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PURPOSE: Exercise-induced arterial hypoxemia (EIAH) is reported to occur in approximately 50% of highly trained male endurance athletes. Few studies have examined EIAH in women and the prevalence remains unclear. It has been reported that some female subjects who develop EIAH possess maximal oxygen consumption (VO2max) values that are within 15% of their predicted value. This is unique to women, where EIAH has generally been reported in men who have a high VO2max. The primary objective of this investigation was to determine the prevalence of EIAH in a large female population with a wide range of VO2max values. It was hypothesized that EIAH would occur with a greater prevalence and at relatively lower predicted VO2max than that previously reported in males. METHODS: Young women (N = 52; 26.5 +/- 4.9 yr) performed a cycle test to exhaustion to determine VO2max, and oxyhemoglobin saturation (SaO2) was monitored via pulse oximetry. All subjects were tested during the early follicular phase of their menstrual cycle. A >/= 4% drop in SaO2 represented EIAH. RESULTS: Values for VO2max were variable (VO2max range: 28.0-61.3 mL x kg(-1) x min(-1)). EIAH was present in 67% of the women with N = 19 displaying mild EIAH (92-94%SaO2) and N = 16 displaying moderate EIAH (87-91%SaO2). CONCLUSION: It appears that the prevalence of EIAH in women is slightly greater than the 50% prevalence value that is typically reported for highly fit men. [ABSTRACT FROM AUTHOR]

The search for the link between negative emotions and later health problems continues to be a dominant theme in behavioral medicine. Although researchers have identified significant relations between illness and anger, most studies focus selectively on one anger domain: either the affective, attitudinal, or behavioral component. In this study, we first related all three components of the AHA! (anger, hostility, and aggressive behavior) syndrome to somatic complaint reports in a male and female young adult population drawn from three countries. In subsequent analyses, we related multidimensional characteristics of anger to illness in those young adults who regularly use tobacco and alcohol. In both the total sample and the substance user analyses, we found that the anger-illness profile varied as a function of gender. [ABSTRACT FROM AUTHOR]

Background: This commentary highlights the evolution of our understanding of physical function (PF) and key models/frameworks that have contributed to the current holistic understanding of PF, which encompasses not only a person's performance but also the environment and any adaptations an individual utilizes. This commentary also addresses how digital health tools can facilitate and complement the assessment of holistic PF and enable both objective and subjective input from the participant in their real-world environment. Lastly, we discuss how successful implementation of digital tools within clinical research requires patient input., Summary: This commentary highlights how our understanding of PF has evolved to be more holistic., Key Messages: Inclusion of digital tools within clinical research can provide a path forward to holistically assess PF in a patient-focused manner., Competing Interests: There is no conflict of interest for any author., (© 2025 The Author(s). Published by S. Karger AG, Basel.)

Background: Safe and effective pharmacologic therapy for atrial fibrillation (AF) in heart failure (HF) is an unmet need. In AF clinical trials, the standard primary endpoint of time to first symptomatic AF event (TTFSE) has several disadvantages, which could theoretically be overcome by measurement of AF-specific symptoms burden during an entire follow-up period., Objectives: The authors sought to develop and validate a method of measuring symptom burden of AF in a HF population., Methods: The authors constructed a patient-reported outcome instrument (Atrial Fibrillation Symptoms Questionnaire [AFSQ]) to function in the setting of AF/HF, and used it to measure symptoms throughout long-term follow-up. The AFSQ queries the presence of 10 new or worsening symptoms, equally divided between those associated with AF or HF. In a 267 patient AF/HF trial comparing 2 AF prevention treatments, the AFSQ was linked to electrocardiography documented AF to form a 2-component clinical outcome assessment (SxB AF ) that was subjected to psychometric testing, anchor validation, and endpoint efficiency comparison to TTFSE., Results: SxB AF exhibited greater efficiency than time to first symptomatic event for treatment difference detection, resulting in smaller projected clinical trial sample sizes. SxB AF correlated well with device-detected AF burden (Spearman's ρ = 0.74; P < 0.0001), while permitting gradation in symptom severity. SxB AF also identified treatment group differences in cardiovascular serious adverse events and AF interventions and in recent-onset AF provided specificity for AF- or worsening HF-associated symptoms (P < 0.001 for each)., Conclusions: Measurement of symptoms burden throughout clinical trial follow-up is feasible in AF/HF and should be useful for evaluating patient-centered outcomes in AF prevention trials. (Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure [GENETIC-AF]; NCT01970501)., Competing Interests: Funding Support and Author Disclosures This study was funded by ARCA Biopharma. Dr Piccini was supported by R01AG074185 from the National Institute on Aging. Drs Carroll, Piccini, Richards, DeMets, and Bristow have served as consultants for ARCA. Dr Piccini has received grants for clinical research from Abbott, the American Heart Association, Boston Scientific, iRhythm, and Philips; and has served as a consultant for ABVF, Abbott, AbbVie, ARCA, Boston Scientific, ElectroPhysiology Frontiers, Kardium, LivaNova, Medtronic, Milestone Pharmaceuticals, Pacira, Sanofi, Philips, and UptoDate. Dr Steinberg has received salary support from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL143156, R56HL168264, R21HL172288) and the American Heart Association/Patient-Centered Outcomes Research Institute (18SFRN34110489); has received research support from Abbott, Boston Scientific, Biosense Webster, Sanofi, and AltaThera; and has served as a consultant for Sanofi, Bayer, Boston Scientific, Element Science, Syneos Health, Milestone, Pfizer, and AltaThera. Dr Bristow has received research support from the National Institute of Allergy and Infectious Diseases, the American Heart Association, and ARCA. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Digital health technologies (DHTs) have the potential to modernize drug development and clinical trial operations by remotely, passively, and continuously collecting ecologically valid evidence that is meaningful to patients' lived experiences. Such evidence holds potential for all drug development stakeholders, including regulatory agencies, as it will help create a stronger evidentiary link between approval of new therapeutics and the ultimate aim of improving patient lives. However, only a very small number of novel digital measures have matured from exploratory usage into regulatory qualification or efficacy endpoints. This shows that despite the clear potential, actually gaining regulatory agreement that a new measure is both fit-for-purpose and delivers value remains a serious challenge. One of the key stumbling blocks for developers has been the requirement to demonstrate that a digital measure is meaningful to patients. This viewpoint aims to examine the co-evolution of regulatory guidance in the United States (U.S.) and best practice for integration of DHTs into the development of clinical outcome assessments. Contextualizing guidance on meaningfulness within the larger shift towards a patient-centric drug development approach, this paper reviews the U.S. Food and Drug Administration (FDA) guidance and existing literature surrounding the development of meaningful digital measures and patient engagement, including the recent examples of rejections by the FDA that further emphasize patient-centricity in digital measures. Finally, this paper highlights remaining hurdles and provides insights into the established frameworks for development and adoption of digital measures in clinical research., (© 2024. The Author(s).)

Evidence of interspecific interactions in the fossil record is rare but offers valuable insights into ancient ecologies. Exceptional fossiliferous sites can preserve complex ecological interactions involving non-biomineralized organisms, but most of these examples are restricted to Cambrian Lagerstätten. Here we report an exceptionally preserved cross-phylum interspecific interaction from the Tremadocian-aged Lower Fezouata Shale Formation of Morocco, which consists of the phragmocone of an orthocone cephalopod that has been extensively populated post-mortem by tubicolous epibionts. Well-preserved transverse bands in a zig-zag pattern and crenulations along the margin of the unbranched tubes indicate that they correspond to pterobranch hemichordates, with a close morphological similarity to rhabdopleurids based on the bush-like growth of the dense tubarium. The discovery of rhabdopleurid epibionts in the Fezouata Shale highlights the paucity of benthic graptolites, which also includes the rooted dendroids Didymograptus and Dictyonema, relative to the substantially more diverse and abundant planktic forms known from this biota. We propose that the rarity of Paleozoic rhabdopleurid epibionts is likely a consequence of their ecological requirement for hard substrates for initial settlement and growth. The Fezouata rhabdopleurid also reveals a 480-million-year-old association of pterobranchs as epibionts of molluscs that persist to the present day., (© 2023. Springer Nature Limited.)

Purpose: Military deployment to dusty, austere environments in Southwest Asia and Afghanistan is associated with symptomatic airways diseases including asthma and bronchiolitis. The utility of chest high-resolution computed tomographic (HRCT) imaging in lung disease diagnosis in this population is poorly understood. We investigated visual assessment of HRCT for identifying deployment-related lung disease compared with healthy controls., Materials and Methods: Chest HRCT images from 46 healthy controls and 45 symptomatic deployed military personnel with clinically confirmed asthma and/or biopsy-confirmed distal lung disease were scored by 3 independent thoracic radiologists. We compared demographic and clinical characteristics and frequency of imaging findings between deployers and controls, and between deployers with asthma and those with biopsy-confirmed distal lung disease, using χ2, Fisher exact or t tests, and logistic regression where appropriate. We also analyzed inter-rater agreement for imaging findings., Results: Expiratory air trapping was the only chest CT imaging finding that was significantly more frequent in deployers compared with controls. None of the 24 deployers with biopsy-confirmed bronchiolitis and/or granulomatous pneumonitis had HRCT findings of inspiratory mosaic attenuation or centrilobular nodularity. Only 2 of 21 with biopsy-proven emphysema had emphysema on HRCT., Conclusions: Compared with surgical lung biopsy, visual assessment of HRCT showed few abnormalities in this small cohort of previously deployed symptomatic veterans with normal or near-normal spirometry., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Professional development of language teachers is one major measure to ensure that teachers remain updated and avoid the risk or leaving the profession. Not all teachers, however, attend professional development (PD) workshops or engage in such activities for the sake of developing professionally. Some teachers attend PD courses on a routine basis with little knowledge of what competencies they are expected to gain as a result, and simply because taking part in such programmes is an institutional requirement. To explore the type of PD activities English teachers in Iran participate in and also to understand the motivations behind their participation, the researchers interviewed 24 English teachers (with the age range of 24-50) working at private language institutes and public high schools. The study found that public school teachers were engaged in very few PD activities, and the type of PD activities private teachers followed ranged from consulting online courses to watching educational videos to reading ELT textbooks. The motivations for taking part in PD activities ranged from 'having no motivation' to 'promoting my English' to 'being able to teach at university'. Further results and implications for teacher education in Iran and beyond are discussed in the paper., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Introduction: To determine if electrolyte or carbohydrate supplementation vs. water would limit the magnitude of dehydration and decline in cognitive function in humans following long-duration hyperthermic-exercise., Methods: 24 subjects performed 3 visits of 2 h walking (3mph/7% grade) in an environmental chamber (33 °C/10% relative humidity). In random order, subjects consumed water (W), electrolytes (Gatorade Zero; E), or electrolytes+carbohydrates (Gatorade; E+C). Throughout exercise (EX), subjects carried a 23 kg pack and drank ad-libitum. Pre-and post-EX, body mass (BM) and plasma osmolality (pOsm) were measured. Physiological Strain Index (PSI) and core temperature (T C ) were recorded every 15 min. Plasma glucose (GLU) was measured every 30 min. Cognitive processing (SCWT) was measured post-EX and compared to baseline (BL). A subset of 8 subjects performed a normothermic (N) protocol (21 °C/ambient humidity) to ascertain how the exercise stimulus influenced hydration status and cognition without heat., Results: There were no significant differences between fluid conditions (W, E, E+C) for BM loss (Δ2.5 ± 0.2, 2.5 ± 0.2, 2.3 ± 0.2 kg), fluid consumption (1.9 ± 0.2, 1.9 ± 0.2, 1.8 ± 0.2L), pOsm (Δ1.5 ± 2.7, 2.2 ± 2.4, 2.0 ± 1.5 mmol/L), peak-PSI (7.5 ± 0.4, 7.0 ± 0.6, 7.9 ± 0.5), and peak-T C (38.7 ± 0.1, 38.6 ± 0.2, 38.8 ± 0.2 °C). GLU decreased significantly in W and E, whereas it increased above BL in E+C at 60, 90, and 120 min (P < 0.05). Compared to BL values (43.6 ± 26 ms), SCWT performance significantly decreased in all conditions (463 ± 93, 422 ± 83, 140 ± 52 ms, P < 0.05). Importantly, compared to W and E, the impairment in SCWT was significantly attenuated in E+C (P < 0.05). As expected, when compared to the heat-stress protocol (W, E, E+C), N resulted in lower BM loss, fluid consumption, and peak-PSI (1.1 ± 0.1 kg, 1.2 ± 0.7L, 4.8, respectively), and improved SCWT performance., Conclusions: These data are the first to suggest that, independent of supplementation variety, cognitive processing significantly decreases immediately following long-duration exercise in the heat in healthy humans. Compared to water and fluids supplemented with only electrolytes, fluids supplemented with carbohydrates significantly blunts this decrease in cognitive function., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hypertension and metabolic syndrome (METSYN) are reportedly high in police forces. This may contribute to health deterioration and absenteeism in police personnel. Police forces comprise of staff in 'operational' and 'non-operational' job types but it is not known if job type is associated to hypertension and METSYN prevalence. This study aimed to explore the prevalence of hypertension and METSYN, the factors associated with the risk of hypertension and METSYN, and compare physiological, psychological, and behavioural factors between operational and non-operational police personnel. Cross-sectional data was collected from 77 operational and 60 non-operational police workers. Hypertension and METSYN were prevalent in 60.5% and 20% of operational and 60.0% and 13.6% of non-operational police personnel, respectively ( p > 0.05). Operational job type, moderate organisational stress (compared with low stress) and lower high-density lipoprotein cholesterol were associated with lower odds of hypertension, whereas increasing body mass index was associated with increased odds of hypertension ( p < 0.05). None of the independent variables were significantly associated with the odds of METSYN. Operational police had several increased cardiometabolic risk markers compared with non-operational police. Given the high prevalence of hypertension and METSYN in operational and non-operational personnel, occupational health interventions are needed for the police and could be informed by the findings of this study.

Background and Aims: Recent studies suggest that long-term endurance training may be damaging to the heart, thus increasing cardiovascular disease (CVD) risk. However, studies utilizing cardiac imaging are conflicting and lack measures of central and peripheral vascular structure and function, which are also independently predictive of CVD events., Methods: We performed a comprehensive assessment of cardiovascular structure and function in long-term (≥ 10 years) ultra-endurance athletes (ATH, 14 M/11 F, 50 ± 1 y) and physically active controls (CON, 9 M/9 F, 49 ± 2 y)., Results: As expected, left ventricular mass and end-diastolic volume (echocardiography) were greater in ATH vs CON, whereas there was no difference in cardiac function at rest. Coronary artery calcium scores (computed tomography) were not statistically different between groups. There was no evidence of myocardial fibrosis (contrast magnetic resonance imaging) in any subject. Aortic stiffness (carotid-femoral pulse wave velocity) was lower in ATH vs CON (6.2 ± 0.2 vs 6.9 ± 0.2 m/s, p < 0.05), whereas carotid intima-media thickness (ultrasound) was not different between groups. Peripheral vascular endothelial function (flow-mediated vasodilation of the brachial artery) and microvascular function (peak blood velocity) in response to 5 min of forearm ischemia were not different between groups. Furthermore, there was no difference in 10-year coronary heart disease risk (ATH; 2.3 ± 0.5 vs CON; 1.6 ± 0.2%, p > 0.05)., Conclusions: Our data indicate that middle-aged ultra-endurance ATH do not have marked signs of widespread cardiovascular dysfunction or elevated CHD risk compared to CON meeting physical activity guidelines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Key Points: During exercise, blood flow to working skeletal muscle increases in parallel with contractile activity such that oxygen delivery is sufficient to meet metabolic demand. K + released from active skeletal muscle fibres could facilitate vasodilatation in proportion to the degree of muscle fibre recruitment. Once released, K + stimulates inwardly rectifying K + (K IR ) channels on the vasculature to elicit an increase in blood flow. In the present study, we demonstrate that K IR channels mediate the rapid vasodilatory response to an increase in exercise intensity. We also show that K IR channels augment vasodilatation during exercise which demands greater muscle fibre recruitment independent of the total amount of work performed. These results suggest that K + plays a key role in coupling the magnitude of vasodilatation to the degree of contractile activity. Ultimately, the findings from this study help us understand the signalling mechanisms that regulate muscle blood flow in humans., Abstract: Blood flow to active skeletal muscle is augmented with greater muscle fibre recruitment. We tested whether activation of inwardly rectifying potassium (K IR ) channels underlies vasodilatation with elevated muscle fibre recruitment when work rate is increased (Protocol 1) or held constant (Protocol 2). We assessed forearm vascular conductance (FVC) during rhythmic handgrip exercise under control conditions and during local inhibition of K IR channels (intra-arterial BaCl 2 ). In Protocol 1, healthy volunteers performed mild handgrip exercise for 3 min, then transitioned to moderate intensity for 30 s. BaCl 2 eliminated vasodilatation during the first contraction at the moderate workload (ΔFVC, BaCl 2 : -1 ± 17 vs. control: 30 ± 28 ml min -1  100 mmHg -1 ; n = 9; P = 0.004) and attenuated the 30 s area under the curve by 56 ± 14% (n = 9; P < 0.0001). In Protocol 2, participants performed two exercise bouts in which muscle fibre recruitment was manipulated while total contractile work was held constant via reciprocal changes in contraction frequency: (1) low fibre recruitment, with contractions at 12.5% maximal voluntary contraction once every 4 s and (2) high fibre recruitment, with contractions at 25% maximal voluntary contraction once every 8 s. Under control conditions, steady-state FVC was augmented in high vs. low fibre recruitment (211 ± 90 vs. 166 ± 73 ml min -1 ⋅100 mmHg -1 ; n = 10; P = 0.0006), whereas BaCl 2 abolished the difference between high and low fibre recruitment (134 ± 59 vs. 134 ± 63 ml min -1  100 mmHg -1 ; n = 10; P = 0.85). These findings demonstrate that K IR channel activation is a key mechanism linking local vasodilatation with muscle fibre recruitment during exercise., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining blood flow during exercise-mediated sympathoexcitation. Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise. In the present study, intra-arterial infusion of ACh or ATP to augment endothelium-dependent signalling during exercise attenuated α 1 -adrenergic vasoconstriction in the contracting muscle of older adults. The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age-related impairment in functional sympatholysis probably results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction., Abstract: The ability of contracting skeletal muscle to attenuate sympathetic α-adrenergic vasoconstriction ('functional sympatholysis') is impaired with age. In young adults, increasing endothelium-dependent vasodilatory signalling during mild exercise augments sympatholysis. In the present study, we tested the hypothesis that increasing endothelium-dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1, n = 8; Protocol 2, n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of phenylephrine (PE; α 1 -agonist) during (i) infusion of an endothelium-dependent vasodilator alone (Protocol 1: ACh or Protocol 2: low dose ATP); (ii) mild handgrip exercise (5% maximum voluntary contraction; MVC); (iii) moderate handgrip exercise (15% MVC); and (iv) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium-dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (ΔFVC: ACh: -31 ± 3 and ATP: -30 ± 4%). PE-mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 5% MVC: -30 ± 9; 15% MVC: -33 ± 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium-dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE-mediated vasoconstriction (ΔFVC: -13 ± 1 and -19 ± 5%, respectively; P < 0.05 vs. all conditions). Our findings demonstrate that, given a sufficient stimulus, endothelium-dependent sympatholysis remains intact in older adults. Strategies aimed at activating such pathways represent a viable approach for improving sympatholysis and thus tissue blood flow and oxygen delivery in older adults., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Introduction: The purpose of this study was to determine the effects of ad libitum flavor and fluid intake on changes in body mass (BM) and physiological strain during moderate intensity exercise in the heat., Methods: Ten subjects (24±3yrs, 7M/3F) performed 60 min of treadmill walking at 1.3 m/s and 7% grade in an environmental chamber set to 33 °C and 10% relative humidity while carrying a 22.7 kg pack on two different occasions. Subjects consumed either plain water or water plus flavor (Infuze), ad libitum, at each visit. Pre and post exercise, fluid consumption (change in fluid reservoir weight) and BM (nude) were measured. During exercise, heart rate (HR), systolic blood pressure (SBP), rate of perceived exertion (RPE), oxygen consumption (VO 2 ), respiratory exchange ratio (RER), core temperature (T C ), and physiological strain index (PSI) were recorded every 15 min during exercise., Results: No significant differences were observed for fluid consumption between fluid conditions (512 ± 97.2 mL water vs. 414.3 ± 62.5 mL Infuze). Despite a significant decrease from baseline, there were no significant differences in overall change of BM (Δ -1.18 vs. -0.64 Kg) or percent body weight loss for water and Infuze conditions, respectively (1.58 ± 0.6 and 0.79 ± 0.2%). Furthermore, there were no significant differences in HR (144 ± 6 vs. 143 ± 8 bpm), SBP (157 ± 5 vs. 155 ± 5 mmHg), RPE, VO 2 (27.4 ± 0.9 vs. 28.1 ± 1.2 ml/Kg/min), RER, T C (38.1 ± 0.1 vs. 37.0 ± 0.1 °C), and peak PSI (5.4 ± 0.4 vs. 5.7 ± 0.8) between conditions., Conclusions: Offering individuals the choice to actively manipulate flavor strength did not significantly influence ad libitum fluid consumption, fluid loss, or physiological strain during 60 min of moderate intensity exercise in the heat., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: On high-resolution computed tomography (HRCT), pulmonary artery (PA) dimensions may hint at the presence of pulmonary hypertension. We aimed to determine how accurately various measures of the PA, as viewed on HRCT, predict right heart catheterisation (RHC)-confirmed pulmonary hypertension., Methods: We retrospectively reviewed patients who had HRCT and RHC between 2010 and 2018. Analyses considered respiratory cycle, pulmonary hypertension diagnostic criteria, time between HRCT and RHC, and subgroup analysis in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD)., Results: Of 620 patients, 375 had pulmonary hypertension. For pulmonary hypertension (defined as mean PA pressure (mPAP) ≥25 mmHg) and from HRCT performed within 60 days of RHC, main PA diameter (MPAD) ≥29 mm had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 88%, 42%, 0.70 and 0.70, respectively, while ratio of the diameter of the PA to the diameter of the ascending aorta (PA:Ao) ≥1.0 showed 53%, 85%, 0.84 and 0.54, respectively. In general, results were similar when the interval between HRCT and RHC varied from 7 to 60 days and when measured on expiratory images. In ILD, the sensitivity of MPAD was higher; in COPD, the specificity of PA:Ao was higher. There was moderately positive correlation between mPAP and inspiratory MPAD, PA:Ao, right PA diameter (RPAD), left PA diameter (LPAD) and (RPAD+LPAD)/2 (r=0.48, 0.51, 0.34, 0.34 and 0.36, respectively), whereas there was weak negative correlation between mPAP and PA angle (r= -0.24)., Conclusions: Findings on HRCT may assist in the diagnosis of RHC-confirmed pulmonary hypertension. MPAD ≥29 mm had high sensitivity and PA:Ao ≥1.0 had high specificity. Compared with the entire cohort, MPAD had greater sensitivity in ILD and PA:Ao had higher specificity in COPD., Competing Interests: Conflict of interest: P. Ratanawatkul has nothing to disclose. Conflict of interest: A. Oh has nothing to disclose. Conflict of interest: J.C. Richards has nothing to disclose. Conflict of interest: J.J. Swigris reports grant support for investigator-initiated studies, and nonbranded, disease-state speaker's bureau fees from Boehringer Ingelheim and Genentech for work outside the scope of the submitted work., (Copyright ©ERS 2020.)

Mammalian and bird ribosomes are nearly twice the mass of prokaryotic ribosomes in part because of their extraordinarily long rRNA tentacles. Human rRNA tentacles are not fully observable in current three-dimensional structures and their conformations remain to be fully resolved. In previous work we identified sequences that favor G-quadruplexes in silico and in vitro in rRNA tentacles of the human large ribosomal subunit. We demonstrated by experiment that these sequences form G-quadruplexes in vitro. Here, using a more recent motif definition, we report additional G-quadruplex sequences on surfaces of both subunits of the human ribosome. The revised sequence definition reveals expansive arrays of potential G-quadruplex sequences on LSU tentacles. In addition, we demonstrate by a variety of experimental methods that fragments of the small subunit rRNA form G-quadruplexes in vitro. Prior to this report rRNA sequences that form G-quadruplexes were confined to the large ribosomal subunit. Our combined results indicate that the surface of the assembled human ribosome contains numerous sequences capable of forming G-quadruplexes on both ribosomal subunits. The data suggest conversion between duplexes and G-quadruplexes in response to association with proteins, ions, or other RNAs. In some systems it seems likely that the integrated population of RNA G-quadruplexes may be dominated by rRNA, which is the most abundant cellular RNA., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Radiologists have a critical role in the evaluation and diagnosis of suspected idiopathic pulmonary fibrosis (IPF). Accurate pattern identification on imaging is key in the multidisciplinary diagnostic process and frequently obviates the need for a surgical lung biopsy. In this review, we describe the clinical and imaging features of IPF in the context of recently revised international guidelines; contrast findings in other diseases that may inform differential diagnosis of fibrotic lung disease; and highlight common complications associated with pulmonary fibrosis.

OBJECTIVE. Birt-Hogg-Dubé (BHD) syndrome, lymphangioleiomyomatosis (LAM), and lymphocytic interstitial pneumonia (LIP) frequently present as isolated cystic lung disease and can be challenging to distinguish. If imaging findings are otherwise unremarkable, the radiologist is unaided by ancillary CT findings in narrowing the diagnosis. We hypothesized that the distribution and morphologic features of lung cysts could be used to differentiate BHD syndrome, LAM, and LIP. Therefore, the purpose of this study was to characterize the CT appearances of these conditions and create a practical CT-based algorithm to differentiate among them. MATERIALS AND METHODS. The study was a retrospective review of the CT images of 16 patients with BHD syndrome, 17 patients with LAM, and 14 patients with LIP. On the basis of the data collected, a CT-based algorithm was created, and the CT images were reviewed again. RESULTS. Lower lung-predominant cysts were significantly more likely to be found in patients with BHD syndrome (100% of patients) or LIP (71-93% of patients) than in patients with LAM (6-12% of patients), who were more likely to have diffuse cysts. Compared with patients with LIP or LAM, patients with BHD syndrome were significantly more likely to have elliptical (floppy) paramediastinal cysts (88-94% of patients with BHD syndrome, 36-43% of patients with LIP, and 6-12% of patients with LAM) or a disproportionate number of paramediastinal cysts (69-88% of patients with BHD syndrome, 0-14% of patients with LIP, and 0-6% of patients with LAM). Our algorithm enabled differentiation of BHD syndrome, LAM, and LIP with a high level of accuracy and high interreader agreement (κ = 0.809). CONCLUSION. Radiologists can use the proposed CT-based algorithm to prospectively and confidently suggest one of these disorders as the favored diagnosis. Of importance, this will allow diagnosing the disorder early and accurately, screening for comorbidities, and prevention of potential complications.

Key Points: In humans, the vasodilatory response to skeletal muscle contraction is mediated in part by activation of inwardly rectifying potassium (K IR ) channels. Evidence from animal models suggest that K IR channels serve as electrical amplifiers of endothelium-dependent hyperpolarization (EDH). We found that skeletal muscle contraction amplifies vasodilatation to the endothelium-dependent agonist ACh, whereas there was no change in the vasodilatory response to sodium nitroprusside, an endothelium-independent nitric oxide donor. Blockade of K IR channels reduced the exercise-induced amplification of ACh-mediated vasodilatation. Conversely, pharmacological activation of K IR channels in quiescent muscle via intra-arterial infusion of KCl independently amplified the vasodilatory response to ACh. This study is the first in humans to demonstrate that specific endothelium-dependent vasodilatory signalling is amplified in the vasculature of contracting skeletal muscle and that K IR channels may serve as amplifiers of EDH-like vasodilatory signalling in humans., Abstract: The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (K IR ) channels. Evidence from animal models suggest that K IR channels function as 'amplifiers' of endothelium-dependent vasodilators. We tested the hypothesis that contracting muscle selectively amplifies endothelium-dependent vasodilatation via activation of K IR channels. We measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of ACh (endothelium-dependent dilator) during resting conditions, handgrip exercise (5% maximum voluntary contraction) or sodium nitroprusside (SNP; endothelium-independent dilator) which served as a high-flow control condition (n = 7, young healthy men and women). Trials were performed before and after blockade of K IR channels via infusion of barium chloride. Exercise augmented peak ACh-mediated vasodilatation (ΔFVC saline: 117 ± 14; exercise: 236 ± 21 ml min -1 (100 mmHg) -1 ; P < 0.05), whereas SNP did not impact ACh-mediated vasodilatation. Blockade of K IR channels attenuated the exercise-induced augmentation of ACh. In eight additional subjects, SNP was administered as the experimental dilator. In contrast to ACh, exercise did not alter SNP-mediated vasodilatation (ΔFVC saline: 158 ± 35; exercise: 121 ± 22 ml min -1 (100 mmHg) -1 ; n.s.). Finally, in a subset of six subjects, direct pharmacological activation of K IR channels in quiescent muscle via infusion of KCl amplified peak ACh-mediated vasodilatation (ΔFVC saline: 97 ± 15, KCl: 142 ± 16 ml min -1  (100 mmHg) -1 ; respectively; P < 0.05). These findings indicate that skeletal muscle contractions selectively amplify endothelium-dependent vasodilatory signalling via activation of K IR channels, and this may be an important mechanism contributing to the normal vasodilatory response to exercise in humans., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Background: In contrast to younger athletes, there is comparatively less literature examining cardiac structure and function in older athletes. However, a progressive accumulation of studies during the past four decades offers a body of literature worthy of systematic scrutiny., Objectives: We conducted a systematic review, meta-analysis and meta-regression of controlled echocardiography studies comparing left ventricular (LV) structure and function in aerobically trained older athletes (> 45 years) with age-matched untrained controls, in addition to investigating the influence of chronological age., Methods: Electronic databases were searched from inception to January 2018 before conducting a random-effects meta-analysis to calculate pooled differences in means, effect size and 95% confidence intervals (CIs). Study heterogeneity was reported using Cochran's Q and I 2 statistic., Results: Overall, 32 studies (644 athletes; 582 controls) were included. Athletes had greater LV end-diastolic diameter (3.65 mm, 95% CI 2.66-4.64), interventricular septal thickness (1.23 mm, 95% CI 0.85-1.60), posterior wall thickness (1.20 mm, 95% CI 0.83-1.56), LV mass (72 g, 95% CI 46-98), LV mass index (28.17 g·m 2 , 95% CI 19.84-36.49) and stroke volume (13.59 mL, 95% CI 7.20-19.98) (all p < 0.01). Athletes had superior global diastolic function [ratio of early (E) to late (A) mitral inflow velocity (E/A) 0.18, 95% CI 0.13-0.24, p < 0.01; ratio of early (e') to late (a') diastolic annular tissue velocity (e'/a') 0.23, 95% CI 0.06-0.40, p = 0.01], lower A (-8.20 cm·s -1 , 95% CI -11.90 to -4.51, p < 0.01) and a' (-0.72 cm·s -1 , 95% CI -1.31 to -0.12, p = 0.02), and more rapid e' (0.96 cm·s -1 , 95% CI 0.05-1.86, p = 0.04). Meta-regression for chronological age identified that athlete-control differences, in the main, are maintained during advancing age., Conclusions: Athletic older men have larger cardiac dimensions and enjoy more favourable cardiac function than healthy, non-athletic counterparts. Notably, the athlete groups maintain these effects during chronological ageing.

Common variable immunodeficiency (CVID) is associated with significant chronic lung disease. The purpose of this paper was to describe the clinical, radiologic, and pathologic findings of CVID-associated lung diseases. These include airways' disease, interstitial lung disease, lymphoma, and mucosa-associated lymphoid tissue lymphoma. In addition, a genetic syndrome termed Kabuki syndrome results in CVID-like immune abnormalities. These patients may also present with CVID-associated lung disease. Awareness and precise identification of CVID-associated lung disease may allow for better assessment of prognosis and direction of therapy.

The increase in interstitial potassium (K + ) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K + in exercise hyperemia, we perfused skeletal muscle with K + before contractions, such that the effect of any endogenously-released K + would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF) (Doppler ultrasound) and forearm vascular conductance (FVC) (FBF/mean arterial pressure) during 4 min of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions, 2) infusion of KCl before the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly before the onset of exercise (control: 39 ± 6 vs. KCl: 81 ± 12 and SNP: 82 ± 13 ml·min -1 ·100 mmHg -1 ; both P < 0.05 vs. control). Infusion of KCl at rest diminished the hyperemic (ΔFBF) and vasodilatory (ΔFVC) response to subsequent exercise by 22 ± 5% and 30 ± 5%, respectively (both P < 0.05 vs. control), whereas SNP did not affect the change in FBF ( P = 0.74 vs. control) or FVC ( P = 0.61 vs. control) from rest to steady-state exercise. These findings implicate the K + ion as an essential vasodilator substance contributing to exercise hyperemia in humans. NEW & NOTEWORTHY Our findings support a significant and obligatory role for potassium signaling in the local vasodilatory and hyperemic response to exercise in humans.

Objective: Incidental pulmonary findings are commonly detected at lung cancer screening chest CT. Though most of these findings are clinically insignificant, it is difficult to prospectively determine which are potentially important to clinical care. The purpose of this review is to discuss the incidental pulmonary findings commonly detected at lung cancer screening chest CT., Conclusion: Incidental pulmonary findings most commonly fall into one of three categories: interstitial lung disease, emphysema, and airways disease (both small and large airways).

Dietary nitrate (NO3-) is converted to nitrite (NO2-) and can be further reduced to the vasodilator nitric oxide (NO) amid a low O 2 environment. Accordingly, dietary NO3- increases hind limb blood flow in rats during treadmill exercise; however, the evidence of such an effect in humans is unclear. We tested the hypothesis that acute dietary NO3- (via beetroot [BR] juice) increases forearm blood flow (FBF) via local vasodilation during handgrip exercise in young adults (n = 11; 25 ± 2 years). FBF (Doppler ultrasound) and blood pressure (Finapres) were measured at rest and during graded handgrip exercise at 5%, 15%, and 25% maximal voluntary contraction (MVC) lasting 4 min each. At the highest workload (25% MVC), systemic hypoxia (80% SaO 2 ) was induced and exercise continued for three additional minutes. Subjects ingested concentrated BR (12.6 mmol nitrate (n = 5) or 16.8 mmol nitrate (n = 6) and repeated the exercise bout either 2 (12.6 mmol) or 3 h (16.8 mmol) postconsumption. Compared to control, BR significantly increased FBF at 15% MVC (184 ± 15 vs. 164 ± 15 mL/min), 25% MVC (323 ± 27 vs. 286 ± 28 mL/min), and 25% + hypoxia (373 ± 39 vs. 343 ± 32 mL/min) and this was due to increases in vascular conductance (i.e., vasodilation). The effect of BR on hemodynamics was not different between the two doses of BR ingested. Forearm VO 2 was also elevated during exercise at 15% and 25% MVC. We conclude that acute increases in circulating NO3- and NO2- via BR increases muscle blood flow during moderate- to high-intensity handgrip exercise via local vasodilation. These findings may have important implications for aging and diseased populations that demonstrate impaired muscle perfusion and exercise intolerance., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Key Points: Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (K IR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α 1 -adrenergic vasoconstriction in resting skeletal muscle would be independent of K IR , NO, PGs and Na + /K + -ATPase activity. Blockade of K IR channels alone or in combination with NO, PGs and Na + /K + -ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α 1 -adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans., Abstract: Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (K IR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α-adrenergic vasoconstriction (sympatholysis). However, K IR channels, NO, PGs and Na + /K + -ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of K IR channels, NO and PG synthesis, and Na + /K + -ATPase would not alter the ability of ATP to blunt α 1 -adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra-arterial infusion of phenylephrine (PE; α 1 -agonist) during ATP or control vasodilatator infusion, before and after K IR channel inhibition alone (barium chloride; n = 7; Protocol 1); NO (l-NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na + /K + -ATPase (ouabain) and K IR channel inhibition (n = 6; Protocol 2). ATP attenuated PE-mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE-mediated ΔFVC: ATP: -16 ± 2; ADO: -38 ± 6; SNP: -59 ± 6%; P < 0.05 vs. ADO and SNP). Blockade of K IR channels alone or combined with NO, PGs and Na + /K + -ATPase, attenuated ATP-mediated vasodilatation (∼35 and ∼60% respectively; P < 0.05 vs. control). However, ATP maintained the ability to blunt PE-mediated vasoconstriction (PE-mediated ΔFVC: K IR blockade alone: -6 ± 5%; combined blockade:-4 ± 14%; P > 0.05 vs. control). These findings demonstrate that intravascular ATP modulates α 1 -adrenergic vasoconstriction via pathways independent of K IR channels, NO, PGs and Na + /K + -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Systemic hypoxia is a physiological and pathophysiological stress that activates the sympathoadrenal system and, in young adults, leads to peripheral vasodilation. We tested the hypothesis that peripheral vasodilation to graded systemic hypoxia is impaired in older healthy adults and that this age-associated impairment is due to attenuated β-adrenergic mediated vasodilation and elevated α-adrenergic vasoconstriction. Forearm blood flow was measured (Doppler ultrasound), and vascular conductance (FVC) was calculated in 12 young (24 ± 1 yr) and 10 older (63 ± 2 yr) adults to determine the local dilatory responses to graded hypoxia (90, 85, and 80% O 2 saturations) in control conditions, following local intra-arterial blockade of β-receptors (propranolol), and combined blockade of α- and β-receptors (phentolamine + propranolol). Under control conditions, older adults exhibited impaired vasodilation to hypoxia compared with young participants at all levels of hypoxia (peak ΔFVC at 80% [Formula: see text] = 4 ± 6 vs. 35 ± 8%; P < 0.01). During β-blockade, older adults actively constricted at 85 and 80% [Formula: see text] (peak ΔFVC at 80% [Formula: see text] = -13 ± 6%; P < 0.05 vs. control), whereas the response in the young was not significantly impacted (peak ΔFVC = 28 ± 8%). Combined α- and β-blockade increased the dilatory response to hypoxia in young adults; however, older adults failed to significantly vasodilate (peak ΔFVC at 80% [Formula: see text]= 12 ± 11% vs. 58 ± 11%; P < 0.05). Our findings indicate that peripheral vasodilation to graded systemic hypoxia is significantly impaired in older adults, which cannot be fully explained by altered sympathoadrenal control of vascular tone. Thus, the impairment in hypoxic vasodilation is likely due to attenuated local vasodilatory and/or augmented vasoconstrictor signaling with age. NEW & NOTEWORTHY We found that the lack of peripheral vasodilation during graded systemic hypoxia with aging is not mediated by the sympathoadrenal system, strongly implicating local vascular control mechanisms in this impairment. Understanding these mechanisms may lead to therapeutic advances for improving tissue blood flow and oxygen delivery in aging and disease., (Copyright © 2017 the American Physiological Society.)

The objectives of this article were: (1) to review common and rare manifestations of systemic and pulmonary Langerhans cell histiocytosis, Rosai-Dorfman disease, Erdheim-Chester disease and juvenile xanthogranuloma; (2) to provide the reader with important pathologic, epidemiologic and clinical features of these diseases. The histiocytoses are a diverse group of diseases which typically manifest with multiorgan involvement. Understanding the pathologic, epidemiologic and clinical features of these entities can help the radiologist suggest an accurate diagnosis of histiocytosis when typical imaging features are encountered.

Asthma is one of the most common diseases of the lung. Asthma manifests with common, although often subjective and nonspecific, imaging features at radiography and high-resolution computed tomography. The primary role of imaging is not to make a diagnosis of asthma but to identify complications, such as allergic bronchopulmonary aspergillosis, or mimics of asthma, such as hypersensitivity pneumonitis. This article reviews the imaging features of asthma as well as common complications and mimics., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Human aging is associated with reduced skeletal muscle perfusion during exercise, which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that 1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (V̇o2) via local vasodilation during graded rhythmic handgrip exercise in older adults (protocol 1), and 2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise (protocol 2). In protocol 1 (n = 8; 65 ± 3 yr), AA did not influence FBF or V̇o2 during rest or 5% maximal voluntary contraction (MVC) exercise, but increased FBF (199 ± 13 vs. 248 ± 16 ml/min and 343 ± 24 vs. 403 ± 33 ml/min; P < 0.05) and V̇o2 (26 ± 2 vs. 34 ± 3 ml/min and 43 ± 4 vs. 50 ± 5 ml/min; P < 0.05) at both 15 and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 (n = 10; 63 ± 2 yr), following AA, FBF was similarly elevated during 15% MVC (∼ 20%); however, vasoconstriction to reflex increases in sympathetic activity during -40 mmHg lower-body negative pressure at rest (ΔFVC: -16 ± 3 vs. -16 ± 2%) or during 15% MVC (ΔFVC: -12 ± 2 vs. -11 ± 4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow and V̇o2 during exercise in older adults via local vasodilation., (Copyright © 2015 the American Physiological Society.)

Diffuse cystic and nodular lung diseases have characteristic imaging findings. The most common causes of cystic lung disease are lymphangioleiomyomatosis and Langerhans cell histiocytosis. Other less common cystic lung diseases include Birt-Hogg-Dube syndrome, lymphocytic interstitial pneumonitis, and light chain deposition disease. Computed tomography is used to differentiate cystic lung disease from emphysema, honeycombing, cavities, and bronchiectasis, which mimic cystic lung disease. Diffuse nodular lung disease are categorized as centrilobular, perilymphatic, and random types. In diffuse nodular lung disease, a specific diagnosis is achieved through a combination of history, physical examination, and imaging findings., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Vaccine biomarkers are critical to many aspects of vaccine development and licensure, including bridging findings in pre-clinical studies to clinical studies, predicting potential adverse events, and predicting vaccine efficacy. Despite advances in our understanding of various biological pathways, and advances in systems analyses of the immune response, there remains much to learn about qualitative and quantitative aspects of the human host response to vaccination. To stimulate discussion and identify opportunities for collaborative ways to advance the field of vaccine biomarkers, A Next Generation Vaccine Biomarker workshop was held in Ottawa. The two day workshop, sponsored by the National Research Council Canada, Canadian Institutes of Health Research, Public Health Agency of Canada, Pfizer, and Medicago, brought together stakeholders from Canadian and international industry, government and academia. The workshop was grouped in themes, covering vaccine biomarker challenges in the pre-clinical and clinical spaces, veterinary vaccines, regulatory challenges, and development of biomarkers for adjuvants and cancer vaccines. The use of case studies allowed participants to identify the needs and gaps requiring innovation. The workshop concluded with a discussion on opportunities for vaccine biomarker discovery, the Canadian context, and approaches for moving forward. This article provides a synopsis of these discussions and identifies steps forward for advancing vaccine biomarker research in Canada.

In healthy humans, ageing is typically associated with reduced skeletal muscle blood flow and vascular conductance during exercise. Further, there is a marked increase in resting sympathetic nervous system (SNS) activity with age, yet whether augmented SNS-mediated α-adrenergic vasoconstriction contributes to the age-associated impairment in exercising muscle blood flow and vascular tone in humans is unknown. We tested the hypothesis that SNS-mediated vasoconstriction is greater in older than young adults and limits muscle (forearm) blood flow (FBF) during graded handgrip exercise (5, 15, 25% maximal voluntary contraction (MVC)). FBF was measured (Doppler ultrasound) and forearm vascular conductance (FVC) was calculated in 11 young (21 ± 1 years) and 12 older (62 ± 2 years) adults in control conditions and during combined local α- and β-adrenoreceptor blockade via intra-arterial infusions of phentolamine and propranolol, respectively. Under control conditions, older adults exhibited significantly lower FBF and FVC at 15% MVC exercise (22.6 ± 1.3 vs. 29 ± 3.3 ml min(-1) 100 g forearm fat-free mass (FFM)(-1) and 21.7 ± 1.2 vs. 33.6 ± 4.0 ml min(-1) 100 g FFM(-1) 100 mmHg(-1); P < 0.05) and 25% MVC exercise (37.4 ± 1.4 vs. 46.0 ± 4.9 ml min(-1) 100 g FFM(-1) and 33.7 ± 1.4 vs. 49.0 ± 5.7 ml min(-1) 100 g FFM(-1) 100 mmHg(-1); P < 0.05), whereas there was no age group difference at 5% MVC exercise. Local adrenoreceptor blockade increased FBF and FVC at rest and during exercise in both groups, although the increase in FBF and FVC from rest to steady-state exercise was similar in young and older adults across exercise intensities, and thus the age-associated impairment in FBF and FVC persisted. Our data indicate that during graded intensity handgrip exercise, the reduced FVC and subsequently lower skeletal muscle blood flow in older healthy adults is not due to augmented sympathetic vasoconstriction, but rather due to impairments in local signalling or structural limitations in the peripheral vasculature with advancing age., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Objectives: To assess the association between exposure, oxidative stress, symptoms, and cardiorespiratory function in wildland firefighters., Methods: We studied two Interagency Hotshot Crews with questionnaires, pulse wave analysis for arterial stiffness, spirometry, urinary 8-iso-prostaglandin F2α (8-isoprostane) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and the smoke exposure marker (urinary levoglucosan). Arterial stiffness was assessed by examining levels of the aortic augmentation index, expressed as a percentage. An oxidative stress score comprising the average of z-scores created for 8-OHdG and 8-isoprostane was calculated., Results: Mean augmentation index % was higher for participants with higher oxidative stress scores after adjusting for smoking status. Specifically for every one unit increase in oxidative stress score the augmentation index % increased 10.5% (95% CI: 2.5, 18.5%). Higher mean lower respiratory symptom score was associated with lower percent predicted forced expiratory volume in one second/forced vital capacity., Conclusions: Biomarkers of oxidative stress may serve as indicators of arterial stiffness in wildland firefighters., (© 2014 Wiley Periodicals, Inc.)

The structure of a antigen-binding fragment (Fab) from the bactericidal monoclonal antibody LPT3-1 specific to lipooligosaccharide (LOS) inner cores from Neisseria meningitidis has been solved in complex with an eight-sugar inner core fragment NmL3 galE lpt3 KOH to 2.69 Å resolution. The epitope is centered about an inner core N-acetylglucosamine residue unique to N. meningitidis and does not include the lipid A moiety, which is disordered in the structure, but is positioned to allow the binding of free and membrane-anchored full-length LOS. All the amino acid residues that contact antigen are of germline origin but, remarkably, two consecutive somatic mutations of serine to glycine in the heavy chain at residues 52 and 52a are positioned to deprive the antibody of advantageous interactions and so weaken binding. However, these mutations are key to allowing selective cross-reactivity with the HepII-3-PEtn inner core variant expressed by 70% of strains. Neisseria meningitidis is a leading cause of disease in the developed world and is especially dangerous to children, who lack the necessary protective antibodies. The structure of Fab LPT3-1 in complex with LOS provides insight into the antibody's selective ability to recognize multiple clinically relevant variations of the LOS inner core from N. meningitidis.

In this study we have prepared glycoconjugates with core oligosaccharides (OS) from the lipopolysaccharide (LPS) of Neisseria meningitidis, thus avoiding the neo-epitopes of the deacylated lipid A region of the derived LPS molecule identified in our previous studies. A comprehensive investigation was performed with glycoconjugates prepared from the most extended to the most truncated core OS still maintaining the conserved inner core epitope. As previously, we have established reproducible bactericidal killing of the homologous antigen elaborating strain, but a failure to kill wild-type strains. In these studies it was evident that the linker molecules used in the conjugation methodologies were dominating the immune response. However, when galE core OS based conjugates were prepared without utilizing linkers, via direct reductive amination, we failed to generate an immune response to even the homologous antigen. We also identified that immunisation with the galE antigen via linker methodologies provoked an immune response that was dependent upon key residues of the conserved inner core OS structure, whereas the immune responses to lgtB and lgtA antigens did not involve the inner core OS. This comprehensive study has, despite our best efforts, cast significant doubt as to the utility of the conserved inner core region of the meningococcal LPS as a potential vaccine antigen.

Novel adjuvants hold the promise for developing effective modern subunit vaccines capable of appropriately modulating the immune response against challenging diseases such as those caused by chronic and/or intracellular pathogens and cancer. Over the past decade there has been intensive research into discovering new adjuvants, however, their translation into routine clinical use is lagging. To stimulate discussion and identify opportunities for networking and collaboration among various stakeholders, a Canadian Adjuvant Initiative Workshop was held in Ottawa. Sponsored by the National Research Council Canada, Canadian Institutes of Health Research and the Vaccine Industry Committee, a two day workshop was held that brought together key Canadian and international stakeholders in adjuvant research from industry, academia and government. To discover innovation gaps and unmet needs, the presentations covered a board range of topics in adjuvant development; criteria for selection of lead adjuvant candidates from an industry perspective, discovery research across Canada, bioprocessing needs and challenges, veterinary vaccines, Canadian vaccine trial capabilities, the Canadian regulatory framework and WHO formulation laboratory experience. The workshop concluded with a discussion on the opportunity to create a Canadian Adjuvant Development Network. This report details the key discussion points and steps forward identified for facilitating adjuvant development research in Canada.

Rationale: Reactive hyperemia (RH) in the forearm circulation is an important marker of cardiovascular health, yet the underlying vasodilator signaling pathways are controversial and thus remain unclear., Objective: We hypothesized that RH occurs via activation of inwardly rectifying potassium (KIR) channels and Na(+)/K(+)-ATPase and is largely independent of the combined production of the endothelial autocoids nitric oxide (NO) and prostaglandins in young healthy humans., Methods and Results: In 24 (23±1 years) subjects, we performed RH trials by measuring forearm blood flow (FBF; venous occlusion plethysmography) after 5 minutes of arterial occlusion. In protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions. For group 1, we studied control (saline), KIR channel inhibition (BaCl2), combined inhibition of KIR channels and Na(+)/K(+)-ATPase (BaCl2 and ouabain, respectively), and combined inhibition of KIR channels, Na(+)/K(+)-ATPase, NO, and prostaglandins (BaCl2, ouabain, L-NMMA [N(G)-monomethyl-L-arginine] and ketorolac, respectively). Group 2 received ouabain rather than BaCl2 in the second trial. In protocol 2 (n=8), the following 3 RH trials were performed: control; L-NMMA plus ketorolac; and L-NMMA plus ketorolac plus BaCl2 plus ouabain. All infusions were intra-arterial (brachial). Compared with control, BaCl2 significantly reduced peak FBF (-50±6%; P<0.05), whereas ouabain and L-NMMA plus ketorolac did not. Total FBF (area under the curve) was attenuated by BaCl2 (-61±3%) and ouabain (-44±12%) alone, and this effect was enhanced when combined (-87±4%), nearly abolishing RH. L-NMMA plus ketorolac did not impact total RH FBF before or after administration of BaCl2 plus ouabain., Conclusions: Activation of KIR channels is the primary determinant of peak RH, whereas activation of both KIR channels and Na(+)/K(+)-ATPase explains nearly all of the total (AUC) RH in humans.

Exercise hyperaemia is regulated by several factors, and one factor known to increase with exercise that evokes a powerful vasomotor action is extracellular ATP. The origin of ATP detected in plasma from exercising muscle of humans is, however, a matter of debate, and ATP has been suggested to arise from sympathetic nerves, blood sources (e.g. erythrocytes), endothelial cells and skeletal myocytes, among others. Therefore, we tested the hypothesis that acute augmentation of sympathetic nervous system activity (SNA) results in elevated plasma ATP draining skeletal muscle, and that SNA superimposition during exercise increases ATP more than exercise alone. We showed that increased SNA via -40 mmHg lower body negative pressure (LBNP) at rest did not increase plasma ATP (51±8 nmol l(-1) at rest versus 58±7 nmol l(-1) with LBNP), nor did it increase [ATP] above levels observed during rhythmic hand-grip exercise (79±11 nmol l(-1) with exercise alone versus 71±8 nmol l(-1) with LBNP). Next, we tested the hypothesis that active perfusion of skeletal muscle is essential to observe increased plasma ATP during exercise. We showed that complete obstruction of blood flow to contracting muscle abolished exercise-mediated increases in plasma ATP (from 90±19 to 49±12 nmol l(-1)), and that cessation of blood flow prior to exercise completely inhibited the typical rise in ATP (3 versus 61%, obstructed versus intact perfusion). The lack of change in ATP during occlusion occurred in the face of continued muscular work and elevated SNA, indicating that the rise of intravascular ATP did not result from these extravascular sources. Our collective observations indicated that the elevation in extracellular ATP observed in blood during exercise was unlikely to originate from sympathetic nerves or the contacting muscle itself, but rather was dependent on intact skeletal muscle perfusion. We conclude that an intravascular source for ATP is essential, which indicates an important role for blood sources (e.g. red blood cells) in augmenting and maintaining elevated plasma ATP during exercise.

Intravascular adenosine triphosphate (ATP) evokes vasodilation and is implicated in the regulation of skeletal muscle blood flow during exercise. Mechanical stresses to erythrocytes and endothelial cells stimulate ATP release in vitro. How mechanical effects of muscle contractions contribute to increased plasma ATP during exercise is largely unexplored. We tested the hypothesis that simulated mechanical effects of muscle contractions increase [ATP](venous) and ATP effluent in vivo, independent of changes in tissue metabolic demand, and further increase plasma ATP when superimposed with mild-intensity exercise. In young healthy adults, we measured forearm blood flow (FBF) (Doppler ultrasound) and plasma [ATP](v) (luciferin-luciferase assay), then calculated forearm ATP effluent (FBF×[ATP](v)) during rhythmic forearm compressions (RFC) via a blood pressure cuff at three graded pressures (50, 100, and 200 mmHg; Protocol 1; n = 10) and during RFC at 100 mmHg, 5% maximal voluntary contraction rhythmic handgrip exercise (RHG), and combined RFC + RHG (Protocol 2; n = 10). [ATP](v) increased from rest with each cuff pressure (range 144-161 vs. 64 ± 13 nmol/l), and ATP effluent was graded with pressure. In Protocol 2, [ATP](v) increased in each condition compared with rest (RFC: 123 ± 33; RHG: 51 ± 9; RFC + RHG: 96 ± 23 vs. Mean Rest: 42 ± 4 nmol/l; P < 0.05), and ATP effluent was greatest with RFC + RHG (RFC: 5.3 ± 1.4; RHG: 5.3 ± 1.1; RFC + RHG: 11.6 ± 2.7 vs. Mean Rest: 1.2 ± 0.1 nmol/min; P < 0.05). We conclude that the mechanical effects of muscle contraction can 1) independently elevate intravascular ATP draining quiescent skeletal muscle without changes in local metabolism and 2) further augment intravascular ATP during mild exercise associated with increases in metabolism and local deoxygenation; therefore, it is likely one stimulus for increasing intravascular ATP during exercise in humans.