect on barrier function. Activated leukocytes from healthy subjects (HS) were coincubated with healthy RBCs (RBCH), GPA-altered RBCs, or GPA-overexpressing (OE) cells and analyzed using FACS. Monocyte CD63 and neutrophil CD66b from patients with SCD at baseline were increased 47% and 27%, respectively, as compared with HS (P = .0017, P = .0162). After transfusion, these markers were suppressed by 22% and 17% (P = .0084, P = .0633). GPA expression in RBCSCD was 38% higher (P = .0291) with decreased Siglec-9 binding compared with RBCH (0.0266). Monocyte CD63 and neutrophil CD66b were suppressed after incubation with RBCH and GPA-OE cells, but not with GPA-altered RBCs. Endothelial barrier dysfunction after lipopolysaccharide challenge was restored fully with exposure to RBCH, but not with RBCSCD, from patients in pain crisis, or with RBCH with altered GPA. Pretransfusion RBCSCD do not effectively maintain the quiescence of leukocytes and endothelium, but quiescence is restored through RBC transfusion, likely by reestablished GPA-Siglec-9 interactions.
Subject(s)
Anemia, Sickle Cell , Vascular Diseases , Humans , Endothelial Cells/metabolism , Glycophorins/metabolism , Erythrocytes/metabolism , Sialic Acid Binding Immunoglobulin-like Lectins/metabolismABSTRACT
Missing transverse momentum is a crucial observable for physics at hadron colliders, being the only constraint on the kinematics of "invisible" objects such as neutrinos and hypothetical dark matter particles. Computing missing transverse momentum at the highest possible precision, particularly in experiments at the energy frontier, can be a challenging procedure due to ambiguities in the distribution of energy and momentum between many reconstructed particle candidates. This paper describes a novel solution for efficiently encoding information required for the computation of missing transverse momentum given arbitrary selection criteria for the constituent reconstructed objects. Pileup suppression using information from both the calorimeter and the inner detector is an integral component of the reconstruction procedure. Energy calibration and systematic variations are naturally supported. Following this strategy, the ATLAS Collaboration has been able to optimise the use of missing transverse momentum in diverse analyses throughout Runs 2 and 3 of the Large Hadron Collider and for future analyses.
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Vatiquinone is a potent inhibitor of 15-lipoxygenase and is in clinical development for the treatment of mitochondrial diseases and other disorders characterised by high levels of oxidative stress and dysregulation of energy metabolism.In rats, 14C-vatiquinone-derived radioactivity was quickly and widely distributed throughout the body and cleared from most tissues by 24 h post-dose following a single oral dose of 14C-vatiquinone.Following oral administration, 94% of dose was recovered within seven days in rats, approximately 61% of dose was recovered within seven days in dogs and approximately 93% of dose was recovered within nine days in human subjects (IND 119220). Faecal excretion was the major route (>56% dose) in all species; urinary excretion was minimal in rats and dogs (<3% dose) but was higher in humans (â¼ 22% dose).Following oral administration, vatiquinone was the dominant circulating component in rats and dogs but was minor in human subjects. There were no plasma metabolites that were more than 10% of total drug related exposures in all species.Following oral administration, vatiquinone was not detectable in urine but was the most prominent component in faeces in rats, dogs, and humans.
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The number of individuals over 50 years of age participating in recreational and competitive running has increased over the past ten years. It has been established that older runners experience a reduction in strength and power. These changes may contribute to different running biomechanics from younger runners. The purpose of this study was to synthesise the current evidence on running biomechanical differences in the lower extremity between masters runners over 50 years and younger runners under 40 years. The systematic data search included CINAHL, MEDLINE, and SPORTDiscus databases. Fourteen cross-sectional studies that compared lower extremity biomechanics of masters runners to younger runners were included. Masters runners demonstrated increased peak hip extension, with mixed results at the knee and ankle. Masters runners demonstrated decreased horizontal, peak propulsive, and active vertical peak ground reaction forces compared to younger runners. Joint powers and moments were consistently decreased at the ankle with no significant differences at the knee or hip. Masters runners demonstrate different kinematics and kinetics compared to younger runners with the greatest changes at the ankle. The results of this review may be beneficial for future studies investigating whether these differences are reversible.
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PURPOSE: A therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2, coronavirus disease 2019, COVID-19) management. Emvododstat (PTC299; 4-chlorophenyl 6-chloro-1-[4-methoxyphenyl]-1,3, 4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by inhibition of dihydroorotate dehydrogenase to reduce the severity of SARS-CoV-2 infections This drug interaction study was performed to determine if emvododstat was an inhibitor of CYP2D6. METHODS: Potential drug-drug interactions between emvododstat and a CYP2D6 probe substrate (dextromethorphan) were investigated by measuring plasma dextromethorphan and metabolite (dextrorphan) concentrations before and after emvododstat administration. On day 1, 18 healthy subjects received an oral dose of 30 mg dextromethorphan followed by a 4-day washout period. On day 5, subjects received an oral dose of 250 mg emvododstat with food. Two hours later, 30 mg dextromethorphan was administered. RESULTS: When given with emvododstat, plasma dextromethorphan concentrations increased substantially, while metabolite levels (dextrorphan) remained essentially the same. Maximum plasma dextromethorphan concentration (Cmax) increased from 2006 to 5847 pg/mL. Dextromethorphan exposure (AUC) increased from 18,829 to 157,400 h·pg/mL for AUC0-last and from 21,585 to 362,107 h·pg/mL for AUC0-inf following administration of emvododstat. When dextromethorphan parameters were compared before and after emvododstat, least squares mean ratios (90% confidence interval) were found to be 2.9 (2.2, 3.8), 8.4 (6.1, 11.5), and 14.9 (10.0, 22.1) for Cmax, AUC0-last, and AUC0-inf, respectively. CONCLUSION: Emvododstat appears to be a strong CYP2D6 inhibitor. No drug-related treatment emergent adverse effects (TEAEs) were considered to be severe or serious. TRIAL REGISTRATION: EudraCT 2021-004626-29, 11 May 2021.
Subject(s)
COVID-19 , Cytochrome P-450 CYP2D6 , Humans , Cytochrome P-450 CYP2D6/metabolism , Dextromethorphan/pharmacokinetics , Dihydroorotate Dehydrogenase , SARS-CoV-2 , Dextrorphan , Drug InteractionsABSTRACT
A therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) management. Emvododstat (PTC299) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by the inhibition of dihydroorotate dehydrogenase (DHODH) to reduce SARS-CoV-2 replication. DHODH is the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. This drug interaction study was performed to determine whether emvododstat was an inhibitor of breast cancer resistance protein (BCRP) transporters in humans. Potential drug-drug interactions (DDIs) between emvododstat and a BCRP transporter substrate (rosuvastatin) were investigated by measuring plasma rosuvastatin concentrations before and after emvododstat administration. There was no apparent difference in rosuvastatin plasma exposure. The geometric means of maximum plasma rosuvastatin concentrations (Cmax ) were 4369 (rosuvastatin) and 5141 pg/mL (rosuvastatin + emvododstat) at 4 h postdose. Geometric mean rosuvastatin area under the concentration-time curve (AUC) from time 0 to the last measurable plasma concentration was 45 616 and 48 975 h·pg/mL when administered alone and after 7 days of b.i.d. emvododstat dosing, respectively. Geometric least squares mean ratios for Cmax and AUC were approximately equal to 1. Overall, administration of multiple doses of 100 mg emvododstat b.i.d. for 7 days in combination with a single dose of rosuvastatin was safe and well tolerated. Emvododstat can be safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates are coadministered.
Subject(s)
COVID-19 , Dihydroorotate Dehydrogenase , Humans , Rosuvastatin Calcium/pharmacology , Rosuvastatin Calcium/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 2 , SARS-CoV-2 , Pyrimidines , Neoplasm Proteins/metabolism , Membrane Transport Proteins/metabolism , Drug InteractionsABSTRACT
Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans. Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively. Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating. Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine.
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Utreloxastat (PTC857) is a 15-lipoxygenase inhibitor being developed to treat amyotrophic lateral sclerosis. This first-in-human study investigated the safety and pharmacokinetics of utreloxastat in healthy volunteers (N = 82) in a double-blind, placebo-controlled trial. The effects of a single ascending dose (100-1000 mg), multiple ascending doses (150-500 mg), and food (500 mg) on the pharmacokinetics and safety of utreloxastat were evaluated. Following single doses, the time to maximum plasma concentration (Cmax ) was observed ≈4 hours after dosing and the terminal half-life ranged from 20 to 25.3 hours. The Cmax and area under the concentration-time curve (AUC) increased slightly over dose proportionally. Following multiple doses (once daily/twice daily), the apparent clearance reduced and terminal half-life was ≥33 hours. There was no apparent difference of exposure following morning or evening doses. Varying diets increased the Cmax and AUCs of utreloxastat but did not alter time to Cmax . There were no gender-based differences in exposure. Utreloxastat showed no marked safety signal following single doses up to 1000 mg and multiple doses over 14 days of 500 mg once daily or 250 mg twice daily. The results support further development of utreloxastat for the treatment of patients with amyotrophic lateral sclerosis at a 250-mg twice-daily dose administered with food.
Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Amyotrophic Lateral Sclerosis/drug therapy , Area Under Curve , Half-Life , Double-Blind Method , KineticsABSTRACT
PURPOSE: There are no standardized approaches for communicating with patients discharged from the emergency department with diagnostic uncertainty. This trial tested efficacy of the Uncertainty Communication Education Module, a simulation-based mastery learning curriculum designed to establish competency in communicating diagnostic uncertainty. METHOD: Resident physicians at 2 sites participated in a 2-arm waitlist randomized controlled trial from September 2019 to June 2020. After baseline (T1) assessment of all participants via a standardized patient encounter using the Uncertainty Communication Checklist (UCC), immediate access physicians received training in the Uncertainty Communication Education Module, which included immediate feedback, online educational modules, a smartphone-based application, and telehealth deliberate practice with standardized patients. All physicians were retested 16-19 weeks later (T2) via in-person standardized patient encounters; delayed access physicians then received the intervention. A final test of all physicians occurred 11-15 weeks after T2 (T3). The primary outcome measured the percentage of physicians in the immediate versus delayed access groups meeting or exceeding the UCC minimum passing standard at T2. RESULTS: Overall, 109 physicians were randomized, with mean age 29 years (range 25-46). The majority were male (n = 69, 63%), non-Hispanic/Latino (n = 99, 91%), and White (n = 78, 72%). At T2, when only immediate access participants had received the curriculum, immediate access physicians demonstrated increased mastery (n = 29, 52.7%) compared with delayed access physicians (n = 2, 3.7%, P < .001; estimated adjusted odds ratio of mastery for the immediate access participants, 31.1 [95% CI, 6.8-143.1]). There were no significant differences when adjusting for training site or stage of training. CONCLUSIONS: The Uncertainty Communication Education Module significantly increased mastery in communicating diagnostic uncertainty at the first postintervention test among emergency physicians in standardized patient encounters. Further work should assess the impact of clinical implementation of these communication skills.
Subject(s)
Internship and Residency , Physicians , Humans , Male , Female , Adult , Middle Aged , Patient Discharge , Uncertainty , Learning , Curriculum , Emergency Service, Hospital , Clinical CompetenceABSTRACT
Spectrally narrow optical resonances can be used to generate slow light, i.e., a large reduction in the group velocity. In a previous work, we developed hybrid 2D semiconductor plasmonic structures, which consist of propagating optical frequency surface-plasmon polaritons interacting with excitons in a semiconductor monolayer. Here, we use coupled exciton-surface plasmon polaritons (E-SPPs) in monolayer WSe2 to demonstrate slow light with a 1300 fold decrease of the SPP group velocity. Specifically, we use a high resolution two-color laser technique where the nonlinear E-SPP response gives rise to ultra-narrow coherent population oscillation (CPO) resonances, resulting in a group velocity on order of 105 m/s. Our work paves the way toward on-chip actively switched delay lines and optical buffers that utilize 2D semiconductors as active elements.