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BACKGROUND AND PURPOSE: Computerized 3-dimensional (3-D) motion measurement systems are used by those interested in human motion. The purposes of this study were (1) to determine the limits of accuracy in determining intersegmental angles during pendular motion at varying speeds and (2) to determine changes in accuracy introduced by autodigitization and digitization by experienced manual raters. METHODS: Angular speed of a T-shaped pendulum was systematically increased by releasing the pendulum from 4 angles (0 degrees [no movement], 45 degrees, 90 degrees, and 120 degrees). Twelve reference angles calculated from markers placed on the pendulum were estimated over 20 frames for 10 trials at each release position. RESULTS: Mean errors across trials and frames for intersegmental angles reconstructed by a 3-D motion measurement system were within +/- 1 degree across all release positions. An analysis of variance and a post hoc Tukey test revealed that the mean error for the autodigitized trials was larger than that for the manually digitized trials. For the autodigitized trials, the static trials (release position=0 degrees) produced less mean error than the trials with movement produced. The ICCs showed a high degree of consistency among all raters, ranging from .707 to .999. CONCLUSION AND DISCUSSION: Our findings support the conclusion that under carefully controlled conditions, a 3-D motion measurement system can produce clinically acceptable measurements of accuracy across a range of angular speeds. Furthermore, acceptable accuracy is possible regardless of the digitization method. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Three-dimensional computerized gait analysis continues to grow in use among physical therapists and other clinical specialists interested in quantitative data regarding human ambulation. This study documented the accuracy of reconstructed angular estimates under static and dynamic conditions using the Ariel Performance Analysis System. METHODS: Angular velocity was systematically increased by raising the release position of a T-shaped pendulum. Angular velocities were examined by releasing the pendulum from four angles (0 degree-static, 45 degrees, 90 degrees, and 120 degrees). Twelve reference angles were estimated over 20 autodigitized frames for 10 trials at each release position. Intraclass correlation coefficients (ICCs) and analysis-of-variance (ANOVA) procedures were used to test the hypothesis that the error of angular estimates grows with increasing angular velocity. RESULTS: Mean errors of the reconstructed angles were consistently within +/- 1.0 degree, regardless of angular velocity. An ANOVA revealed a statistically significant angular velocity effect, characterized by release position. The 90-degree release position produced the greatest error, followed by the 120-, 45-, and 0-degree release positions. The error was not significantly different between the 120- and 45-degree release positions. Intraclass correlation coefficients greater than .90 were found for all frame-to-frame angular velocities, except for the 90-degree release position. The angle estimates consistently underestimated the reference angles, regardless of release position. CONCLUSION AND DISCUSSION: The results suggest that clinically accurate angular estimates can be obtained across the range of angular velocities used in this study. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy. Most (80%) children with XLMTM have profound muscle weakness and hypotonia at birth resulting in severe respiratory insufficiency, the inability to sit up, stand or walk, and early mortality. At birth, 85-90% of children with XLMTM require mechanical ventilation, with more than half requiring invasive ventilator support. Historically, ventilator-dependent children with neuromuscular-derived respiratory failure of this degree and nature, static or progressive, are not expected to achieve complete independence from mechanical ventilator support. In the ASPIRO clinical trial (NCT03199469), participants receiving a single intravenous dose of an investigational gene therapy (resamirigene bilparvovec) started showing significant improvements in daily hours of ventilation support compared with controls by 24 weeks post-dosing, and 16 of 24 dosed participants achieved ventilator independence between 14 and 97 weeks after dosing. At the time, there was no precedent or published guidance for weaning chronically ventilated children with congenital neuromuscular diseases off mechanical ventilation. When the first ASPIRO participants started showing dramatically improved respiratory function, the investigators initiated efforts to safely wean them off ventilator support, in parallel with primary protocol respiratory outcome measures. A group of experts in respiratory care and physiology and management of children with XLMTM developed an algorithm to safely wean children in the ASPIRO trial off mechanical ventilation as their respiratory muscle strength increased. The algorithm developed for this trial provides recommendations for assessing weaning readiness, a stepwise approach to weaning, and monitoring of children during and after the weaning process., (© 2024. The Author(s).)

Purpose: The System for Improving and Measuring Procedure Learning (SIMPL), a smartphone-based operative assessment application, was developed to assess the intraoperative performance of surgical residents. This study aims to examine the reliability of the SIMPL assessment and determine the optimal number of procedures for a reliable assessment., Methods: In this retrospective observational study, we analyzed data collected between 2015 and 2023 from 4,616 residents across 94 General Surgery Residency programs in the United States that utilized the SIMPL smartphone application. We employed multivariate generalizability theory and initially conducted generalizability studies to estimate the variance components associated with procedures. We then performed decision studies to estimate the reliability coefficient and the minimum number of procedures required for a reproducible assessment., Results: We estimated that the reliability of the assessment of surgical trainees’ intraoperative autonomy and performance using SIMPL exceeded 0.70. Additionally, the optimal number of procedures required for a reproducible assessment was 10, 17, 15, and 17 for postgraduate year (PGY) 2, PGY 3, PGY 4, and PGY 5, respectively. Notably, the study highlighted that the assessment of residents in their senior years necessitated a larger number of procedures compared to those in their junior years., Conclusion: The study demonstrated that the SIMPL assessment is reliably effective for evaluating the intraoperative performance of surgical trainees. Adjusting the number of procedures based on the trainees’ training stage enhances the assessment process’s accuracy and effectiveness.

Background: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated., Methods: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed., Findings: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants., Interpretation: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study., Funding: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.)., Competing Interests: Declaration of interests MWL has received research funding from Astellas Gene Therapies∗ to his academic institution (Medical College of Wisconsin) and to his company (Diverge Translational Science Laboratory) for work related to the present manuscript; has received research grants or contracts to his academic institution (Medical College of Wisconsin) from Solid Biosciences, Kate Therapeutics, Taysha Therapeutics, Ultragenyx, and Prothelia; has received consulting fees from Astellas Gene Therapies∗, Encoded Therapeutics, Modis Therapeutics, Lacerta Therapeutics, AGADA Biosciences, Dynacure, Affinia, Voyager, BioMarin, Locanabio, and Vertex Pharmaceuticals; has received speaker fees and reimbursement for travel related to sponsored research from Astellas Gene Therapies∗; has received personal fees for scientific advisory board participation for Astellas Gene Therapies∗ and Solid Biosciences, and his institution has received payment from Taysha Therapeutics for his advisory board participation; he is currently CEO, founder, and owner of Diverge Translational Science Laboratory, which continues to work under contracts from many gene therapy companies including Astellas Gene Therapies∗, Solid Biosciences, Rocket Pharma, Kate Therapeutics, Carbon Biosciences, Dynacure, Nationwide Children's Hospital, Taysha Gene Therapies, and Ultragenyx. BS (Schoser) has received grants/contracts, honoraria, and support for attending meetings from Astellas Gene Therapies∗ has participated in Advisory Boards for Dynacure. MM has received personal fees and study funding to her institution from Astellas Gene Therapies∗ in relation to the present manuscript. CAS has received royalties from Elsevier for the book “Muscle Biopsy. A Practical Approach”. KAJ has received consulting fees from Astellas Gene Therapies∗ in relation to the present manuscript and other activities. PBS has received research funding from Astellas Gene Therapies∗ to support clinical trial investigations relating to the present manuscript; has received research contracts from Biogen, Dyne, Fulcrum, Pfizer, PTC Therapeutics, Reveragen, Sanofi, Sarepta, and Solid Biosciences; has received consulting fees from Alexion, Argenx, Biogen, Novartis Gene Therapies, Pfizer, UCB, and Sarepta; has received honoraria for lectures or presentations from Alexion, Argenx, Biogen, Catalyst, CSL Behring, Genentech, and Grifols; and has participated on Independent Data Monitoring Committees for Encoded Therapeutics, Excision BioTherapeutics, and Taysha. NLK reports research grants paid to her institution from AMO Pharma, Argenx, Astellas Gene Therapies∗, Biogen, Biohaven, Novartis, NS Pharma, Sarepta, Reveragen, Roche, and Scholar Rock; has received payment for educational presentations from Sarepta; and has participated in a Data Safety Monitoring Board for Sarepta and Advisory Boards for Argenx, BioMarin, Fibrogen, Roche, and Sarepta. BKS has received institutional research grants or contracts to serve as an INCEPTUS and ASPIRO study site from Astellas Gene Therapies∗. JJD has received research grants from NIH, CIHR, and Astellas Gene Therapies∗; has received support for attending annual meetings from the World Muscle Society (as Executive Board Member) and TREAT NMD (as Chair of Executive Board); and receives annual honoraria as a Scientific Advisory Board member for the RYR1 Foundation. WMF has received support for study materials and study personnel relating to the present manuscript from Astellas Gene Therapies∗; consulting fees from Sarepta, PTC Therapeutics, Novartis, and Roche; personal compensation from Novartis and Biogen, and institutional funding from Roche, for lectures; and has served on Scientific Advisory Boards for DGM and Glykogenosis e.V. CGB reports study funding relating to the present manuscript paid to NINDS; and has participated in data safety monitoring or advisory boards without financial compensation, in his capacity of representing NIH. AMS is a principal investigator in the ASPIRO study. AB has received speaker's honoraria from Pfizer and Roche; and has participated in advisory boards at for Pfizer and Roche. SN, ARF, DNS, ET, and URQ report no conflicts of interests. MB and MJP are full-time employees of Diverge Translational Science Laboratory. EO and SD report no conflicts of interest. PK is a full-time employee of Diverge Translational Science Laboratory. SNK report no conflicts of interest. HM is a full-time employee of Diverge Translational Science Laboratory. MVA, CW, and HGD report no conflicts of interest. AHB received study funding relating to the present manuscript; reports grants or contracts received from NIH, MDA (USA), and the Chan Zuckerberg Initiative, and from AFM Telethon, Alexion Pharmaceuticals Inc., Avidity, Dynacure SAS, Kate Therapeutics, and Pfizer Inc. He has received consulting fees from Astellas Gene Therapies∗, Dynacure, GLG Inc., Guidepoint Global, Kate Therapeutics, and Roche; has received support for attending meetings from Kate Therapeutics and MDA; holds equity in Kate Therapeutics and Kinea Bio, and is an inventor on a US patent describing a method for gene therapy of XLMTM. SC, EC, JL, CS, WM, BS (Sepulveda), FV are former employees of Astellas Gene Therapies∗. ESJ and SR are former employees and stockholders in Astellas Gene Therapies∗. SP was Chief Medical Officer and a stockholder in Astellas Gene Therapies∗ when the study was designed and initiated; he is no longer a stockholder and currently consults independently with a wide variety of companies and academic institutions primarily on Clinical Development matters. ∗Formerly Audentes Therapeutics, Inc., (Copyright © 2023. Published by Elsevier B.V.)

Oral demonstration of knowledge is an effective learning and assessment strategy. It has been shown that generating explanations to oneself, or self-explaining, can improve student understanding of information. This can be achieved via student-generated videos. The quantitative effects of student-generated videos on learning and assessment in postsecondary education are unknown. To our knowledge, this is the first study to analyze the effects asynchronous student-generated videos have on student learning and assessment in a large-enrollment (∼400 students), undergraduate physiology course. Students were charged with making self-generated videos discussing major physiological concepts and uploading these videos to Flip for assessment. Flip is an online, social education platform for asynchronous video-based discussion. In the present study, we combined four semesters ( n = 1,100 students) of Flip data and analyzed the effects it had on student examination performance. Specifically, we first analyzed how students performed on exam questions corresponding to their Flip prompts in comparison to students not assigned those prompts [25/44 (57%) were statistically significantly different]. Second, we analyzed the association between Flip prompt score and performance on corresponding exam questions [39/44 (89%) were statistically significantly different]. Third, we analyzed the association between cumulative Flip score and performance on all corresponding, and noncorresponding exam questions. Finally, we analyzed the association between cumulative Flip score and averaged exam performance. There was a positive association ( r = 0.54). Taken together, our data suggest that asynchronous student-generated Flip videos can facilitate student learning and assessment in a large-enrollment, undergraduate physiology course. NEW & NOTEWORTHY Oral demonstration of knowledge is an effective learning and assessment strategy. Student-generated videos have been shown to improve learning and assessment in secondary education. To our knowledge, this is the first study to analyze the effects asynchronous student-generated Flip videos have on student learning and assessment in postsecondary education. The results of the present study suggest that asynchronous student-generated Flip videos can facilitate student learning and assessment in a large-enrollment (∼400 students), undergraduate physiology course.

Objective: As medical education systems increasingly move toward competency-based training, it is important to understand the tools available to assess competency and how these tools are utilized. The Society for Improving Medical Professional Learning (SIMPL) offers a smart phone-based assessment system that supports workplace-based assessment of residents' and fellows' operative autonomy, performance, and case complexity. The purpose of this study was to characterize implementation of the SIMPL app within vascular surgery integrated residency (0+5) and fellowship (5+2) training programs., Methods: SIMPL operative ratings recorded between 2018 and 2022 were collected from all participating vascular surgery training institutions (n = 9 institutions with 5+2 and 0+5 programs; n = 4 institutions with 5+2 program only). The characteristics of programs, trainees, faculty, and SIMPL operative assessments were evaluated using descriptive statistics., Results: Operative assessments were completed for 2457 cases by 85 attendings and 86 trainees, totaling 4615 unique operative assessment ratings. Attendings included dictated feedback in 52% of assessments. Senior-level residents received more assessments than junior-level residents (postgraduate year [PGY]1-3, n = 439; PGY4-5, n = 551). Performance ratings demonstrated increases from junior to senior trainees for both resident and fellow cohorts with "performance-ready" or "exceptional performance" ratings increasing by nearly two-fold for PGY1 to PGY5 residents (28.1% vs 40.6%), and from first- to second-year fellows (PGY6, 46.7%; PGY7, 60.3%). Similar gains in autonomy were demonstrated as trainees progressed through training. Senior residents were more frequently granted autonomy with "supervision only" than junior residents (PGY1, 8.7%; PGY5, 21.6%). "Supervision only" autonomy ratings were granted to 21.8% of graduating fellows. Assessment data included a greater proportion of complex cases for senior compared with junior fellows (PGY6, 20.9% vs PGY7, 26.5%). Program Directors felt that faculty and trainee buy-in were the main barriers to implementation of the SIMPL assessment app., Conclusions: This is the first description of the SIMPL app as an operative assessment tool within vascular surgery that has been successfully implemented in both residency and fellowship programs. The assessment data demonstrates expected progressive gains in trainees' autonomy and performance, as well as increasing case complexity, across PGY years. Given the selection of SIMPL as the assessment platform for required American Board of Surgery and Vascular Surgery Board Entrustable Professional Activities assessments, understanding facilitators and barriers to implementation of workplace-based assessments using this app is imperative, particularly as we move toward competency-based medical education., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Ticks and tick-borne diseases represent major threats to the public health of the Mongolian population, of which an estimated 26% live a traditional nomadic pastoralist lifestyle that puts them at increased risk for exposure. Ticks were collected by dragging and removal from livestock in Khentii, Selenge, Tuv, and Umnugovi aimags (provinces) during March-May 2020. Using next-generation sequencing (NGS) with confirmatory PCR and DNA sequencing, we sought to characterize the microbial species present in Dermacentor nuttalli (n = 98), Hyalomma asiaticum (n = 38), and Ixodes persulcatus (n = 72) tick pools. Rickettsia spp. were detected in 90.4% of tick pools, with Khentii, Selenge, and Tuv tick pools all having 100% pool positivity. Coxiella spp. were detected at an overall pool positivity rate of 60%, while Francisella spp. were detected in 20% of pools and Borrelia spp. detected in 13% of pools. Additional confirmatory testing for Rickettsia-positive pools demonstrated Rickettsia raoultii (n = 105), Candidatus Rickettsia tarasevichiae (n = 65) and R. slovaca/R. sibirica (n = 2), as well as the first report of Candidatus Rickettsia jingxinensis (n = 1) in Mongolia. For Coxiella spp. reads, most samples were identified as a Coxiella endosymbiont (n = 117), although Coxiella burnetii was detected in eight pools collected in Umnugovi. Borrelia species that were identified include Borrelia burgdorferi sensu lato (n = 3), B. garinii (n = 2), B. miyamotoi (n = 16), and B. afzelii (n = 3). All Francisella spp. reads were identified as Francisella endosymbiont species. Our findings emphasize the utility of NGS to provide baseline data across multiple tick-borne pathogen groups, which in turn can be used to inform health policy, determine regions for expanded surveillance, and guide risk mitigation strategies., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Introduction: Pompe disease is an inherited disease characterized by a deficit in acid-α-glucosidase (GAA), an enzyme which degrades lysosomal glycogen. The phrenic-diaphragm motor system is affected preferentially, and respiratory failure often occurs despite GAA enzyme replacement therapy. We hypothesized that the continued use of diaphragm pacing (DP) might improve ventilator-dependent subjects' respiratory outcomes and increase ventilator-free time tolerance., Methods: Six patients (3 pediatric) underwent clinical DP implantation and started diaphragm conditioning, which involved progressively longer periods of daily, low intensity stimulation. Longitudinal respiratory breathing pattern, diaphragm electromyography, and pulmonary function tests were completed when possible, to assess feasibility of use, as well as diaphragm and ventilatory responses to conditioning., Results: All subjects were eventually able to undergo full-time conditioning via DP and increase their maximal tolerated time off-ventilator, when compared to pre-implant function. Over time, 3 of 6 subjects also demonstrated increased or stable minute ventilation throughout the day, without positive-pressure ventilation assistance., Discussion: Respiratory insufficiency is one of the main causes of death in patients with Pompe disease. Our results indicate that DP in Pompe disease was feasible, led to few adverse events and stabilized breathing for up to 7 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Liberati, Byrne, Fuller, Croft, Pitts, Ehrbar, Leon-Astudillo and Smith.)

Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries ( n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes.

Borrelia miyamotoi is a relapsing fever spirochete that shares the same vector as Lyme disease causing Borrelia. This epidemiological study of B. miyamotoi was conducted in rodent reservoirs, tick vectors and human populations simultaneously. A total of 640 rodents and 43 ticks were collected from Phop Phra district, Tak province, Thailand. The prevalence rate for all Borrelia species was 2.3% and for B. miyamotoi was 1.1% in the rodent population, while the prevalence rate was quite high in ticks collected from rodents with an infection rate of 14.5% (95% CI: 6.3-27.6%). Borrelia miyamotoi was detected in Ixodes granulatus collected from Mus caroli and Berylmys bowersi, and was also detected in several rodent species (Bandicota indica, Mus spp., and Leopoldamys sabanus) that live in a cultivated land, increasing the risk of human exposure. Phylogenetic analysis revealed that the B. miyamotoi isolates detected in rodents and I. granulatus ticks in this study were similar to isolates detected in European countries. Further investigation was conducted to determine the serological reactivity to B. miyamotoi in human samples received from Phop Phra hospital, Tak province and in rodents captured from Phop Phra district using an in-house, direct enzyme-linked immunosorbent assay (ELISA) assay with B. miyamotoi recombinant glycerophosphodiester-phosphodiesterase (rGlpQ) protein as coated antigen. The results showed that 17.9% (15/84) of human patients and 9.0% (41/456) of captured rodents had serological reactivity to B. miyamotoi rGlpQ protein in the study area. While a low level of IgG antibody titers (100-200) was observed in the majority of seroreactive samples, higher titers (400-1,600) were also detected in both humans and rodents. This study provides the first evidence of B. miyamotoi exposure in human and rodent populations in Thailand and the possible roles of local rodent species and Ixodes granulatus tick in its enzootic transmission cycle in nature., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The development of wearable technology, which enables motion tracking analysis for human movement outside the laboratory, can improve awareness of personal health and performance. This study used a wearable smart sock prototype to track foot-ankle kinematics during gait movement. Multivariable linear regression and two deep learning models, including long short-term memory (LSTM) and convolutional neural networks, were trained to estimate the joint angles in sagittal and frontal planes measured by an optical motion capture system. Participant-specific models were established for ten healthy subjects walking on a treadmill. The prototype was tested at various walking speeds to assess its ability to track movements for multiple speeds and generalize models for estimating joint angles in sagittal and frontal planes. LSTM outperformed other models with lower mean absolute error (MAE), lower root mean squared error, and higher R -squared values. The average MAE score was less than 1.138° and 0.939° in sagittal and frontal planes, respectively, when training models for each speed and 2.15° and 1.14° when trained and evaluated for all speeds. These results indicate wearable smart socks to generalize foot-ankle kinematics over various walking speeds with relatively low error and could consequently be used to measure gait parameters without the need for a lab-constricted motion capture system., Competing Interests: The authors declare no competing interests exist., (© The Author(s) 2023.)

Objective: Frailty is a clinical syndrome associated with slow recovery after vascular surgery. However, the degree and length of functional impairment frail patients experience after surgery is unclear. The objective of this study was to prospectively measure changes in functional status among frail and non-frail patients undergoing a spectrum of different vascular surgery procedures., Methods: Patients consented to undergo elective minor and major vascular surgery procedures at an academic medical center between May 2018 and March 2019 were prospectively identified. Prior to surgery, all patients underwent provider assessment of frailty using the validated Clinical Frailty Scale (CFS), as well as baseline assessment of functional status using the Katz Activities of Daily Living (ADL) index and the Lawton Instrumental Activities of Daily Living (iADL) index. These same instruments were used to evaluate each patient's functional status at 2-weeks, 1-month, 1-year, and 2-year time points following surgery. Changes in iADL and ADL scores among frail (CFS ≥5) and non-frail patients were compared using paired Wilcoxon signed-rank tests and logistic regression models., Results: A total of 126 patients were assessed before and after minor (55%) and major (45%) vascular procedures, of which 43 patients (34%) were determined to be frail prior to surgery. Frail patients were older and more likely than non-frail patients to have medical comorbidities including chronic kidney disease, chronic obstructive pulmonary disease, or diabetes (all P < .05). When compared with the non-frail cohort, frail patients had significantly lower ADL and iADL scores before surgery and experienced a greater decline in ability to independently complete ADL and iADL activities after surgery that was sustained at 2 years (P < .05 and P < .001, respectively). After risk-adjustment, frailty was associated with an increased likelihood of decline in ADLs (odds ratio, 5.4; 95% confidence interval, 1.9-15.4; P < .05) and iADLs (odds ratio, 6.3; 95% confidence interval, 2.6-15.1; P < .001) at 2 years following surgery., Conclusions: Frail patients experience a significant decline in ability to perform ADL and iADLs that persists 2 years following vascular surgery. These data highlight the degree of functional decline occurring immediately following surgery, as well as risk for long-term, sustained impairment that should be shared with frail patients before undergoing a procedure., (Published by Elsevier Inc.)

Objective: Statins are considered standard-of-care medical therapy for patients undergoing lower extremity bypass (LEB) procedures for chronic limb-threatening ischemia (CLTI). It is unclear, however, whether up-titrating and maintaining patients on higher-intensity statin medications following LEB improves limb salvage outcomes. This study was designed to evaluate whether high-intensity statin therapy impacts the risk of amputation and reintervention following LEB for patients with CLTI., Methods: The IBM MarketScan database was used to identify adult patients (18-99 years old) who underwent a LEB for CLTI between 2008 and 2017. Patients lacking insurance covering drug reimbursement or those who already had undergone amputation before time of bypass were excluded. Using pharmacy claims and national drug codes to define statin intensity, patients were stratified into three groups: high-intensity, low-intensity, and limited statin therapy. The association between intensity of statin therapy and need for reintervention and/or major amputation after LEB was analyzed using Kaplan-Meier curves and risk-adjusted Cox proportional hazard models., Results: A total of 25,907 patients who underwent LEB for CLTI were identified, of which 6696 (26%) were maintained on high-dose statins, 9297 (36%) were on low-dose statins, and 9914 (38%) had inconsistent pharmacy claims for statin therapy after surgery. Patients on high-intensity statins were, on average, younger and more likely to be male with comorbid disease (diabetes, hypertension, hyperlipidemia, obesity, renal insufficiency, ischemic heart disease, cerebrovascular disease, and tobacco abuse) than patients on low-intensity statins or limited statin therapy (P < .001 for all comparisons). Following LEB, 6649 patients (25.6%) required a reintervention, and 2550 patients (9.8%) went on to have a major amputation during follow-up. Patients maintained on high-intensity statins after LEB had a significantly lower likelihood of requiring a reintervention (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.45-0.51; P < .001) or amputation (HR, 0.27; 95% CI, 0.24-0.30; P < .001) as compared with patients on limited statin therapy. Further, there was a dose-dependent effect for these outcomes relative to patients on low-intensity statins in risk-adjusted models, and it was independent of whether an autologous vein graft was used for the LEB. Finally, among patients who underwent a reintervention, high-dose statin therapy also significantly reduced the HR for subsequent amputation (HR, 0.21; 95% CI, 0.18-0.25; P < .001)., Conclusions: Patients with CLTI on high-intensity therapy following LEB had a significantly lower risk of requiring subsequent reintervention and amputation when compared with patients on low-intensity statins or with limited statin use. These data suggest that patients with CLTI should be up-titrated and/or maintained on high-intensity statins following revascularization whenever possible., (Published by Elsevier Inc.)

Objectives: Vascular surgery integrated residency (VSIR) programs are highly competitive; however, criteria for resident selection remain opaque and non-standardized. The already unclear selection criteria will be further impacted by the impending transition of the United States Medical Licensing Examination (USMLE) Step 1 from numeric scores to a binary pass/fail outcome. The purpose of this study was to investigate the historical and anticipated selection criteria of VSIR applicants., Methods: This was a cross-sectional, nationwide, 59-item survey that was sent to all VSIR program directors (PDs). Data was analyzed using the Fisher exact test if categorical and the Mann-Whitney U test and the Kruskal-Wallis test if ordinal., Results: Forty of 69 PDs (58%) responded to the survey. University-based programs constituted 85% of responders. Most VSIR PDs (65%) reported reviewing between 101 to 150 applications for 1 to 2 positions annually. Forty-two percent of the responding PDs reported sole responsibility for inviting applicants to interview, whereas 50% had a team of faculty responsible for reviewing applications. On a five-point Likert scale, letters of recommendation (LOR) from vascular surgeons or colleagues (a person the PD knows) were the most important objective criteria. Work within a team structure was rated highest among subjective criteria. The majority of respondents (72%) currently use the Step 1 score as a primary method to screen applicants. Regional differences in use of Step 1 score as a primary screening method were: Midwest (100%), Northeast (76%), South (43%), and West (40%) (P = .01). PDs responded that that they will use USMLE Step 2 score (42%) and LOR (10%) to replace USMLE Step 1 score. The current top ranked selection criteria are letters from a vascular surgeon, USMLE Step 1 score and overall LOR. The proposed top ranked selection criteria after transition of USMLE Step 1 to pass/fail include LOR overall followed by Step 2 score., Conclusions: This is the first study to evaluate the selection criteria used by PDs for VSIR. The landscape of VSIR selection criteria is shifting and increasing transparency is essential to applicants' understanding of the selection process. The transition of USMLE Step 1 to a pass/fail report will shift the attention to Step 2 scores and elevate the importance of other relatively more subjective criteria. Defining VSIR program selection criteria is an important first step toward establishing holistic review processes that are transparent and equitable., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition noteworthy for upper and lower motor neuron death. Involvement of respiratory motor neuron pools leads to progressive pathology. These impairments include decreases in neural activation and muscle coordination, progressive airway obstruction, weakened airway defenses, restrictive lung disease, increased risk of pulmonary infections, and weakness and atrophy of respiratory muscles. These neural, airway, pulmonary, and neuromuscular changes deteriorate integrated respiratory-related functions including sleep, cough, swallowing, and breathing. Ultimately, respiratory complications account for a large portion of morbidity and mortality in ALS. This state-of-the-art review highlights applications of respiratory therapies for ALS, including lung volume recruitment, mechanical insufflation-exsufflation, non-invasive ventilation, and respiratory strength training. Therapeutic acute intermittent hypoxia, an emerging therapeutic tool for inducing respiratory plasticity will also be introduced. A focus on emerging evidence and future work underscores the common goal to continue to improve survival for patients living with ALS.

Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.

Background: The quality and effectiveness of vascular surgery education should be evaluated based on patient care outcomes. To investigate predictive associations between trainee performance and subsequent patient outcomes, a critical first step is to determine the conceptual alignment of educational competencies with clinical outcomes in practice. We sought to generate expert consensus on the conceptual alignment of the Accreditation Council for Graduate Medical Education (ACGME) Vascular Surgery subcompetencies with patient care outcomes across different Vascular Quality Initiative (VQI) registries., Methods: A national panel of vascular surgeons with expertise in both clinical care and education were recruited to participate in a modified Delphi expert consensus building process to map ACGME Vascular Surgery subcompetencies (educational markers of resident performance) to VQI clinical modules (patient outcomes). A master list of items for rating was created, including the 31 ACGME Vascular Surgery subcompetencies and 8 VQI clinical registries (endovascular abdominal aortic aneurysm repair, open abdominal aortic aneurysm, thoracic endovascular aortic repair, carotid endarterectomy, carotid artery stent, infrainguinal, suprainguinal, and peripheral vascular intervention). These items were entered into an iterative Delphi process. Positive consensus was reached when 75% or more of the participants ranked an item as mandatory. Intraclass correlations (ICCs) were used to evaluate consistency between experts for each Delphi round., Results: A total of 13 experts who contributed to the development of the Vascular Surgery Milestones participated; 12 experts (92%) participated in both rounds of the Delphi process. Two rounds of Delphi were conducted, as suggested by excellent expert agreement (round 1, ICC = 0.79 [95% confidence interval, 0.74-0.84]; round 2, ICC = 0.97 [95% confidence interval, 0.960-.98]). Using the predetermined consensus cutoff threshold, the Delphi process reduced the number of subcompetencies mapped to patient care outcomes from 31 to a range of 9 to 15 across the 8 VQI clinical registries. Practice-based learning and improvement, and professionalism subcompetencies were identified as less relevant to patient outcome variables captured by the VQI registries after the final round, and the only the systems-based practice subcompetency that was identified as relevant was radiation safety in two of the endovascular registries., Conclusions: A national panel of vascular surgeon experts reported a high degree of agreement on the relevance of ACGME subcompetencies to patient care outcomes as captured in the VQI clinical registry. Systems-based practice, practice-based learning and improvement, and professionalism competencies were identified as less relevant to patient outcomes after specific surgical procedures., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Tick-borne diseases are a major public health concern in Mongolia. Nomadic pastoralists, which make up ~ 26% of Mongolia's population, are at an increased risk of both tick bite exposure and economic loss associated with clinical disease in herds. This study sought to further characterize tick-borne pathogens present in Dermacentor ticks ( n  = 1,773) sampled in 2019 from 15 of Mongolia's 21 aimags (provinces). The ticks were morphologically identified and sorted into 377 pools which were then screened using Next-Generation Sequencing paired with confirmatory PCR and DNA sequence analysis. Rickettsia spp. were detected in 88.33% of pools, while Anaplasma spp. and Bartonella spp. were detected in 3.18 and 0.79% of pools, respectively. Khentii had the highest infection rate for Rickettsia spp. (76.61%; CI: 34.65-94.79%), while Arkhangai had the highest infection rate for Anaplasma spp. (7.79%; CI:4.04-13.72%). The exclusive detection of Anaplasma spp. in tick pools collected from livestock supports previous work in this area that suggests livestock play a significant role in disease maintenance. The detection of Anaplasma, Bartonella, and Rickettsia demonstrates a heightened risk for infection throughout Mongolia, with this study, to our knowledge, documenting the first detection of Bartonella melophagi in ticks collected in Mongolia. Further research deploying NGS methods is needed to characterize tick-borne pathogens in other endemic tick species found in Mongolia, including Hyalomma asiaticum and Ixodes persulcatus ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Altantogtokh, Lilak, Takhampunya, Sakolvaree, Chanarat, Matulis, Poole-Smith, Boldbaatar, Davidson, Hertz, Bolorchimeg, Tsogbadrakh, Fiorenzano, Lindroth and von Fricken.)

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia., Competing Interests: Declaration of interests G.R.S. has received research funding from Esperion Therapeutics, Espervita Therapeutics, Poxel Pharmaceuticals, Nestle, and Novo Nordisk; honoraria and/or consulting fees from Astra Zeneca, Eli-Lilly, Esperion Therapeutics, Poxel Pharmaceuticals, and Merck; and is a founder and shareholder of Espervita Therapeutics. S.L.P. is employed by Esperion Therapeutics. Bempedoic acid was provided by Esperion Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Audio features such as inharmonicity, noisiness, and spectral roll-off have been identified as correlates of "noisy" sounds. However, such features are likely involved in the experience of multiple semantic timbre categories of varied meaning and valence. This paper examines the relationships of stimulus properties and audio features with the semantic timbre categories raspy/grainy/rough , harsh/noisy , and airy/breathy . Participants ( n = 153) rated a random subset of 52 stimuli from a set of 156 approximately 2-s orchestral instrument sounds representing varied instrument families (woodwinds, brass, strings, percussion), registers (octaves 2 through 6, where middle C is in octave 4), and both traditional and extended playing techniques (e.g., flutter-tonguing, bowing at the bridge). Stimuli were rated on the three semantic categories of interest, as well as on perceived playing exertion and emotional valence. Correlational analyses demonstrated a strong negative relationship between positive valence and perceived physical exertion. Exploratory linear mixed models revealed significant effects of extended technique and pitch register on valence, the perception of physical exertion, raspy/grainy/rough , and harsh/noisy . Instrument family was significantly related to ratings of airy/breathy . With an updated version of the Timbre Toolbox (R-2021 A), we used 44 summary audio features, extracted from the stimuli using spectral and harmonic representations, as input for various models built to predict mean semantic ratings for each sound on the three semantic categories, on perceived exertion, and on valence. Random Forest models predicting semantic ratings from audio features outperformed Partial Least-Squares Regression models, consistent with previous results suggesting that non-linear methods are advantageous in timbre semantic predictions using audio features. Relative Variable Importance measures from the models among the three semantic categories demonstrate that although these related semantic categories are associated in part with overlapping features, they can be differentiated through individual patterns of audio feature relationships., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Reymore, Beauvais-Lacasse, Smith and McAdams.)

Ticks are known vectors for a variety of pathogens including bacteria, viruses, fungi, and parasites. In this study, bacterial communities were investigated in active life stages of three tick genera ( Haemaphysalis, Dermacentor , and Amblyomma ) collected from Khao Yai National Park in Thailand. Four hundred and thirty-three questing ticks were selected for pathogen detection individually using real-time PCR assays, and 58 of these were subjected to further metagenomics analysis. A total of 62 ticks were found to be infected with pathogenic bacteria, for a 14.3% prevalence rate, with Amblyomma spp. exhibiting the highest infection rate (20.5%), followed by Haemaphysalis spp. (14.5%) and Dermacentor spp. (8.6%). Rickettsia spp. were the most prevalent bacteria (7.9%) found, followed by Ehrlichia spp. (3.2%), and Anaplasma spp. and Borrelia spp. each with a similar prevalence of 1.6%. Co-infection between pathogenic bacteria was only detected in three Haemaphysalis females, and all co-infections were between Rickettsia spp. and Anaplasmataceae ( Ehrlichia spp. or Anaplasma spp.), accounting for 4.6% of infected ticks or 0.7% of all examined questing ticks. The prevalence of the Coxiella -like endosymbiont was also investigated. Of ticks tested, 65.8% were positive for the Coxiella -like endosymbiont, with the highest infection rate in nymphs (86.7%), followed by females (83.4%). Among tick genera, Haemaphysalis exhibited the highest prevalence of infection with the Coxiella -like endosymbiont. Ticks harboring the Coxiella -like endosymbiont were more likely to be infected with Ehrlichia spp. or Rickettsia spp. than those without, with statistical significance for Ehrlichia spp. infection in particular ( p -values = 0.003 and 0.917 for Ehrlichia spp. and Rickettsia spp., respectively). Profiling the bacterial community in ticks using metagenomics revealed distinct, predominant bacterial taxa in tick genera. Alpha and beta diversities analyses showed that the bacterial community diversity and composition in Haemaphysalis spp. was significantly different from Amblyomma spp. However, when examining bacterial diversity among tick life stages (larva, nymph, and adult) in Haemaphysalis spp., no significant difference among life stages was detected. These results provide valuable information on the bacterial community composition and co-infection rates in questing ticks in Thailand, with implications for animal and human health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Takhampunya, Sakolvaree, Chanarat, Youngdech, Phonjatturas, Promsathaporn, Tippayachai, Tachavarong, Srinoppawan, Poole-Smith, McCardle and Chaorattanakawee.)

Although divergent dengue viruses (DENVs) have been isolated in insects, nonhuman primates, and humans, their relationships to the four canonical serotypes (DENV 1-4) are poorly understood. One virus isolated from a dengue patient, DKE-121, falls between genotype and serotype levels of sequence divergence to DENV-4. To examine its antigenic relationship to DENV-4, we assessed serum neutralizing and protective activity. Whereas DENV-4-immune mouse sera neutralize DKE-121 infection, DKE-121-immune sera inhibit DENV-4 less efficiently. Passive transfer of DENV-4 or DKE-121-immune sera protects mice against homologous, but not heterologous, DENV-4 or DKE-121 challenge. Antigenic cartography suggests that DENV-4 and DKE-121 are related but antigenically distinct. However, DENV-4 vaccination confers protection against DKE-121 in nonhuman primates, and serum from humans immunized with a tetravalent vaccine neutralize DENV-4 and DKE-121 infection equivalently. As divergent DENV strains, such as DKE-121, may meet criteria for serotype distinction, monitoring their capacity to impact dengue disease and vaccine efficacy appears warranted., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation and is on the scientific advisory boards of Moderna and Immunome. The Diamond Laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. The Vasilakis laboratory has received unrelated funding support in sponsored research agreements from Public Health Vaccines., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Salsalate is a prodrug of salicylate that lowers blood glucose in people with type 2 diabetes. AMP-activated protein kinase (AMPK) is an αβγ heterotrimer which inhibits macrophage inflammation and the synthesis of fatty acids and cholesterol in the liver through phosphorylation of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), respectively. Salicylate binds to and activates AMPKβ1-containing heterotrimers that are highly expressed in both macrophages and liver, but the potential importance of AMPK and ability of salsalate to reduce atherosclerosis have not been evaluated., Methods: ApoE -/- and LDLr -/- mice with or without (-/-) germline or bone marrow AMPKβ1, respectively, were treated with salsalate, and atherosclerotic plaque size was evaluated in serial sections of the aortic root. Studies examining the effects of salicylate on markers of inflammation, fatty acid and cholesterol synthesis and proliferation were conducted in bone marrow-derived macrophages (BMDMs) from wild-type mice or mice lacking AMPKβ1 or the key AMPK-inhibitory phosphorylation sites on ACC (ACC knock-in (KI)-ACC KI) or HMGCR (HMGCR-KI)., Results: Salsalate reduced atherosclerotic plaques in the aortic roots of ApoE -/- mice, but not ApoE -/- AMPKβ1 -/- mice. Similarly, salsalate reduced atherosclerosis in LDLr -/- mice receiving wild-type but not AMPKβ1 -/- bone marrow. Reductions in atherosclerosis by salsalate were associated with reduced macrophage proliferation, reduced plaque lipid content and reduced serum cholesterol. In BMDMs, this suppression of proliferation by salicylate required phosphorylation of HMGCR and the suppression of cholesterol synthesis., Conclusions: These data indicate that salsalate suppresses macrophage proliferation and atherosclerosis through an AMPKβ1-dependent pathway, which may involve HMGCR phosphorylation and cholesterol synthesis. Since rapidly-proliferating macrophages are a hallmark of atherosclerosis, these data indicate further evaluation of salsalate as a potential therapeutic agent for treating atherosclerotic cardiovascular disease., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

With the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here, we developed a panel of neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) that bound the receptor binding domain of the spike protein at distinct epitopes and blocked virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Although several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by ancestral SARS-CoV-2 strains, others induced escape variants in vivo or lost neutralizing activity against emerging strains. One mAb, SARS2-38, potently neutralized all tested SARS-CoV-2 variants of concern and protected mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engaged a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of neutralizing antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Some of the mAbs described in this study have been licensed by Washington University to Bio X Cell. D.H.F is a founder of Courier Therapeutics and has received funding support in a sponsored research agreement from Emergent BioSolutions. J.E.C. has served as a consultant for Eli Lilly and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is the founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from AstraZeneca and IDBiologics. The Boon laboratory has received funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences, AbbVie, and Nano Targeting & Therapy Biopharma., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic., (© 2021. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seropositivity was assessed for 3,066 individuals visiting hospitals in St. Louis, Missouri, during July 2020, November 2020, or January 2021. Seropositivity in children increased from 5.22% in July to 21.16% in January. In the same time frame, seropositivity among adults increased from 4.52% to 19.03%, prior to initiation of mass vaccination. IMPORTANCE This study determined the percentage of children and adult samples from the St. Louis metropolitan area in Missouri with SARS-CoV-2 antibodies during three collection periods spanning July 2020 to January 2021. By January 2021, 20.68% of the tested individuals had antibodies. These results show the evolution of the SARS-CoV-2 pandemic in St. Louis, Missouri, and provide a snapshot of the extent of infection just prior to the start of mass vaccination.

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-h noninvasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-yr period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm 2 ) and cervical motoneurons (soma size: 487 ± 189 µm 2 ) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1,363 ± 677 µm 2 ) and sacral motoneurons (soma size: 1,411 ± 633 µm 2 ) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle. NEW & NOTEWORTHY This case study offered a unique opportunity to investigate longitudinal changes in phrenic neurophysiology in an individual with severe, ventilator-dependent, late-onset Pompe disease. Additional diaphragm and neural tissue histology upon autopsy confirmed significant neuromuscular degeneration, and it provided novel insights regarding rostral to caudal variability in the neuropathology. These findings suggest that a successful treatment approach for ventilator-dependent Pompe disease should target the central nervous system, in addition to skeletal muscle.

Standards for the fatigue testing of wearable sensing technologies are lacking. The majority of published fatigue tests for wearable sensors are performed on proof-of-concept stretch sensors fabricated from a variety of materials. Due to their flexibility and stretchability, polymers are often used in the fabrication of wearable sensors. Other materials, including textiles, carbon nanotubes, graphene, and conductive metals or inks, may be used in conjunction with polymers to fabricate wearable sensors. Depending on the combination of the materials used, the fatigue behaviors of wearable sensors can vary. Additionally, fatigue testing methodologies for the sensors also vary, with most tests focusing only on the low-cycle fatigue (LCF) regime, and few sensors are cycled until failure or runout are achieved. Fatigue life predictions of wearable sensors are also lacking. These issues make direct comparisons of wearable sensors difficult. To facilitate direct comparisons of wearable sensors and to move proof-of-concept sensors from "bench to bedside", fatigue testing standards should be established. Further, both high-cycle fatigue (HCF) and failure data are needed to determine the appropriateness in the use, modification, development, and validation of fatigue life prediction models and to further the understanding of how cracks initiate and propagate in wearable sensing technologies.

Background: Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed., Methods: Using a multistage modified Delphi process, twenty global experts across nine countries developed consensus-based recommendations on how to dose and administer medical cannabis in patients with chronic pain., Results: There was consensus that medical cannabis may be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed. A routine protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg CBD twice daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. A conservative protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg once daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC. A rapid protocol where the clinician initiates the patient on a balanced THC:CBD variety at 2.5-5 mg of each cannabinoid once or twice daily and titrates by 2.5-5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day., Conclusions: In summary, using a modified Delphi process, expert consensus-based recommendations were developed on how to dose and administer medical cannabis for the treatment of patients with chronic pain.

Background: Recent approvals for novel agents such as the small molecule Janus kinase inhibitors (JAKi), combined with the advent of biosimilars has widened the gamut of available therapeutic options in the treatment of rheumatoid arthritis (RA). This combined with the introduction of mandatory non- medical switches to biosimilars in some jurisdictions by both public and private payors has led to a significant increase in the volume of therapeutic changes for patients. Pharmacists are well positioned to ensure effective and safe transitions, however there is a significant unmet need for objective and subjective clinical guidance around therapy as well disease state monitoring in RA that facilitates best practices throughout the patient journey., Objective: In this paper we aim to create a consensus derived monitoring algorithm for pharmacists to facilitate best practices throughout therapeutic transitions from originator biologic to other originator biologics, biosimilars, and Janus kinase inhibitors in RA., Methods: The Nominal Group Technique (NGT) was used to understand if consensus could be found among the participants. Clinically relevant questions were developed to capture solutions to the identified unmet need. The faculty considered the questions as individuals, and privately generated answers/ideas. After discussion and consideration, the participants ranked the ideas and established a consensus., Results: Based on the outcome of the consensus discussions, an algorithm was created to help guide pharmacists through therapeutic transitions in RA. The tool covers important topics such as pre-transition considerations, avoiding the nocebo effect for biosimilars, specific considerations for each drug or class, monitoring efficacy, and when to refer., Conclusions: New classes of anti-rheumatic drugs including JAKi, along with the introduction of biosimilars are presenting more opportunity for therapeutic changes and monitoring in patients with RA. We hope our evidence-based consensus derived guidance tool will assist frontline pharmacists in supporting their patients to a successful therapeutic transition in RA., Competing Interests: CONFLICT OF INTEREST JC is a consultant for Abbvie, Amgen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Roche, and UCB, and has received grant/research support from Abbvie, UCB, Novartis, and Pfizer. DC is a consultant and occasional speaker for Abbvie, Amgen, Celgene, Eli Lilly, Gilead, Milan, Novartis, Pfizer, Roche, Sandoz, Tevapharm and UCB. AS is has been a consultant and occasional speaker for Abbvie, Amgen, Aspen, Eli Lilly, Emergent, JNJ, Merck, Pfizer and Spectrum Therapeutics. GT has been a conferencier for Abbvie, AstraZeneca, Pfizer, Sandoz, and Sanofi. CW has been a consultant/advisor for UCB and Janssen and has received grants/honoraria from Amgen, AbbVie, Janssen, Merck, Pfizer, and UCB., (Copyright: © Pharmacy Practice.)

Objective: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a marked increase in hospital usage, medical resource scarcity, and rationing of surgical procedures. This has created the need for strategies to triage surgical patients. We have described our experience using the American College of Surgeons (ACS) COVID-19 guidelines for triage of vascular surgery patients in an academic surgery practice., Methods: We used the ACS guidelines as a framework to direct the triage of vascular surgery patients during the COVID-19 pandemic. We retrospectively analyzed the results of this triage during the first month of surgical restriction at our hospital. Patients undergoing surgery were identified by reviewing the operating room schedule. We reviewed the electronic medical records (EMRs) and assigned an ACS category, condition, and tier class to each completed surgery. Surgeries that were postponed during the same period were identified from a prospectively maintained list. We reviewed the EMRs for all postponed surgeries and assigned an ACS category, condition, and tier class to each surgery. We reviewed the EMRs for all postponed procedures to identify any adverse events related to the treatment delay., Results: We performed 69 surgeries in 52 patients during the study period. All surgeries were performed to treat emergent, urgent, or time-sensitive elective diagnoses. Of the 69 surgeries, 47 (68%) were from tier 3 and 22 (32%) from tier 2b. We did not perform any surgeries from tier 1 or 2a. We postponed surgery for 66 patients during the same period, of which 36 (55%) were from tier 1, 22 (33%) from tier 2a, 5 (8%) from tier 2b, and 3 (5%) could not be assigned a tier class. No tier 3 surgeries were postponed. Of the 66 patients, 3 (4.5%) experienced an adverse event that could be attributed to the treatment delay., Conclusions: The ACS triage guidelines provided an effective method to decrease vascular surgical volumes during the COVID-19 pandemic without an increase in patient morbidity. We believe the clinical utility of the guidelines would be strengthened by incorporating the SURGCON/VASCCON (surgical activity condition/vascular activity condition) threat level alert system., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Next generation sequencing (NGS) technology has been used for a wide range of epidemiological and surveillance studies. Here, we used amplicon-based NGS to species identify Rickettsia and their arthropod hosts from entomological surveillance., Methods: During 2015-2016, we screened 1825 samples of rodents and ectoparasites collected from rodents and domestic mammals (dog, cat, and cattle) across Thailand for Rickettsia . The citrate synthase gene was amplified to identify Rickettsia to species, while the Cytochrome Oxidase subunit I ( CO I) and subunit II ( CO II) genes were used as target genes for ectoparasite identification. All target gene amplicons were pooled for library preparation and sequenced with Illumina MiSeq platform., Result: The highest percentage of Rickettsia DNA was observed in fleas collected from domestic animals (56%) predominantly dogs. Only a few samples of ticks from domestic animals, rodent fleas, and rodent tissue were positive for Rickettisia DNA. NGS based characterization of Rickettsia by host identified Rickettsia asembonensis as the most common bacteria in positive fleas collected from dogs (83.2%) while " Candidatus Rickettsia senegalensis" was detected in only 16.8% of Rickettsia positive dog fleas. Sequence analysis of CO I and CO II revealed that almost all fleas collected from dogs were Ctenocephalides felis orientis . Other Rickettsia species were detected by NGS including Rickettsia heilongjiangensis from two Haemaphysalis hystricis ticks, and Rickettsia typhi in two rodent tissue samples., Conclusion: This study demonstrates the utility of NGS for high-throughput sequencing in the species characterization/identification of bacteria and ectoparasite for entomological surveillance of rickettsiae. A high percentage of C. f. orientis are positive for R. asembonensis . In addition, our findings indicate there is a risk of tick-borne Spotted Fever Group rickettsiosis, and flea-borne murine typhus transmission in Tak and Phangnga provinces of Thailand.

Reported coronavirus disease 2019 (COVID-19) case counts likely underestimate the true prevalence because mild or asymptomatic cases often go untested. Here, we use a sero-survey to estimate the seroprevalence of IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the St. Louis, MO, metropolitan area in a symptom-independent manner. Five hundred three adult and 555 pediatric serum/plasma samples were collected from patients presenting to Barnes-Jewish Hospital or St. Louis Children's Hospital between 14 April 2020 and 12 May 2020. We developed protocols for in-house enzyme-linked immunosorbent assays (ELISAs) using spike and nucleoprotein and used the assays to estimate a seroprevalence rate based on our samples. Overall IgG seropositivity was estimated to be 1.71% (95% credible interval [CI], 0.04% to 3.38%) in pediatric samples and 3.11% (95% CI, 0.92% to 5.32%) in adult samples. Seropositivity was significantly lower in children under 5 years of age than in adults, but rates between adults and children aged 5 or older were similar. Of the 176 samples tested from children under 4 years of age, none were positive. IMPORTANCE This study determined the percentages of both children and adult samples from the greater St. Louis metropolitan area who had antibodies to SARS-CoV-2 in late April to early May 2020. Approximately 1.7 to 3.1% of the tested individuals had antibodies, indicating that they had previously been infected by SARS-CoV-2. These results demonstrate that the extent of infection was about 10 times greater than the number of confirmed cases at that time. Furthermore, it demonstrated that by 5 years of age, children were infected to an extent similar to that of adults., (Copyright © 2021 Smith et al.)

Background: In-training examinations (ITEs) are intended for low-stakes, formative assessment of residents' knowledge, but are increasingly used for high-stake purposes, such as to predict board examination failures., Objective: The aim of this review was to investigate the relationship between performance on ITEs and board examination performance across medical specialties., Methods: A search of the literature for studies assessing the strength of the relationship between ITE and board examination performance from January 2000 to March 2019 was completed. Results were categorized based on the type of statistical analysis used to determine the relationship between ITE performance and board examination performance., Results: Of 1407 articles initially identified, 89 articles underwent full-text review, and 32 articles were included in this review. There was a moderate-strong relationship between ITE and board examination performance, and ITE scores significantly predict board examination scores for the majority of studies. Performing well on an ITE predicts a passing outcome for the board examination, but there is less evidence that performing poorly on an ITE will result in failing the associated specialty board examination., Conclusions: There is a moderate to strong correlation between ITE performance and subsequent performance on board examinations. That the predictive value for passing the board examination is stronger than the predictive value for failing calls into question the "common wisdom" that ITE scores can be used to identify "at risk" residents. The graduate medical education community should continue to exercise caution and restraint in using ITE scores for moderate to high-stakes decisions., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Introduction: Proper insulin injection technique has demonstrated positive clinical outcomes in patients with diabetes. A Canadian-based practice reflective was undertaken to evaluate the current state of understanding of injection technique practices by patients administering insulin, and the importance physicians place on proper injection technique., Methods: Twenty-four sites across Canada completed a practice profile survey and enrolled adult non-pregnant patients with either type 1 or type 2 diabetes injecting insulin using an insulin pen. Seven areas of proper injection technique to be evaluated were identified by the study steering committee: size of injection site, use of a skin lift, needle reuse, length of the needle, duration of the needle in the skin, injection into lipohypertrophic tissue, and applied injection force. During a scheduled visit, each patient filled out the Injection Technique Survey and the physician documented the answers via an electronic database., Results: Almost all physicians surveyed agreed (96%) that proper insulin injection technique is important or very important and 80% indicated they were either completely confident or fairly confident in discussing overall insulin injection technique. All patients surveyed were making at least one insulin injection technique error within the following categories: applied injection force (76%), area size of injection site (64%), duration of pen needle in skin (61%), pen needle reuse (39%), performs a skin lift with a 4 or 5 mm needle (38%), uses a longer pen needle than required (34%), and injection of insulin into lipohypertrophic tissue (37%)., Conclusion: Patients commonly make insulin injection errors. Patient and physician education on optimal insulin injection technique continues to be an unmet medical need for the treatment of patients with diabetes. Prospective trials examining the impact of new technology, diabetes educational teams, and e-learning as educational interventions are potential avenues to explore in future studies to support improved insulin injection technique.

The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread., Competing Interests: Declaration of Interests M.S.D. is a consultant for Inbios, Vir Biotechnology, and NGM Biopharmaceuticals and on the Scientific Advisory Board of Moderna. The Diamond laboratory has received unrelated funding support from Moderna, Vir Biotechnology, and Emergent BioSolutions. M.S.D., D.T.C., A.O.H., and I.P.D. have filed a disclosure with Washington University for possible development of ChAd-SARS-CoV-2. M.J.H. is a member of the DSMB for AstraZeneca and founder of NuPeak Therapeutics. The Baric laboratory has received unrelated funding support from Takeda, Pfizer, and Eli Lilly., (Copyright © 2020 Elsevier Inc. All rights reserved.)