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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.)

The use of a robotic surgical platform has become common place in thoracic surgery programs throughout the United States. Formal training paradigms need to be reevaluated to allow for effective and efficient training of thoracic surgery residents and fellows. The utilization of video-based coaching and simulation are effective adjuncts in robotics training., Competing Interests: Disclosure B. Mitzman—Proctor, Intuitive Surgical., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Program directors in surgical disciplines need more tools from the ACGME to help them use Milestone ratings to improve trainees' performance. This is especially true in competencies that are notoriously difficult to measure, such as professionalism (PROF) and interpersonal and communication skills (ICS). It is now widely understood that skills in these two areas have direct impact on patient care outcomes. This study investigated the potential for generating early predictors of final Milestone ratings within the PROF and ICS competency categories., Design: This retrospective cohort study utilized Milestone ratings from all ACGME-accredited vascular surgery training programs, covering residents and fellows who completed training in June 2019. The outcome measure studied was the rate of achieving the recommended graduation target of Milestone Level 4 (possible range: 1-5), while the predictors were the Milestone ratings attained at earlier stages of training. Predictive probability values (PPVs) were calculated for each of the 3 PROF and two ICS sub-competencies to estimate the probability of trainees not reaching the recommended graduation target based on their previous Milestone ratings., Setting: All ACGME-accredited vascular surgery training programs within the United States., Participants: All trainees completing a 2 year vascular surgery fellowship (VSF) in June 2019 (n = 119) or a 5 year integrated vascular surgery residency (IVSR) in June 2019 (n = 52) were included in the analyses., Results: The overall rate of failing to achieve the recommended graduation target across all PROF and ICS sub-competencies ranged from 7.7% to 21.8% of all trainees. For trainees with a Milestone rating at ≤ 2.5 with 1 year remaining in their training program, the predictive probability of not achieving the recommended graduation target ranged from 37.0% to 71.5% across sub-competencies, with the highest risks observed under PROF for "Administrative Tasks" (71.5%) and under ICS for "Communication with the Healthcare Team" (56.7%)., Conclusions: As many as 1 in 4 vascular surgery trainees did not achieve the ACGME vascular surgery Milestones targets for graduation in at least one of the PROF and ICS sub-competencies. Biannual ACGME Milestone assessment ratings of PROF and ICS during early training can be used to predict achievement of competency targets at time of graduation. Early clues to problems in PROF and ICS enable programs to address potential deficits early in training to ensure competency in these essential non-technical skills prior to entering unsupervised practice., (Copyright © 2022 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Dr L.M.F. received effort support from the American College of Surgeons George H. A. Clowes, Jr., MD, FACS, Memorial Research Career Development Award. The remaining authors report no conflicts of interest.

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.

Background: Sleep disordered breathing (SDB) is common in patients with neuromuscular diseases, including spinal muscular atrophy (SMA). While polysomnography (PSG) findings have been described in natural history studies of patients with SMA, reports regarding PSG in treated children are limited to nusinersen. We aim to describe the sleep characteristics in a cohort of children treated with Onasemnogene-abeparvovec., Methods: We conducted a cross-sectional cohort study of children with SMA followed at the University of Florida Center for neuromuscular and rare diseases and had a diagnostic or split night PSG after SMA treatment., Results: Eight children were included in the cohort (four female), aged 5-250 days at diagnosis. Five children had two survival motor neuron 2 (SMN2) copies, two had three SMN2 copies and one subject had four SMN2 copies. Median age at the time of treatment was 46.5 days (range 20-257). All children received onasemnogene-abeparvovec (OA) before their PSG; in addition to OA, one received nusinersen and one received risdiplam. Apnea hypopnea index (AHI) ranged from 3.6 to 24.1/h. REM AHI was higher than NREM AHI. Median Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP-Intend) score at the time of PSG was 55 (range 33-64). There was no correlation between age at treatment, CHOP-Intend score and AHI., Conclusion: SDB is common in treated children with SMA, regardless of age at diagnosis, treatment and neuromotor scores. While AHI may not be the only indicator of SDB in this population, indications, timing of PSG in this cohort remain unknown., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: This study aims to evaluate whether graduates of integrated vascular surgery residency (IVSR) programs achieve similar surgical outcomes in clinical practice as compared to graduates of vascular surgery fellowships (VSF)., Summary of Background Data: Early sub-specialization through IVSR programs decreases the total years of surgical training. However, it is unclear whether IVSR graduates achieve comparable outcomes to fellowship-trained surgeons once in clinical practice., Methods: We identified all vascular surgeons who finished IVSR and VSF programs between 2013-2017 using American Board of Surgery data, which was linked to the Vascular Quality Initiative registry (2013-2019) to evaluate provider-specific clinical outcomes following carotid, lower extremity, and aortic aneurysm repair procedures. The association between training models and the composite outcome of 1-year mortality, major adverse cardiac events and/or other major complications were analyzed using mixed-effects logistic regression models., Results: A total of 338 surgeons (31% IVSR, 69% VSF) submitted cases into the Vascular Quality Initiative registry, including 8155 carotid, 21,428 lower extremity, and 5800 aortic aneurysm repair procedures. Composite 1-year outcome rates were comparable between IVSR and VSF-trained surgeons following carotid endarterectomy (8%-IVSR vs 7%-VSF), lower extremity revascularization (19%-IVSR vs 16%-VSF), and aortic aneurysm repair (13%-IVSR vs 13%-VSF) procedures. These findings among IVSR-trained surgeons persisted following risk adjustment for severity of patient disease and indications for undertaking carotid [aOR: 1.04 (0.84-1.28)], lower extremity [aOR: 1.03 (0.84-1.26)], and aortic [aOR: 0.96 (0.76-1.21)] procedures when compared to VSF-trained surgeons., Conclusions: Despite fewer total years of training, graduates of IVSR programs achieve equivalent surgical outcomes as fellowship-trained vascular surgeons once in practice. These results suggest that concerns about differential competence among integrated residency graduates are not warranted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Patients living with Amyotrophic Lateral Sclerosis (ALS) experience respiratory weakness and, eventually, failure due to inspiratory motor neuron degeneration. Routine pulmonary function tests (e.g., maximum inspiratory pressure (MIP)) are used to assess disease progression and ventilatory compromise. However, these tests are poor discriminators between respiratory drive and voluntary respiratory function at rest. To better understand ALS disease progression, we can look into compensatory strategies and how patients consciously react to the occlusion and the effort produced to meet the ventilatory challenge of the occlusion. This ventilatory challenge, especially beyond the P 0.1 (200 ms and 300 ms), provides information regarding the patient's ability to recruit additional respiratory muscles as a compensatory strategy. Utilizing a standard P 0.1 protocol to assess respiratory drive, we extend the occlusion time analysis to 200 ms and 300 ms (Detected Occlusion Response (DOR)) in order to capture compensatory respiratory mechanics. Furthermore, we followed an Acute Intermittent Hypoxia (AIH) protocol known to increase phrenic nerve discharge to evaluate the compensatory strategies. Inspiratory pressure, the rate of change in pressure, and pressure generation normalized to MIP were measured at 100 ms, 200 ms, and 300 ms after an occlusion. Airway occlusions were performed three times during the experiment (i.e., baseline, 30 and 60 minutes post-AIH). Results indicated that while AIH did not elicit change in the P 0.1 or MIP, the DOR increased for ALS patients. These results support the expected therapeutic role of AIH and indicate the potential of the DOR as a metric to detect compensatory changes., (Copyright © 2022. Published by Elsevier B.V.)

Background: It is unclear whether shortened training of integrated vascular surgery residencies (IVSR) has detrimental effects on graduates' performance. We sought to investigate whether there is a difference in frail patient outcomes based on the training paradigm completed by their surgeon., Methods: IVSR and vascular surgery fellowship (VSF)-trained surgeons were identified in the American Board of Surgery database and linked to the Vascular Quality Initiative registry (2013-2019) to evaluate provider-specific patient outcomes for frail patients following vascular procedures using mixed-effects logistic regression., Results: 105 IVSR graduates (31%) and 233 VSF graduates (69%) were included. Composite 1-year outcomes of frail patients were comparable between IVSR and VSF-trained surgeons following carotid endarterectomy (16%-IVSR vs 25%-VSF; p = 0.76), lower extremity revascularization (37%-IVSR vs 36%-VSF; p = 0.83), and aortic aneurysm repair (25%-IVSR vs 23%-VSF; p = 0.89)., Conclusions: The type of training paradigm completed by vascular surgeons was not associated with differences in their post-operative outcomes in frail patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Psychological safety is known to improve team performance and organizational learning. The related concept of "educational safety" has recently emerged to describe an environment in which learners can unreservedly focus on learning and professional growth, without worrying about the potential repercussions of interpersonal risk-taking. Educational safety is crucial for optimal learning in clinical environments, and yet is difficult to establish due to constant performance assessment, fear of failure, and pervasive hierarchies. In this perspective, we propose a framework for conceptualizing educational safety in surgical learning environments, and explore current threats to educational safety. We also discuss strategies for combating these threats, as well as the importance of further research to evaluate the impact of educational safety on surgical learning outcomes., (Published by Elsevier Inc.)

The epidemiological profile of rabies virus within Mongolia remains poorly characterized despite 21,302 domestic animal cases being reported between 1970-2005. This lack of knowledge is particularly concerning given that roughly 26% of the population lives a pastoral herding lifestyle and livestock production contributes up to 18% of Mongolia's total gross domestic product (GDP). The gaps in knowledge of the rabies disease ecology within Mongolia combined with the lack of routine vaccination of domestic animals and wildlife poses a significant threat to the more than 60 million heads of livestock within Mongolia. Animal rabies case data from the General Authority for Veterinary Services and National Center for Zoonotic Diseases were used in this study. Each data point included year of report, an animal descriptor, geographic coordinates and the aimag (province) of origin. A total of 2,359 animal rabies cases were reported between 2012-2018. Cattle were the most commonly reported animal overall (861 cases), followed by goats (268), sheep (251) and dogs (221) within the domestic animal category. Red foxes were responsible for most reported wildlife cases (317) followed by wolves (151). Most rabid animals were reported in the Khuvsgul, Uvurkhangai and Govi-Altai aimags, and a positive correlation was found between livestock numbers per soum and the number of rabies cases reported. Rabies poses a significant threat to the Mongolian economy and the health of human and animal populations within Mongolia. The close association of the nomadic pastoralists with both domestic animals and wildlife represents a significant threat for disease emergence and necessitates studies that describe the ecology of rabies, which may threaten these populations., (© 2022 The Authors. Zoonoses and Public Health published by Wiley-VCH GmbH.)

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.)

Background: Vascular surgery is facing an impending workforce shortage as the population ages and the demand for vascular surgical services increases. The integrated vascular surgery residency (0+5) paradigm is well-established and provides a mechanism to increase the number of board-certified vascular surgeons. Recruitment of medical students to these programs has proven challenging with unfilled positions in each of the past 2 years. The aim of this study is to explore factors that influence medical students' interest in vascular surgery and their decision to ultimately pursue a career in the field., Methods: Medical students listed on the Society for Vascular Surgery "Find a VSIG (Vascular Surgery Interest Group)" webpage were contacted via email to participate in the study. A snowball sampling technique was employed to recruit additional participants, including recent medical school graduates who had matched into a 0+5 program. Fifteen students participated in 5 focus groups. Directed content analysis was employed to qualitatively analyze focus group transcripts., Results: Five domains were identified as influencing students' decision to pursue vascular surgery. Experiential learning facilitated early exploration of the field. The intellectuality of the specialty was a feature that attracted students to vascular surgery. In addition, the professional identify of vascular surgeons as comprehensive care providers was appealing. Students identified with their mentors' relationships as observed during clinical encounters. Long-term mentorship was important in sustaining students' interest., Conclusion: Medical students pursue a career in vascular surgery based on early exposure to the specialty, experiential learning through hands-on VSIG events, clinical experiences, and longitudinal faculty mentorship. The unique aspects of the specialty, including professional identity and intellectuality, should be highlighted to both attract and maintain students' interest in the field. These findings can be used by national vascular surgery leaders, practicing vascular surgeons, and faculty and student leadership of VSIGs to optimize recruitment programs and increase the vascular surgery workforce., (Copyright © 2021. Published by Elsevier Inc.)

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.)

Background: Transitioning from trainee to attending surgeon requires learners to become educators. The purpose of this study is to evaluate educational strategies utilized by surgeons, define gaps in preparation for operative teaching, and identify opportunities to support this transition., Methods: A web-based, Association of Surgical Education approved survey was distributed to attending surgeons., Results: There were 153 respondents. Narrating actions was the most frequently reported educational model, utilized by 74% of junior faculty [JF] (0-5yrs) and 63% of senior faculty [SF] (>6yrs). Other models used included educational time-outs (29% JF, 27% SF), BID teaching model (36% JF, 51% SF), and Zwisch model (13% JF, 25% SF). Compared with 91% JF, 65% SF reported struggling with instruction (p < 0.001). Five themes emerged as presenting difficulty during the resident to attending transition: lack of relationships, ongoing learning, systems-based, cognitive load, impression management., Conclusions: Our results represent a needs assessment in the transition from learner to educator in the OR., (Published by Elsevier Inc.)

There are eight Anopheles spp. present in the Republic of Korea (ROK), including five members of the Anopheles Hyrcanus Group that cannot be identified using current morphological methods. The vector competence of only Anopheles sinensis s.s., An. lesteri, and An. kleini have been investigated. As the geographical distribution of Anopheles spp. varies in the ROK, determining the relative vector competence of the Anopheles spp. provides a basis for delineating malaria risks to Korean populations and U.S. military/civilian populations deployed to the ROK. Anopheles belenrae and An. pullus, collected from a malaria high-risk area in the ROK, were evaluated for vector competence of P. vivax. A total of 1,000 each of An. dirus (Thai strain), and Korean strains of An. pullus and An. belenrae were fed on P. vivax infected blood collected from Thai patients via artificial membrane feeding. The overall oocyst infection rates for An. dirus, An. pullus, and An. belenrae dissected on days 8-9 postfeed were 64.1, 12.0, and 11.6%, respectively. The overall sporozoite infection rates for those species dissected on days 14-15 postfeed were 84.5, 3.4, and 5.1% respectively. The salivary gland sporozoite indices for positive females with +4 (>1,000 sporozoites) were observed in An. dirus (72.8%), but not observed for either An. pullus or An. belenrae. Most sporozoite-positive An. pullus (83.3%) and An. belenrae (71.4%) females were observed with only +1 (1-10 sporozoites) salivary glands. These data indicate that both An. belenrae and An. pullus are very poor vectors of P. vivax., (Published by Oxford University Press on behalf of Entomological Society of America 2022.)

Objective: To assess the current barriers in robotic surgery training for general surgery residents., Design: Multi-institutional web-based survey., Setting: 9 academic medical centers with a general surgery residency., Participants: General surgery residents of at least PGY-3 training level., Results: 163 general surgery residents were contacted with 80 responses (49.1%). The most common responders were PGY-3s (38.8%) followed by PGY-5s (27.5%). The Northeast represented 42.5% of responses. Colorectal cases were the most common robotic case residents were involved in (51.3%). Residents' typical roles were assisting at the bedside (31.3%) and splitting time between assisting at the bedside and operating at the surgeon console (31.3%). 43% report to be either extremely or somewhat dissatisfied with their robotic surgery experience. 62.5% report they do not intend to integrate robotic surgery into their future practice. 93.8% of residents have a standardized robotic curriculum. 47.5% report using the simulator only during required didactic time with 52.5% having the robotic simulator conveniently located. The majority of residents report that the presence of dual consoles and first-assists in robotic cases enhance their robotic training (93% - 62%, respectively). 72.5% felt like they had more autonomy during laparoscopic cases and 96.8% of residents felt that an attendings' lack of experience impacted their time operating at the surgeon console., Conclusions: General surgery residents report lack of effective OR teaching, real clinical experience, and simulated experience as main barriers in their robotic surgery training. Dual consoles and first-assistants are favorably looked upon. Lack of attending experience and comfort were universally negatively associated with resident participation. For residents interested in robotic surgery, advocating for more robust investment in dual consoles, first-assistants, and faculty development would likely improve their robotic surgery training experience. However, residency programs should consider whether robotic surgery should be a core competency of an already time restricted training paradigm., (Copyright © 2021 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: The mouthpiece is the standard interface for spirometry tests. Although the use of a mouthpiece can be challenging for patients with orofacial weakness, maintaining a proper seal with a facemask can be an issue for healthy individuals during forceful efforts. We compared respiratory muscle activity and tests using a mouthpiece and facemask in healthy adults to investigate whether they can be used interchangeably., Methods: In this observational study, subjects (n=12) completed forced vital capacity, maximal respiratory pressure, and peak cough flow with a mouthpiece and facemask. Root mean square values of the genioglossus, diaphragm, scalene, and sternocleidomastoid were compared between conditions., Results: When switching from a mouthpiece to a facemask, significantly higher values were seen for peak cough flow (average bias= -54.36 L/min, p<0.05) and the difference seen with MEP and MIP were clinically significant (average bias: MEP=27.33, MIP=-5.2). Additionally, submental activity was significantly greater when MIP was conducted with a mouthpiece. No significant differences were seen in respiratory muscle activity during resting breathing or spirometry., Conclusion: There are clinically significant differences with cough and MEP tests and neck muscles are activated differently based on interface. Considering the small sample size, our findings suggest a facemask may be used to complete some PFTs., Competing Interests: Disclosures: All authors have no conflict of interest

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.)

The primary purpose of this study was to determine prevalence of the Male Athlete Triad (MAT) conditions: low energy availability (EA), low bone mineral density (BMD), and low testosterone in male collegiate athletes from different sports. Participants included 44 collegiate male athletes (age, 20.4 ± 0.2 years; body mass index, 25.3 ± 1.3 kg/m 2 ) from 7 sports (cross country, soccer, basketball, wrestling, track, golf, and baseball). Resting metabolic rate, 3-day food intake, 7-day exercise energy expenditure, body composition, and reproductive and metabolic hormones were assessed. Of the total participants, 15% had low EA, 0% had low BMD, 28% had low total testosterone (TT), and 80% had low calculated free testosterone (cFT). There were no significant correlations between EA, BMD, TT, and cFT. Insulin and sex hormone binding globulin (SHBG) were below and on the upper end of the reference range for healthy male adults, respectively. Insulin was negatively correlated with total ( r = -0.330, p  = 0.043) and lumbar spine BMD z-scores ( r = -0.413, p  = 0.010). Low TT and low cFT were the most prevalent MAT conditions among all athletes. Further research should investigate the relationship between insulin and SHBG and the role of these hormones in the MAT. Novelty: Assessment of energy availability alone is not sufficient to identify physiological disturbances in collegiate male athletes. Low total and/or free testosterone may be present in some collegiate male athletes, regardless of BMD status. Low insulin and high SHBG concentration may portray the presence of conditions of the MAT in male collegiate athletes.

Background: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF)., Research Question: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function?, Study Design and Methods: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI., Results: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H 2 O and peak cough flows < 270 L/min., Interpretation: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death., Objective: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study., Methods: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed., Results: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort., Conclusions: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

This review focuses on the interview and match process with the purpose of broadly reviewing challenges in the current surgical residency selection process, detailing potential solutions, and identifying future avenues of investigation., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s), under exclusive licence to Association for Surgical Education 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O 2 , 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Surgical faculty and residents are responsible for the clinical education of medical students during their core surgical clerkship, sub-internships, and clinical electives. Much attention has been paid to faculty development in teaching, as well as residents-as-teachers programs, to enhance student learning in the surgical environment. This focus to "train the trainers" has not addressed what medical students can do to take ownership of and improve their own learning, as partners in educational interactions. The purpose of this exploratory study was to investigate how medical students' attitudes and actions can enhance clinical teaching interactions during surgical rotations., Methods: Previously collected data from a multiple case study that explored the learning environment at a single academic medical center was analyzed to understand the roles that students play in their learning. The data includes transcriptions from semi-structured interviews with four 4th year mediacl students, three general surgery residents, and four surgery attendings, and focus groups with two sets of 3rd year medical students. Two authors employed thematic analysis to code the data., Results: Findings were organized into five themes: eagerness, humility, confidence, team player, and adaptability. Each attitudinal theme was associated with specific actions that students adopted to encourage teaching behaviors from resident and faculty surgeons during their surgery rotations. Participants discussed the importance of students "seek[ing] out opportunities" for learning (eagerness) and being "willing to be wrong" (humility). Student expressions of confidence in their knowledge and skills were marked by following "steps that I know," which signaled to teachers that they could be entrusted to participate in patient care. Students categorized as team players "follow[ed] up on information without specifically being told." Finally, students categorized as adaptable responded to "immediate feedback" by making "adjustments.", Conclusions: Medical students are important stakeholders and contributors to teaching interactions and are likely to impact their own learning experience through the adoption of key attitudes and associated actions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.)

Objectives: The COVID-19 pandemic resulted in the cancellation of in-person testing across the country. We sought to understand the feasibility of conducting virtual oral examinations as well as solicit opinions of vascular surgery program directors (PD) regarding the use of virtual platforms to conduct both low stakes mock oral examinations with their trainees and potentially "real" high stakes certifying examinations (CE) moving forward., Methods: Forty-four senior vascular surgery trainees from 17 institutions took part in a virtual mock oral examination conducted by 38 practicing vascular surgeons via Zoom. Each examination lasted 30 minutes with four clinical scenarios. An anonymous survey pertaining to the conduct of the examination and opinions on feasibility of using virtual examinations for the vascular surgery CE was sent to all examiners and examinees. A similar survey was sent to all vascular surgery program directors., Results: The overall pass rate was 82% (36/44 participants) with no correlation with training paradigm. 32/44 (73%) of trainees, 29/38 (76%) of examiners and 49/103 (48%) of PDs completed the surveys. Examinees and examiners thought the experience was beneficial and PDs also thought the experience would be beneficial for their trainees. While the majority of trainees and examiners believed they were able to communicate and express (or evaluate) knowledge and confidence as easily virtually as in person, PDs were less likely to agree confidence could be assessed virtually. The majority of respondents thought the CE of the Vascular Surgery Board of the American Board of Surgery could be offered virtually, although no groups thought virtual exams were superior to in person exams. While cost benefit was perceived in virtual examinations, the security of the examination was a concern., Conclusions: Performing virtual mock oral examinations for vascular surgery trainees is feasible. Both vascular surgery trainees as well as PDs feel that virtual CEs should be considered by the Vascular Surgery Board., Competing Interests: Conflict of Interests The authors have no competing interests to declare, (Copyright © 2021. Published by Elsevier Inc.)

Background: Surgeons provide patient care in complex health care systems and must be able to participate in improving both personal performance and the performance of the system. The Accreditation Council for Graduate Medical Education (ACGME) Vascular Surgery Milestones are utilized to assess vascular surgery fellows' (VSF) achievement of graduation targets in the competencies of Systems Based Practice (SBP) and Practice Based Learning and Improvement (PBLI). We investigate the predictive value of semiannual milestones ratings for final achievement within these competencies at the time of graduation., Methods: National ACGME milestones data were utilized for analysis. All trainees entering the 2-year vascular surgery fellowship programs in July 2016 were included in the analysis (n = 122). Predictive probability values (PPVs) were obtained for each SBP and PBLI sub-competencies by biannual review periods, to estimate the probability of VSFs not reaching the recommended graduation target based on their previous milestones ratings., Results: The rate of nonachievement of the graduation target level 4.0 on the SBP and PBLI sub-competencies at the time of graduation for VSFs was 13.1-25.4%. At the first time point of assessment, 6 months into the fellowship program, the PPV of the SBP and PBLI milestones for nonachievement of level 4.0 upon graduation ranged from 16.3-60.2%. Six months prior to graduation, the PPVs across the 6 sub-competencies ranged from 14.6-82.9%., Conclusions: A significant percentage of VSFs do not achieve the ACGME Vascular Surgery Milestone targets for graduation in the competencies of SBP and PBLI, suggesting a need to improve curricula and assessment strategies in these domains across vascular surgery fellowship programs. Reported milestones levels across all time point are predictive of ultimate achievement upon graduation and should be utilized to provide targeted feedback and individualized learning plans to ensure graduates are prepared to engage in personal and health care system improvement once in unsupervised practice., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Value is defined as health outcomes important to patients relative to cost of achieving those outcomes: Value = Quality/Cost. For inguinal hernia repair, Level 1 evidence shows no differences in long-term functional status or recurrence rates when comparing surgical approaches. Differences in value reside within differences in cost. The aim of this study is to compare the value of different surgical approaches to inguinal hernia repair: Open (Open-IH), Laparoscopic (Lap-IH), and Robotic (R-TAPP)., Methods: Variable and fixed hospital costs were compared among consecutive Open-IH, Lap-IH, and R-TAPP repairs (100 each) performed in a university hospital. Variable costs (VC) including direct materials, labor, and variable overhead ($/min operating room [OR] time) were evaluated using Value Driven Outcomes, an internal activity-based costing methodology. Variable and fixed costs were allocated using full absorption costing to evaluate the impact of surgical approach on value. As cost data is proprietary, differences in cost were normalized to Open-IH cost., Results: Compared to Open-IH, VC for Lap-IH were 1.02X higher (including a 0.81X reduction in cost for operating room [OR] time). For R-TAPP, VC were 2.11X higher (including 1.36X increased costs for OR time). With allocation of fixed cost, a Lap-IH was 1.03X more costly, whereas R-TAPP was 3.18X more costly than Open-IH. Using equivalent recurrence as the quality metric in the value equation, Lap-IH decreases value by 3% and R-TAPP by 69% compared to Open-IH., Conclusions: Use of higher cost technology to repair inguinal hernias reduces value. Incremental health benefits must be realized to justify increased costs. We expect payors and patients will incorporate value into payment decisions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, 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.

Aims: Opioid misuse and overuse have contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids., Results: In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid-related complications, despite psychological or physical interventions. There was consensus observed to initiate with a cannabidiol (CBD)-predominant oral extract in the daytime and consider adding tetrahydrocannabinol (THC). When adding THC, start with 0.5-3 mg, and increase by 1-2 mg once or twice weekly up to 30-40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as-needed medication to control pain and/or the cannabis dose has been optimised. The opioid tapering schedule may be 5%-10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥30% reduction in pain intensity, a ≥25% reduction in opioid dose, a reduction in opioid dose to <90 mg MED and/or reduction in opioid-related adverse events., Conclusions: This five-stage modified Delphi process led to the development of consensus-based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids., (© 2020 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

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.)

Purpose: Perioperative hyperglycemia is common and is associated with significant morbidity. Although patient characteristics and surgery influence perioperative glucose metabolism, anesthetics have a significant impact. We hypothesized that mice that were obese and insulin-resistant would experience greater hyperglycemia in response to sevoflurane anesthesia compared with lean controls. We further hypothesized that sevoflurane-induced hyperglycemia would be attenuated by salsalate pre-treatment., Methods: Lean and obese male C57BL/6J mice were anesthetized with sevoflurane for 60 min with or without pre-treatment of 62.5 mg·kg -1 salsalate. Blood glucose, plasma insulin, and glucose uptake into different tissues were measured., Results: Under sevoflurane anesthesia, obese mice had higher blood glucose compared to lean mice. Increases in blood glucose were attenuated with acute salsalate pre-treatment at 60 min under anesthesia in obese mice (mean ± standard error of the mean [SEM], delta blood glucose; vehicle 5.79 ± 1.09 vs salsalate 1.91 ± 1.32 mM; P = 0.04) but did not reach statistical significance in lean mice (delta blood glucose, vehicle 4.39 ± 0.55 vs salsalate 2.79 ± 0.71 mM; P = 0.10). This effect was independent of changes in insulin but associated with an approx. 1.7-fold increase in glucose uptake into brown adipose tissue (vehicle 45.28 ± 4.57 vs salsalate 76.89 ± 12.23 µmol·g -1 tissue·hr -1 ; P < 0.001)., Conclusion: These data show that salsalate can reduce sevoflurane-induced hyperglycemia in mice. This indicates that salsalate may represent a new class of therapeutics that, in addition to its anti-inflammatory and analgesic properties, may be useful to reduce perioperative hyperglycemia.