Headpulse measurement can reliably identify large-vessel occlusion stroke in prehospital suspected stroke patients: Results from the EPISODE-PS-COVID study.

BACKGROUND: Large-vessel occlusion (LVO) stroke represents one-third of acute ischemic stroke (AIS) in the United States but causes two-thirds of poststroke dependence and >90% of poststroke mortality. Prehospital LVO stroke detection permits efficient emergency medical systems (EMS) transport to an endovascular thrombectomy (EVT)-capable center. Our primary objective was to determine the feasibility of using a cranial accelerometry (CA) headset device for prehospital LVO stroke detection. Our secondary objective was development of an algorithm capable of distinguishing LVO stroke from other conditions. METHODS: We prospectively enrolled consecutive adult patients suspected of acute stroke from 11 study hospitals in four different U.S. geographical regions over a 21-month period. Patients received device placement by prehospital EMS personnel. Headset data were matched with clinical data following informed consent. LVO stroke diagnosis was determined by medical chart review. The device was trained using device data and Los Angeles Motor Scale (LAMS) examination components. A binary threshold was selected for comparison of device performance to LAMS scores. RESULTS: A total of 594 subjects were enrolled, including 183 subjects who received the second-generation device. Usable data were captured in 158 patients (86.3%). Study subjects were 53% female and 56% Black/African American, with median age 69 years. Twenty-six (16.4%) patients had LVO and 132 (83.6%) were not LVO (not-LVO AIS, 33; intracerebral hemorrhage, nine; stroke mimics, 90). COVID-19 testing and positivity rates (10.6%) were not different between groups. We found a sensitivity of 38.5% and specificity of 82.7% for LAMS ≥ 4 in detecting LVO stroke versus a sensitivity of 84.6% (p < 0.0015 for superiority) and specificity of 82.6% (p = 0.81 for superiority) for the device algorithm (CA + LAMS). CONCLUSIONS: Obtaining adequate recordings with a CA headset is highly feasible in the prehospital environment. Use of the device algorithm incorporating both CA and LAMS data for LVO detection resulted in significantly higher sensitivity without reduced specificity when compared to the use of LAMS alone.

Custom nasal obturator for velopharyngeal dysfunction: Digitizing the fabrication process.

Nasal obturation using a removable medical device is a suitable treatment option for patients with velopharyngeal dysfunction. In the United Kingdom in recent years, the use of nasal obturation has increased because of the successful collaborations among the Speech and Language Therapy, Restorative Dentistry, and Maxillofacial departments. However, fabrication of the devices requires specialist skill and considerable time. A digital process which facilitates the rapid, cost effective production of a light, comfortable, unobtrusive nasal obturator is described.

Inhaled Nanoparticles Accumulate at Sites of Vascular Disease.

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.

Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice.

OBJECTIVE: Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE-/-) mice. METHODS: ApoE-/- mice were fed a 'Western diet' (8 weeks) to induce 'complex' atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 µL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery. RESULTS: Brachiocephalic atherosclerotic plaques were larger in ApoE-/- mice treated with DEP (59 ± 10%) than in controls (32 ± 7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4 ± 0.2 vs 1.8 ± 0.2; P = 0.048) and buried fibrous layers (1.2 ± 0.2 vs 0.4 ± 0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation. CONCLUSIONS: Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.

Vascular effects of urocortins 2 and 3 in healthy volunteers.

BACKGROUND: Urocortin 2 and urocortin 3 are endogenous peptides with an emerging role in cardiovascular pathophysiology. We assessed their pharmacodynamic profile and examined the role of the endothelium in mediating their vasomotor effects in vivo in man. METHODS AND RESULTS: Eighteen healthy male volunteers (23±4 years) were recruited into a series of double-blind, randomized crossover studies using bilateral forearm venous occlusion plethysmography during intra-arterial urocortin 2 (3.6 to 120 pmol/min), urocortin 3 (1.2 to 36 nmol/min), and substance P (2 to 8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole), and nitric oxide synthase (L-NMMA). Urocortins 2 and 3 evoked arterial vasodilatation (P<0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L-NMMA reduced vasodilatation to substance P and urocortin 2 (P≤0.001 for both) but had little effect on urocortin 3 (P>0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P>0.05 for all). In the presence of all 3 inhibitors, urocortin 2- and urocortin 3-induced vasodilatation was attenuated (P<0.001 for all) to a greater extent than with L-NMMA alone (P≤0.005). CONCLUSIONS: Urocortins 2 and 3 cause potent and prolonged arterial vasodilatation without tachyphylaxis. These vasomotor responses are at least partly mediated by endothelial nitric oxide and cytochrome P450 metabolites of arachidonic acid. The role of urocortins 2 and 3 remains to be explored in the setting of human heart failure, but they have the potential to have major therapeutic benefits. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov//. Unique identifier: NCT01096706 and NCT01296607.

Diesel exhaust particulate induces pulmonary and systemic inflammation in rats without impairing endothelial function ex vivo or in vivo.

BACKGROUND: Inhalation of diesel exhaust impairs vascular function in man, by a mechanism that has yet to be fully established. We hypothesised that pulmonary exposure to diesel exhaust particles (DEP) would cause endothelial dysfunction in rats as a consequence of pulmonary and systemic inflammation. METHODS: Wistar rats were exposed to DEP (0.5 mg) or saline vehicle by intratracheal instillation and hind-limb blood flow, blood pressure and heart rate were monitored in situ 6 or 24 h after exposure. Vascular function was tested by administration of the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in vivo and ex vivo in isolated rings of thoracic aorta, femoral and mesenteric artery from DEP exposed rats. Bronchoalveolar lavage fluid (BALF) and blood plasma were collected to assess pulmonary (cell differentials, protein levels & interleukin-6 (IL-6)) and systemic (IL-6), tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP)) inflammation, respectively. RESULTS: DEP instillation increased cell counts, total protein and IL-6 in BALF 6 h after exposure, while levels of IL-6 and TNFα were only raised in blood 24 h after DEP exposure. DEP had no effect on the increased hind-limb blood flow induced by ACh in vivo at 6 or 24 h. However, responses to SNP were impaired at both time points. In contrast, ex vivo responses to ACh and SNP were unaltered in arteries isolated from rats exposed to DEP. CONCLUSIONS: Exposure of rats to DEP induces both pulmonary and systemic inflammation, but does not modify endothelium-dependent vasodilatation. Other mechanisms in vivo limit dilator responses to SNP and these require further investigation.

The biological effects of subacute inhalation of diesel exhaust following addition of cerium oxide nanoparticles in atherosclerosis-prone mice.

BACKGROUND: Cerium oxide (CeO(2)) nanoparticles improve the burning efficiency of fuel, however, little is known about health impacts of altered emissions from the vehicles. METHODS: Atherosclerosis-prone apolipoprotein E knockout (ApoE(-/-)) mice were exposed by inhalation to diluted exhaust (1.7 mg/m(3), 20, 60 or 180 min, 5 day/week, for 4 weeks), from an engine using standard diesel fuel (DE) or the same diesel fuel containing 9 ppm cerium oxide nanoparticles (DCeE). Changes in hematological indices, clinical chemistry, atherosclerotic burden, tissue levels of inflammatory cytokines and pathology of the major organs were assessed. RESULTS: Addition of CeO(2) to fuel resulted in a reduction of the number (30%) and surface area (10%) of the particles in the exhaust, whereas the gaseous co-pollutants were increased (6-8%). There was, however, a trend towards an increased size and complexity of the atherosclerotic plaques following DE exposure, which was not evident in the DCeE group. There were no clear signs of altered hematological or pathological changes induced by either treatment. However, levels of proinflammatory cytokines were modulated in a brain region and liver following DCeE exposure. CONCLUSIONS: These results imply that addition of CeO(2) nanoparticles to fuel decreases the number of particles in exhaust and may reduce atherosclerotic burden associated with exposure to standard diesel fuel. From the extensive assessment of biological parameters performed, the only concerning effect of cerium addition was a slightly raised level of cytokines in a region of the central nervous system. Overall, the use of cerium as a fuel additive may be a potentially useful way to limit the health effects of vehicle exhaust. However, further testing is required to ensure that such an approach is not associated with a chronic inflammatory response which may eventually cause long-term health effects.

Direct impairment of vascular function by diesel exhaust particulate through reduced bioavailability of endothelium-derived nitric oxide induced by superoxide free radicals.

BACKGROUND: Diesel exhaust particulate (DEP) is a key arbiter of the adverse cardiovascular effects of air pollution. OBJECTIVES: We assessed the in vitro effects of DEP on vascular function, nitric oxide (NO) availability, and the generation of oxygen-centered free radicals. METHODS: We assessed the direct vascular effects of DEP (10-100 microg/mL) in isolated rat aortic rings using myography. We investigated NO scavenging and oxygen-centered free radical generation using an NO electrode and electron paramagnetic resonance (EPR) with the Tempone-H (1-hydroxyl-2,2,6,6-tetramethyl-4-oxo-piperidine) spin trap, respectively. RESULTS: Acetylcholine-induced relaxation was attenuated by DEP (maximum relaxation reduced from 91 +/- 4% to 49 +/- 6% with 100 microg/mL DEP; p < 0.001) but was restored by superoxide dismutase (SOD; maximum relaxation, 73 +/- 6%; p < 0.001). DEP caused a modest inhibition of relaxation to NO donor drugs, an effect that could be reversed by SOD (p < 0.01). At 10 microg/mL, DEP did not affect verapamil-induced relaxation (p = 0.73), but at 100 microg/mL DEP inhibited relaxation (p < 0.001) by a mechanism independent of SOD. NO concentrations generated by 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO; 10 microM) were reduced by DEP (100 microg/mL; from 5.2 +/- 0.4 to 3.3 +/- 0.4 microM; p = 0.002). Free radical generation was increased by DEP (10 microg/mL; 9-fold increase in EPR spectra; p = 0.004) in a manner that could be attenuated by SOD (p = 0.015). CONCLUSIONS: DEP caused oxidative stress through the generation of oxygen-centered free radicals that reduced the bioavailability of endothelium-derived NO without prior interaction with the lung or vascular tissue. These findings provide a mechanism for the adverse cardiovascular effects of particulate air pollution.

Differential effects of doses and forms of dietary selenium on immune cell numbers in the skin of ultraviolet-irradiated and unirradiated mice.

The effect of three different doses of dietary L-selenomethionine (SM) and sodium selenite (SS) on skin selenium (Se) content, glutathione peroxidase (GPx) activity, Langerhans cell (LC) and mast cell numbers in ultraviolet radiation-B (UVB)-irradiated and unirradiated C3H/HeN mice was determined. After weaning, groups of mice were given Se-deficient, Se-adequate, or Se-high diets. Six weeks later, some animals in each group were exposed to a single UVB dose (acute), while others were exposed three times weekly for the following 40 weeks (chronic). The skin Se content and GPx activity increased in all the Se-supplemented groups, and the latter was not altered by UVB exposure. Generally, the Se-containing diets caused an increase in LC numbers at 6 weeks and a further rise at 40 weeks, but did not prevent the loss induced by acute or chronic UVB radiation. Skin mast cell numbers were highest in animals fed the Se-deficient diet after 6 and 40 weeks. Acute and chronic UVB radiation decreased the mast cell number and dietary Se did not prevent the reduction. While the present study shows that Se plays an important role in governing the number of LCs and mast cells in the skin, no protective effect against the immunomodulating properties of UVB radiation on these cell types was observed. However, this conclusion may only apply to the experimental conditions chosen, and additional studies at different Se dosages and reduced intensities of chronic UVB exposure are required to confirm the results.

Lack of effect of oral selenite on p53 associated gene expression during TL01 therapy of psoriasis patients.

Selenium (Se) has protective properties against ultraviolet (UV)-induced changes in skin cells in vitro but little is known about such activity in human subjects. In the present study, seven patients with psoriasis ingested 400 microg of sodium selenite daily during a 4 week course of whole-body narrow-band UVB (TL01) therapy while six more psoriasis patients, similarly irradiated, ingested a placebo. Skin biopsies, collected at the start and end of the phototherapy were analysed for phosphorylated p53, Fas, Bcl-2, Bax and oxidized guaninosine, and for numbers of Langerhans and sunburn cells. Following the TL01 therapy, no significant difference was observed for any of these markers when the Se group was compared with the placebo group of patients, although p53 and Bcl-2 expression decreased in the Se supplemented group.

On being a supervisor: the importance of feedback and how to give it.

OBJECTIVE: We outline some of the dominant opinions regarding the provision of formative feedback, as expressed by both trainees and their supervisors. METHODS: Trainee psychiatrists and their supervisors were interviewed and asked to identify 'good' as opposed to 'poor' supervision. RESULTS: A recurrent theme in interview data was that of formative feedback. Trainees expressed a desire to receive it, but some supervisors discussed misgivings and a lack of skill in providing such feedback. CONCLUSIONS: Formative feedback is an essential part of the supervisor's role. We describe the principles of how to best deliver feedback, in order to increase supervisors' confidence and ability in utilizing this learning and teaching skill.