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Aim: Physical exercise triggers the secretion of small extracellular vesicles (sEVs) into the circulation in humans, enabling signalling crosstalk between tissues. Exercise‐derived EVs and their cargo have been proposed to mediate adaptations to exercise; however, our understanding of how exercise‐derived EV protein cargo is modulated by factors such as aerobic fitness and age of an individual is currently unknown. Here, we examined the circulating sEV proteome following aerobic exercise in healthy males of different ages and aerobic fitness to understand exercise‐induced EV response during the aging process. Methods: Twenty‐eight healthy men completed a bout of 20‐min cycling exercise at 70% estimated VO2peak. Small EVs were isolated from blood samples collected before and immediately after exercise, and then quantified using particle analysis and Western blotting. Small EV proteome was examined using quantitative proteomic analysis. Results: We identified a significant increase in 13 proteins in small plasma EVs following moderate‐to‐vigorous intensity exercise. We observed distinct changes in sEV proteome after exercise in young, mature, unfit, and fit individuals, highlighting the impact of aerobic fitness and age on sEV protein secretion. Functional enrichment and pathway analysis identified that the majority of the significantly altered sEV proteins are associated with the innate immune system, including proteins known to be damage‐associated molecular patterns (DAMPs). Conclusion: Together, our findings suggest that exercise‐evoked acute stress can positively challenge the innate immune system through the release of signalling molecules such as DAMPs in sEVs, proposing a novel EV‐based mechanism for moderate‐to‐vigorous intensity exercise in immune surveillance pathways. [ABSTRACT FROM AUTHOR]

Aging is associated with a loss of metabolic homeostasis, with cofactors such as nicotinamide adenine dinucleotide (NAD+) declining over time. The decrease in NAD+ production has been linked to the age‐related loss of circulating extracellular nicotinamide phosphoribosyltransferase (eNAMPT), the rate‐limiting enzyme in the NAD+ biosynthetic pathway. eNAMPT is found almost exclusively in extracellular vesicles (EVs), providing a mechanism for the distribution of the enzyme in different tissues. Currently, the physiological cause for the release of eNAMPT is unknown, and how it may be affected by age and physical exercise. Here, we show that release of small EVs into the bloodstream is stimulated following moderate intensity exercise in humans. Exercise also increased the eNAMPT content in EVs, most prominently in young individuals with higher aerobic fitness. Both mature fit and young unfit individuals exhibited a limited increase in EV‐eNAMPT release following exercise, indicating that this mechanism is related to both the age and physical fitness of a person. Notably, unfit mature individuals were unable to increase the release of eNAMPT in EVs after exercise, suggesting that lower fitness levels and aging attenuate this important signalling mechanism in the body. EVs isolated from exercising humans containing eNAMPT were able to alter the abundance of NAD+ and SIRT1 activity in recipient cells compared to pre‐exercise EVs, indicating a pathway for inter‐tissue signalling promoted through exercise. Our results suggest a mechanism to limit age‐related NAD+ decline, through the systemic delivery of eNAMPT via EVs released during exercise. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that the magnitude of changes in indirect muscle damage markers would be greater after maximal elbow flexor eccentric exercise in the supinated (shorter biceps brachii) than neutral wrist (longer) position, and the difference in the magnitude would be associated with greater elongation over contractions for the supinated than neutral position, rather than the initial muscle length. Ten untrained men (21‐39 years) performed two bouts of 10 sets of 6 maximal isokinetic eccentric contractions of the elbow flexors in the supinated position for one arm and neutral position for the other arm separated by 2 weeks in a randomized order. Biceps brachii myotendinous junction (MTJ) movements during eccentric contractions were recorded by B‐mode ultrasonography, and the displacement from the start to end of each contraction was quantified. Peak torque (supinated: 367.8 ± 112.5 Nm, neutral: 381.5 ± 120.4 Nm) and total work (1816 ± 539 J, 1865 ± 673 J) produced during eccentric contractions were similar between conditions. The average MTJ displacement increased (P <.05) from the 1st set (8.0 ± 2.0 mm) to 10th set (15.8 ± 1.9 mm) for the supinated condition, but no such increase was found in the neutral condition (1st set: 5.1 ± 1.0 mm, 10th set: 5.0 ± 0.8 mm). Changes in indirect muscle damage markers (maximal voluntary isometric contraction torque, range of motion, serum creatine kinase activity, and muscle soreness) after exercise were greater (P <.05) for the supinated than neutral condition. These results suggest that the greater muscle damage marker changes for the supinated than neutral wrist position was associated with the greater muscle lengthening (strain). [ABSTRACT FROM AUTHOR]

Background: Expression of programmed death ligand 1 (PD‐L1) by cutaneous squamous cell carcinomas has been shown to correlate with advanced disease and risk of metastasis. Lymphocyte activation gene 3 (LAG‐3, or CD223) is an inhibitory receptor that interacts with the PD‐L1 axis, which has been shown to be a marker of immune exhaustion and a potential immunotherapy target. However, the role of LAG‐3 in cutaneous squamous cell carcinoma has not been established. Methods: We reviewed 18 cases of locally advanced and/or metastatic cutaneous squamous cell carcinomas and assessed for PD‐L1 expression, presence or absence of tumor‐infiltrating lymphocytes (TILs), and expression of LAG‐3 by TILs. Results: PD‐L1 expression was present in 11 of 13 locally advanced primary tumors and 5 of 5 metastases. TILs were present in all 18 tumors, of which 14 cases were positive for LAG‐3 expression. In positive cases, LAG‐3 was expressed on average by 32% of TILs. Conclusions: Advanced cutaneous squamous cell carcinomas frequently express PD‐L1 and are associated with an inflammatory response. LAG‐3 expression by TILs was identified in a majority of cases. Our findings suggest that LAG‐3 positive tumor‐associated inflammatory cells may play a role in the development of advanced disease and offer another potential target for drug therapy. [ABSTRACT FROM AUTHOR]

Diagnosis: Branchio-oculo-facial syndrome (BOFS) Clinical course and dermatopathology Cytogenetic testing revealed a normal female karyotype. Both BOR and BOFS can present with hearing loss, renal anomalies, and nasolacrimal stenosis, but BOFS can be distinguished by its characteristic facial abnormalities and skin lesions.1 CHARGE syndrome may also be considered, but it can be associated with cardiac defects and choanal atresia which are not typically found in patients with BOFS, and similarly lacks the typical facial features and skin defects of BOFS.5 DATA AVAILABILITY STATEMENT Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Keywords: developmental defects; genetic diseases; mechanisms EN developmental defects genetic diseases mechanisms 929 931 3 09/01/21 20210701 NES 210701 Case Presentation A 7-month-old girl status post bilateral complete cleft lip repair presented with brightly erythematous fleshy plaques located bilaterally on the neck (Figure 1A,B). [Extracted from the article]

Acute slow breathing may have beneficial effects on cardiovascular regulation by affecting hemodynamics and the autonomic nervous system. Whether breathing at the resonance frequency (RF), a breathing rate that maximizes heart rate oscillations, induces differential effects to that of slow breathing is unknown. We compared the acute effects of breathing at either RF and RF + 1 breaths per minute on muscle sympathetic nervous activity (MSNA) and baroreflex function. Ten healthy men underwent MSNA, blood pressure (BP), and heart rate (HR) recordings while breathing for 10 min at their spontaneous breathing (SB) rate followed by 10 min at both RF and RF + 1 randomly assigned and separated by a 10‐min recovery. Breathing at either RF or RF + 1 induced similar changes in HR and HR variability, with increased low frequency and decreased high frequency oscillations (p < .001 for both). Both respiration rates decreased MSNA (−5.6 and −7.3 bursts per min for RF and RF + 1 p < .05), with the sympathetic bursts occurring more often during mid‐inspiration to early expiration (+57% and + 80%) and longer periods of silence between bursts were seen (p < .05 for RF + 1). Systolic BP was decreased only during RF (−4.6 mmHg, p < .05) but the decrease did not differ to that seen during RF + 1 (−3.1 mmHg). The sympathetic baroreflex function remained unchanged at either breathing rates. The slope of the cardiac baroreflex function was unaltered but the cardiac baroreflex efficiency was improved during both RF and RF + 1. Acute breathing at either RF or RF + 1 has similar hemodynamic and sympatho‐inhibitory effects in healthy men. [ABSTRACT FROM AUTHOR]

Exercise has been demonstrated to have considerable effects upon haemostasis, with activation dependent upon the duration and intensity of the exercise bout. In addition, markers of coagulation and fibrinolysis have been shown to possess circadian rhythms, peaking within the morning (0600-1200 h). Therefore, the time of day in which exercise is performed may influence the activation of the coagulation and fibrinolytic systems. This study aimed to examine coagulation and fibrinolytic responses to short-duration high-intensity exercise when completed at different times of the day. Fifteen male cyclists (VO2max: 60.3 ± 8.1 ml kg-1 min-1) completed a 4-km cycling time trial (TT) on five separate occasions at 0830, 1130, 1430, 1730 and 2030. Venous blood samples were obtained pre- and immediately post-exercise, and analysed for tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombin-anti-thrombin complexes (TAT) and D-Dimer. Exercise significantly increased plasma concentrations of TF (p < .0005), TFPI (p < .0006), TAT complexes (p < .0012) and D-Dimer (p < .0003). There was a time-of-day effect in pre-exercise TF (p = .004) and TFPI (p = .031), with 0830 greater than 1730 (p .001), while 1730 was less than 2030 h (p = .008), respectively. There was no significant effect of time of day for TAT (p = .364) and D-Dimer (p = .228). Power output, TT time and heart rate were not significantly different between TTs (p > .05); however, percentage VO2max was greater at 1730 when compared to 2030 (p = .04). Due to a time-of-day effect present within TF, peaking at 0830, caution should be applied when prescribing short-duration high-intensity exercise bout within the morning in populations predisposed to hypercoagulability. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Reducing time to reperfusion for ST‐segment elevation myocardial infarction (STEMI) is essential in improving outcomes. Consequently, numerous strategies have been employed to reduce median door‐to‐balloon time (DTBT). Methods: CODE STEMI is an ED physician‐activated STEMI notification system. On activation, an announcement is made over the hospital's public announcement (PA) system. We prospectively analysed all in‐hours STEMI patients who had primary percutaneous coronary intervention (PPCI) Pre‐CODE STEMI (2014) and after CODE STEMI was implemented (2015). The primary end‐points were median DTBT and the proportion of STEMI patients achieving a DTBT ≤90 min. The secondary end‐points were in‐hospital outcomes, and a composite of major adverse cardiac events (MACE) and hospital readmission rates at 30 days and 12 months. Results: There were 41 and 42 patients in Pre‐CODE STEMI and CODE STEMI groups respectively. Baseline characteristics were similar. DTBT was significantly reduced by 22.1 min from 67.1 ± 34.9 min Pre‐CODE STEMI to 45.0 ± 22.7 min (P = 0.001) in the CODE STEMI group. Door‐to‐door time (DTDT) was also reduced from 46.3 ± 30.9 min to 29.4 ± 23.3 min (P = 0.006). A greater proportion of CODE STEMI patients achieved the target DTBT ≤90 min (95.2% vs 73.2%, P = 0.007). CODE STEMI patients had less systolic dysfunction measured by a left ventricle ejection fraction of ≤40% (10.0% vs 27.8%, P = 0.07). There were trends to lower in‐hospital mortality rates (4.8% vs 9.8%, P = 0.43), MACE at 30 days and 12 months (4.8% vs 9.8%, P = 0.43; 11.9% vs 22.0%, P = 0.25). Conclusion: The novel in‐hospital in‐hours CODE STEMI notification system significantly reduced DTBT in patients undergoing PPCI. [ABSTRACT FROM AUTHOR]

Health care reform is upon us, including changes in models of care delivery and physician and institution compensation. The resulting tsunami of uncertainty offers physiatrists the opportunity to relocate to higher ground and help the specialty thrive as well as to identify the possible quagmires into which practices could sink. For this reason, it is prudent for physiatrists to more carefully consider how their professional lives may be altered in the aftermath of reform. We believe that understanding and preparation will facilitate opportunities and mitigate challenges. In this essay, we will discuss various alternative scenarios that represent population health and health care delivery in the year 2032, the real-world opportunities and challenges for the physiatrist in the present and in the next 2 decades, along with ideas as to how physiatry can thrive in the post–health care reform world. [ABSTRACT FROM AUTHOR]

Arteriovenous fistulas (AVFs) are considered superior to arteriovenous grafts and catheters. Nevertheless, AVF prevalence in the United States remains under the established target. The complication rates and financial cost of vascular access continue to rise and disproportionately contribute to the burgeoning health care costs. The relationship between financial incentives for a type of vascular access and rate of access placement is unclear. All chronic hemodialysis patients (n=99) receiving care at Philadelphia Veterans Affairs Medical Center as of August 1, 2008 were participants. Demographic characteristics, vascular access type, and nonrelative value unit compensation were assessed as predictors, and the vascular access prevalence rate, operative times, and frequency of access interventions were analyzed. A 73.7% AVF rate was achieved in this cohort of patients with 51.5% diabetes mellitus. The number of access procedures per patient per year remained constant over time. The Philadelphia Veterans Affairs Medical Center, a single payer system, achieved superior AVF prevalence and exceeded the national AVF target. Financial incentives for arteriovenous graft placement currently exist in the United States, as there is similar Medicare reimbursement for arteriovenous graft and basilic vein transposition, despite longer operative times for basilic vein transpositions. The high AVF prevalence at the Philadelphia Veterans Affairs Medical Center may be due to the VA nonrelative value unit-driven system that allows for interdisciplinary care, priority of AVFs, and frequent use of basilic vein transposition surgery, when appropriate. We have identified an important, hypothesis-generating example of a nonrelative value unit-based approach to vascular access yielding superior results with respect to patient care and cost. [ABSTRACT FROM AUTHOR]

Few studies exist in the literature investigating the impact of idiopathic Parkinson's Disease (IPD) on swallow-related quality of life. We therefore aimed in this project to: (1) evaluate swallow-specific quality of life in IPD; (2) delineate potential relationships between IPD duration and severity with swallow-specific quality of life; (3) investigate relationships between swallow-specific quality of life and general health-related quality of life; and (4) investigate relationships between swallow-specific quality of life and depression. Thirty-six patients diagnosed with IPD with and without dysphagia filled out self-report assessments of the SWAL-QOL, Parkinson's Disease Questionnaire-39 (PDQ-39), and Beck Depression Inventory (BDI). A series of Mann Whitney U tests were performed between non-dysphagic and dysphagic groups for the total SWAL-QOL score and the 10 SWAL-QOL domains. Spearman's Rho correlation analyses were performed between the SWAL-QOL and (1) PDQ-39; (2) Hoehn and Yahr stage; (3) PD disease duration; (4) UPDRS 'on' score; and (5) the BDI. The dysphagia swallowing group reported significant reductions compared to the non-dysphagic group for the total SWAL-QOL score ( P = 0.02), mental health domain score ( P = 0.002) and social domain score ( P = 0.002). No relationships existed between swallow-specific quality of life and disease duration or severity. Significant relationships existed between swallow-specific quality of life and general health-related quality of life ( rs =−0.56, P = 0.000) and depression ( rs = −0.48, P = 0.003). These exploratory data highlight the psychosocial sequelae that swallowing impairment can have in those with IPD and suggest a possible association between swallowing, social function, and depression. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Wolf's isotopic response describes the occurrence of a dermatologic condition at the site of a prior healed unrelated condition. Our report details a case of varicella occurring as a secondary condition at the site of a prior immunization reaction; herpesvirus infection has not been reported as a secondary condition in cases of Wolf's isotopic response before. Current hypotheses favor the involvement of neurohormonal modulation of local immunity in response to various forms of injury as a model for explaining these phenomena. [ABSTRACT FROM AUTHOR]

Skin fragility is a well-established complication of isotretinoin therapy for severe or resistant acne and presents a challenge to traditional modes of epilation such as waxing. As such, other less traumatic hair removal methods are desired. Herein we present the threading technique as an alternative form of epilation for patients in whom waxing is contraindicated secondary to concerns over skin fragility. [ABSTRACT FROM AUTHOR]

Aging is associated with a loss of metabolic homeostasis, with cofactors such as nicotinamide adenine dinucleotide (NAD + ) declining over time. The decrease in NAD + production has been linked to the age-related loss of circulating extracellular nicotinamide phosphoribosyltransferase (eNAMPT), the rate-limiting enzyme in the NAD + biosynthetic pathway. eNAMPT is found almost exclusively in extracellular vesicles (EVs), providing a mechanism for the distribution of the enzyme in different tissues. Currently, the physiological cause for the release of eNAMPT is unknown, and how it may be affected by age and physical exercise. Here, we show that release of small EVs into the bloodstream is stimulated following moderate intensity exercise in humans. Exercise also increased the eNAMPT content in EVs, most prominently in young individuals with higher aerobic fitness. Both mature fit and young unfit individuals exhibited a limited increase in EV-eNAMPT release following exercise, indicating that this mechanism is related to both the age and physical fitness of a person. Notably, unfit mature individuals were unable to increase the release of eNAMPT in EVs after exercise, suggesting that lower fitness levels and aging attenuate this important signalling mechanism in the body. EVs isolated from exercising humans containing eNAMPT were able to alter the abundance of NAD + and SIRT1 activity in recipient cells compared to pre-exercise EVs, indicating a pathway for inter-tissue signalling promoted through exercise. Our results suggest a mechanism to limit age-related NAD + decline, through the systemic delivery of eNAMPT via EVs released during exercise., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)