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Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O 2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia-neuronal activity-to-vascular response-the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae., (© 2024. The Author(s).)

Mutations in PSEN1 were first discovered as a cause of Alzheimer's disease (AD) in 1995, yet the mechanism(s) by which the mutations cause disease still remains unknown. The generation of novel mouse models assessing the effects of different mutations could aid in this endeavor. Here we report on transgenic mouse lines made with the Δ440 PSEN1 mutation that causes AD with parkinsonism:- two expressing the un-tagged human protein and two expressing a HA-tagged version. Detailed characterization of these lines showed that Line 305 in particular, which expresses the untagged protein, develops age-dependent memory deficits and pathologic features, many of which are consistent with features found in AD. Key behavioral and physiological alterations found in the novel 305 line included an age-dependent deficit in spontaneous alternations in the Y-maze, a decrease in exploration of the center of an open field box, a decrease in the latency to fall on a rotarod, a reduction in synaptic strength and pair-pulse facilitation by electrophysiology, and profound alterations to cerebral blood flow regulation. The pathologic alterations found in the line included, significant neuronal loss in the hippocampus and cortex, astrogliosis, and changes in several proteins involved in synaptic and mitochondrial function, Ca2+ regulation, and autophagy. Taken together, these findings suggest that the transgenic lines will be useful for the investigation of AD pathogenesis., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Telecare and telehealth are important care-at-home services used to support individuals to live more independently at home. Historically, these technologies have reactively responded to issues. However, there has been a recent drive to make better use of the data from these services to facilitate more proactive and predictive care., Objective: This review seeks to explore the ways in which predictive data analytics techniques have been applied in telecare and telehealth in at-home settings., Methods: The PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist was adhered to alongside Arksey and O'Malley's methodological framework. English language papers published in MEDLINE, Embase, and Social Science Premium Collection between 2012 and 2022 were considered and results were screened against inclusion or exclusion criteria., Results: In total, 86 papers were included in this review. The types of analytics featuring in this review can be categorized as anomaly detection (n=21), diagnosis (n=32), prediction (n=22), and activity recognition (n=11). The most common health conditions represented were Parkinson disease (n=12) and cardiovascular conditions (n=11). The main findings include: a lack of use of routinely collected data; a dominance of diagnostic tools; and barriers and opportunities that exist, such as including patient-reported outcomes, for future predictive analytics in telecare and telehealth., Conclusions: All papers in this review were small-scale pilots and, as such, future research should seek to apply these predictive techniques into larger trials. Additionally, further integration of routinely collected care data and patient-reported outcomes into predictive models in telecare and telehealth offer significant opportunities to improve the analytics being performed and should be explored further. Data sets used must be of suitable size and diversity, ensuring that models are generalizable to a wider population and can be appropriately trained, validated, and tested., (©Euan Anderson, Marilyn Lennon, Kimberley Kavanagh, Natalie Weir, David Kernaghan, Marc Roper, Emma Dunlop, Linda Lapp. Originally published in the Online Journal of Public Health Informatics (https://ojphi.jmir.org/), 07.08.2024.)

Background: Studies routinely evaluate high ankle sprains in isolation, but recent data suggest that these injuries are often associated with concomitant pathology, potentially influencing return to full participation., Hypothesis: In National Football League (NFL) players, isolated high ankle sprains are rare and syndesmosis injuries with concomitant pathology will result in increased time to return to full participation., Study Design: Cross-sectional study., Level of Evidence: Level 3., Methods: Distal tibiofibular syndesmosis injuries sustained by NFL players between 2017 and 2019 were identified through NFL Injury Surveillance Database queries and verified with video analysis. Each injury underwent a comprehensive magnetic resonance imaging (MRI) review. Regression modeling was utilized to explore the influence of numerous imaging findings on time to return to full participation., Results: There were 83 external rotation ankle injuries involving the syndesmosis. Isolated distal tibiofibular syndesmosis injuries were rare (n = 11; 13%) and more often associated with other ligamentous injury (deltoid ligament and lateral ligamentous complex) and/or fractures. Regression modeling resulted in clustering of 3 injury pattern groups for time to return to full participation across numerous imaging findings: syndesmosis injury-fracture combinations (250 days [interquartile range [IQR,] 142-266 days]), syndesmosis injury with complete deep deltoid tear or acute diastasis (175 days [IQR, 20-248 days]), and all other syndesmosis injuries (27 days [IQR, 18-46 days])., Conclusion: In NFL athletes with external rotation ankle injuries, isolated distal tibiofibular syndesmosis injuries were rare and more often associated with concomitant pathology. Time to return to full participation was affected by an associated fracture and complete deep deltoid ligament tear or diastasis but no other relevant MRI variables such as lateral ligament complex involvement or the presence of osteochondral lesions or bone contusions., Competing Interests: The following authors declared potential conflicts of interest: M.J.C. has received royalties or licenses from Arthrex, Stryker, and Smith & Nephew, consulting fees from Donjoy, and patents from Tenova Tenodesis Screw. M.M.H. has received consulting fees from the National Football League (NFL) and is a full-time employee of IQVIA. N.W. has received consulting fees from the NFL and is a full-time employee of the Green Bay Packers. E.M.S. has received consulting fees from the NFL and is a full-time employee of Biocore. C.M.O. has received consulting fees from the NFL and is a full-time employee of Biocore. R.B.A. has received royalties or licenses from Stryker and Artelon, and consulting fees from Stryker, Envois, Arthrex, Artelon, OsteoRemedies, and Nuvasive.

Fundamental motor skills (FMS) are the cornerstone of a child's motor development, but concerns remain on the current level of FMS competencies, and intervention is required. This evaluation investigated if a targeted Early Years FMS intervention, delivered by a specialist physical education (PE) provider, improved the FMS of 4-5-year-old children across multiple sites., Methods: The Early Years FMS intervention ran for 18 weeks, 1 h/week, using a standardised programme of activities to develop FMS competencies across 219 children from 15 schools in the Midlands, UK. An adapted assessment was employed as a measure of FMS, assessing locomotor, object control, and stability skills at weeks 1, 9, and 18. The FMS were each rated as green = competent, amber = working towards, or red = not meeting the standards of the skill. A description of key programme implementation characteristics was described., Findings: Statistically significant increases in FMS competencies were achieved for 80% of participants at 18 weeks. Key implementation characteristics for the intervention included consistent staffing, a standardised programme, and a variety of pedagogical approaches delivered by specialist PE staff., Conclusion: This evaluation provided important insights into the effectiveness and implementation of the Early Years FMS intervention to improve FMS competencies in children aged 4-5 years.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1 ) consensus on endpoints mirroring the lived experiences of patients with IPF; 2 ) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3 ) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Background: The introduction of clinical pharmacy services is part of a multi-disciplinary approach to reduce pressure on primary care. Ascertaining the impact of clinical pharmacists in general practice is vital to ensure intended benefits are achieved. However, this is complicated by poor quality evidence, multiple interventions, and a lack of agreement regarding outcome measures., Objectives: To develop an outcomes framework for clinical pharmacy services delivered in Scottish general practice using a consensus methodology., Methods: A modified nominal group technique (NGT) was conducted using Microsoft Teams and Qualtrics. This involved a pre-NGT questionnaire, silent generation of ideas, round robin, discussions, ranking, and a final consensus exercise. A selective sampling strategy recruited experienced pharmacists from Scottish health regions. NGT ranking results were used to signify relative importance of the outcome areas. NGT discussions underwent inductive thematic analysis to explore key areas considered., Result: Overall, 13 (median: 24 years of experience) pharmacists participated, representing 11 of 14 Scottish regions. In total, 21 outcome areas, derived from the literature and a pre-NGT questionnaire, were considered during the NGT ranking exercise. Consensus identified five important outcome areas: Patient Experience, Medication Related Adverse Events, Cost-Effectiveness, Medication Optimisation, and Health Related Quality of Life. Thematic analysis highlighted the importance of the outcome framework's target audience, factors influencing the interpretation of outcomes, and the feasibility of the associated outcome measures., Conclusions: The five key outcome areas will facilitate evidence-based decisions regarding service delivery. Future work should develop a measurement plan, involving routinely collected sources of outcomes data. The feasibility of collecting outcomes in the real-world context should be considered, identifying measures which are easy to collect within existing data infrastructures. This paper describes a replicable method to gain consensus for a national approach to data collection from a strong theoretical basis using an online methodology., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite the availability of extensive literature on the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes, the evidence is still controversial. We aimed to provide a comprehensive assessment of the effect of ACEIs/ARBs on COVID-19-related outcomes by summarising the currently available evidence., Methods: An umbrella review was conducted using Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1 February 2021. Systematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19-related clinical outcomes were eligible. Studies' quality was appraised using the AMSTAR 2 Critical Appraisal Tool. Data were analysed using the random-effects modelling including several subgroup analyses. Heterogenicity was assessed using I 2 statistic. The study protocol was registered in PROSPERO (CRD42021233398) and reported using PRISMA guidelines., Results: Overall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR = 0.80, 95%CI = 0.75-0.86; I 2  = 51.9%), death/ICU admission as composite outcome (OR = 0.86, 95%CI = 0.80-0.92; I 2  = 43.9%), severe COVID-19 (OR = 0.86, 95%CI = 0.78-0.95; I 2  = 68%) and hospitalisation (OR = 1.23, 95%CI = 1.04-1.46; I 2  = 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR = 0.63, 95%CI = 0.47-0.84) and were of moderate quality (OR = 0.74, 95%CI = 0.63-0.85)., Conclusions: Collective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Abstract: Neuropathic pain, such as that seen in diabetes mellitus, results in part from central sensitisation in the dorsal horn. However, the mechanisms responsible for such sensitisation remain unclear. There is evidence that disturbances in the integrity of the spinal vascular network can be causative factors in the development of neuropathic pain. Here we show that reduced blood flow and vascularity of the dorsal horn leads to the onset of neuropathic pain. Using rodent models (type 1 diabetes and an inducible endothelial-specific vascular endothelial growth factor receptor 2 knockout mouse) that result in degeneration of the endothelium in the dorsal horn, we show that spinal cord vasculopathy results in nociceptive behavioural hypersensitivity. This also results in increased hypoxia in dorsal horn neurons, depicted by increased expression of hypoxia markers such as hypoxia inducible factor 1α, glucose transporter 3, and carbonic anhydrase 7. Furthermore, inducing hypoxia through intrathecal delivery of dimethyloxalylglycine leads to the activation of dorsal horn neurons as well as mechanical and thermal hypersensitivity. This shows that hypoxic signalling induced by reduced vascularity results in increased hypersensitivity and pain. Inhibition of carbonic anhydrase activity, through intraperitoneal injection of acetazolamide, inhibited hypoxia-induced pain behaviours. This investigation demonstrates that induction of a hypoxic microenvironment in the dorsal horn, as occurs in diabetes, is an integral process by which neurons are activated to initiate neuropathic pain states. This leads to the conjecture that reversing hypoxia by improving spinal cord microvascular blood flow could reverse or prevent neuropathic pain., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Introduction: The coronavirus (COVID-19) pandemic has impacted healthcare worldwide. It has altered service delivery and posed challenges to practitioners in relation to workload, well-being and support. Within primary care, changes in physicians' activities have been identified and innovative work solutions implemented. However, evidence is lacking regarding the impact of the pandemic on pharmacy personnel who work in primary care., Aim: To explore the impact of the pandemic on the working practice (including the type of services provided) and job satisfaction of pharmacists and pharmacy technicians within Scottish general practice. Due to the stressful nature of the pandemic, we hypothesise that job satisfaction will have been negatively affected., Methods: An online questionnaire was distributed in May-July 2021, approximately 15 months since initial lockdown measures in the UK. The questionnaire was informed by previous literature and underwent expert review and piloting. Analysis involved descriptive statistics, non-parametric statistical tests and thematic analysis., Results: 180 participants responded (approximated 16.1% response rate): 134 pharmacists (74.4%) and 46 technicians (25.6%). Responses indicated greater involvement with administrative tasks and a reduction in the provision of clinical services, which was negatively perceived by pharmacists. There was an increase in remote working, although most participants continued to have a physical presence within general practices. Face-to-face interactions with patients reduced, which was negatively perceived by participants, and telephone consults were considered efficient yet less effective. Professional development activities were challenged by increased workloads and reduced support available. Although workplace stress was apparent, there was no indication of widespread job dissatisfaction., Conclusion: The pandemic has impacted pharmacists and technicians, but it is unknown if changes will be permanent, and there is a need to understand which changes should continue. Future research should explore the impact of altered service delivery, including remote working, on patient care.

Background: Bioprosthetic valve thrombosis may have implications for valve function and durability., Objectives: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves., Methods: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves. In a prospective cross-sectional study, patients with either bioprosthetic or normal native aortic valves underwent echocardiography, CT angiography, and 18F-GP1 PET-CT., Results: Flow cytometric analysis, histology, immunohistochemistry, and autoradiography demonstrated selective binding of 18F-GP1 to activated platelet glycoprotein IIb/IIIa receptors and thrombus adherent to prosthetic valves. In total, 75 participants were recruited: 53 with bioprosthetic valves (median time from implantation 37 months [IQR: 12-80 months]) and 22 with normal native aortic valves. Three participants had obstructive valve thrombosis, and a further 3 participants had asymptomatic hypoattenuated leaflet thickening on CT angiography. All bioprosthetic valves, but none of the native aortic valves, demonstrated focal 18F-GP1 uptake on the valve leaflets: median maximum target-to-background ratio 2.81 (IQR: 2.29-3.48) vs 1.43 (IQR: 1.28-1.53) (P < 0.001). Higher 18F-GP1 uptake was independently associated with duration of valve implantation and hypoattenuated leaflet thickening. All 3 participants with obstructive valve thrombosis were anticoagulated for 3 months, leading to resolution of their symptoms, improvement in mean valve gradients, and a reduction in 18F-GP1 uptake., Conclusions: Adherence of activated platelets is a common and sustained finding on bioprosthetic aortic valves. 18F-GP1 uptake is higher in the presence of thrombus, regresses with anticoagulation, and has potential use as an adjunctive clinical tool. (18F-GP1 PET-CT to Detect Bioprosthetic Aortic Valve Thrombosis; NCT04073875)., Competing Interests: Funding Support and Author Disclosures This work was funded by the British Heart Foundation, London, United Kingdom (RG/16/10/32375 and PG/19/40/34422). The Edinburgh Clinical Research Facilities and Edinburgh Imaging facility is supported by the National Health Service Research Scotland (NRS) through National Health Service Lothian Health Board. This work and Drs Bing, Tzolos, Williams, Dweck, and Newby are supported by the British Heart Foundation (PG/19/40/34422, FS/ICRF/20/26002, FS/CRTF/20/24086, FS/14/78/31020, CH/09/002, RG/16/10/32375, RE/18/5/34216, FS/SCRF/21/32010). Dr van Beek is supported by the Scottish Imaging Network. Dr Sellers is supported by fellowships from the Michael Smith Foundation for Health Research and the Canadian Institutes of Health Research. Drs Koglin and Stephens are employees of Life Molecular Imaging GmbH, who provided reagents for radiotracer production. Dr Leipsic is supported by a Canadian Research Chair in Advanced CardioPulmonary Imaging and the Jon DeHaan Award for Innovation in Cardiology; is a consultant for Edward Lifesciences; and provides computed tomography core laboratory services to Edwards Lifesciences, Medtronic, Neovasc, Aegis, and Tendyne, for which no direct compensation is received. Dr Williams is supported by The Chief Scientist Office of the Scottish Government Health and Social Care Directorates (PCL/17/04). Dr Newby is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Relative to two-dimensional (2D) culture, three-dimensional (3D) culture of primary neurons has yielded increasingly physiological responses from cells. Electrospun nanofiber scaffolds are frequently used as a 3D biomaterial support for primary neurons in neural tissue engineering, while hydrophobic surfaces typically induce aggregation of cells. Poly-l-lactic acid (PLLA) was electrospun as aligned PLLA nanofiber scaffolds to generate a structure with both qualities. Primary cortical neurons from E18 Sprague-Dawley rats cultured on aligned PLLA nanofibers generated 3D clusters of cells that extended highly aligned, fasciculated neurite bundles within 10 days. These clusters were viable for 28 days and responsive to AMPA and GABA. Relative to the 2D culture, the 3D cultures exhibited a more developed profile; mass spectrometry demonstrated an upregulation of proteins involved in cortical lamination, polarization, and axon fasciculation and a downregulation of immature neuronal markers. The use of artificial neural network inference suggests that the increased formation of synapses may drive the increase in development that is observed for the 3D cell clusters. This research suggests that aligned PLLA nanofibers may be highly useful for generating advanced 3D cell cultures for high-throughput systems.

Background: Serum lipoproteins, such as high-density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical end-points in IPF., Methods: Clinical data and serum lipids were analysed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicentre cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical end-points (forced vital capacity, 6-min walk distance, gender age physiology (GAP) index, death or lung transplantation) were examined using Pearson's correlation and multivariable analyses., Results: Serum concentrations of small HDL particles measured using nuclear magnetic resonance spectroscopy (S-HDLP NMR ) correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLP NMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLP NMR were associated with lower odds of death or its competing outcome, lung transplantation (OR 0.9 for each 1-μmol·L -1 increase in S-HDLP NMR , p<0.05), at 1, 2 and 3 years from study entry in a combined cohort of all IPF subjects., Conclusions: Higher serum levels of S-HDLP NMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLP NMR may modify mortality risk in patients with IPF., Competing Interests: Conflict of interest: A.V. Barochia has nothing to disclose. Conflict of interest: M. Kaler has nothing to disclose. Conflict of interest: N. Weir has nothing to disclose. Conflict of interest: E.M. Gordon has nothing to disclose. Conflict of interest: D.M. Figueroa has nothing to disclose. Conflict of interest: X. Yao has nothing to disclose. Conflict of interest: M. Lemma WoldeHanna has nothing to disclose. Conflict of interest: M. Sampson has nothing to disclose. Conflict of interest: A.T. Remaley has nothing to disclose. Conflict of interest: G. Grant has nothing to disclose. Conflict of interest: S.D. Barnett has nothing to disclose. Conflict of interest: S.D. Nathan is a consultant and is on the speakers’ bureau for Roche-Genentech and Boehringer Ingelheim, and has received research funding from both companies. Conflict of interest: S.J. Levine has nothing to disclose., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2021. For commercial reproduction rights and permissions contact permissions@ersnet.org.)

Due to work load pressures in primary care, increasing efforts are being made internationally to implement pharmacists working alongside general practitioners. While there is wide interest in the contributions pharmacists can make within primary care, there is limited research which explores the competencies pharmacists need to safely and effectively provide care in this arena. Therefore, a modified eDelphi study was conducted between July 2019 and January 2020 among pharmacists working in General Practice in Scotland in order to (a) generate a list of competencies required to undertake pharmacotherapy tasks within General Practice using content analysis; and (b) establish consensus regarding the importance of these competencies using a rating scale ranging from 1 ("not important") to 10 ("very important"). A framework of competencies was developed, containing eight competency categories with a total of 31 individual competency items. Overall, study participants considered all eight competency categories as being important, with a mode of 10 and a median >8; agreement among participants was high, with the majority of individual competency items rated 8 or above by more than 75% of participants. There was, however, variation in responses with regards to specific tasks such as medicines reconciliation and medication compliance reviews. Findings indicate that the GP setting requires a broad set of competencies-covering areas including the use of IT systems; clinical knowledge; and communicating with patients and other healthcare professionals. This implies that further emphasis on clinical and consultation skills should be added to training programmes aimed at GP pharmacists; furthermore, ongoing support is also needed with regards to generic skills such as the use of IT systems, documentation, and general procedures and processes within primary care, some of which might need to be tailored to the specific practice context., (© 2021 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

Prostaglandin E 2 (PGE 2 ) has been widely proposed to mediate neurovascular coupling by dilating brain parenchymal arterioles through activation of prostanoid EP4 receptors. However, our previous report that direct application of PGE 2 induces an EP1-mediated constriction strongly argues against its direct action on arterioles during neurovascular coupling, the mechanisms sustaining functional hyperemia. Recent advances have highlighted the role of capillaries in sensing neuronal activity and propagating vasodilatory signals to the upstream penetrating parenchymal arteriole. Here, we examined the effect of capillary stimulation with PGE 2 on upstream arteriolar diameter using an ex vivo capillary-parenchymal arteriole preparation and in vivo cerebral blood flow measurements with two-photon laser-scanning microscopy. We found that PGE 2 caused upstream arteriolar dilation when applied onto capillaries with an EC 50 of 70 nM. The response was inhibited by EP1 receptor antagonist and was greatly reduced, but not abolished, by blocking the strong inward-rectifier K + channel. We further observed a blunted dilatory response to capillary stimulation with PGE 2 in a genetic mouse model of cerebral small vessel disease with impaired functional hyperemia. This evidence casts previous findings in a different light, indicating that capillaries are the locus of PGE 2 action to induce upstream arteriolar dilation in the control of brain blood flow, thereby providing a paradigm-shifting view that nonetheless remains coherent with the broad contours of a substantial body of existing literature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GW declared a shared affiliation, with no collaboration, with one of the authors AJ to the handling editor at the time of the review., (Copyright © 2021 Rosehart, Longden, Weir, Fontaine, Joutel and Dabertrand.)

Young patients presenting with cryptogenic stroke should be investigated for cardiac and extra-cardiac sources of emboli. We present a patient who was investigated for a cardiac source of emboli, following multiple ischaemic strokes and migraine with aura over a period of 17 years. The events were initially thought to be related to a patent foramen ovale (PFO) on bubble contrast echocardiography, however, due to an unusual flow pattern to the left heart, she underwent a CT angiogram to exclude intrapulmonary shunting. This confirmed the presence of a moderate sized congenital pulmonary arteriovenous fistula in the left lung. Transcatheter occlusion of the vascular malformation has resolution of her symptoms. Bubble contrast echocardiography is routinely used to diagnose a PFO in these cases, but extreme caution is required during the procedure to differentiate the pattern of flow seen in patients with a pulmonary arteriovenous malformation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Current literature examining the prospective relation of circulating omega-3 (n-3) and omega-6 (n-6) PUFAs and atrial fibrillation (AF) is limited to predominantly white populations., Objectives: We investigated the association of circulating n-3 and n-6 PUFAs with incident AF in participants from the Multi-Ethnic Study of Atherosclerosis., Methods: A total of 6229 participants (mean age = 62 y; 53% female; 39% white, 27% black, 22% Hispanic, and 12% Chinese) who were free of baseline AF and with plasma phospholipid PUFAs measured at baseline using GC were prospectively followed for the development of AF. Incident AF was ascertained using International Classification of Diseases-9 codes from hospital discharge records and Medicare claims data with follow-up through 2014. Multivariable Cox proportional hazards regression analysis was performed to determine the risk of incident AF., Results: During a median follow-up of 12.9 y, 813 (13%) participants developed AF. Each higher SD increment in arachidonic acid (AA; 20:4n-6) concentrations was associated with an 11% decreased risk of incident AF (HR: 0.89; 95% CI: 0.82, 0.96). Similarly, higher overall n-6 PUFA concentrations were also associated with a reduced AF risk (HR per SD increment: 0.93; 95% CI: 0.87, 1.00). Although no significant overall associations were observed for any individual n-3 PUFAs, higher circulating concentrations of DHA (22:6n-3) and EPA (20:5n-3) were associated with a decreased AF risk in blacks and Hispanics (DHA only) but not whites or Chinese Americans., Conclusions: In a multiethnic cohort of individuals free of baseline cardiovascular disease, higher plasma concentrations of n-6 PUFAs, particularly AA, were associated with a reduced risk of incident AF. Important differences in AF risk were also noted across race/ethnicity for the n-3 PUFAs DHA and EPA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for G s -coupled GPCRs and ATP-sensitive potassium (K ATP ) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca 2+ channels and G q , G i/o , and G 12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Hariharan, Weir, Robertson, He, Betsholtz and Longden.)

Background Positron emission tomography (PET) using 18 F-sodium fluoride ( 18 F-fluoride) to detect microcalcification may provide insight into disease activity in coronary atherosclerosis. This study aimed to investigate the relationship between 18 F-fluoride uptake and progression of coronary calcification in patients with clinically stable coronary artery disease. Methods Patients with established multivessel coronary atherosclerosis underwent 18 F-fluoride PET-computed tomography angiography and computed tomography calcium scoring, with repeat computed tomography angiography and calcium scoring at one year. Coronary PET uptake was analyzed qualitatively and semiquantitatively in diseased vessels by measuring maximum tissue-to-background ratio. Coronary calcification was quantified by measuring calcium score, mass, and volume. Results In a total of 183 participants (median age 66 years, 80% male), 116 (63%) patients had increased 18 F-fluoride uptake in at least one vessel. Individuals with increased 18 F-fluoride uptake demonstrated more rapid progression of calcification compared with those without uptake (change in calcium score, 97 [39-166] versus 35 [7-93] AU; P <0.0001). Indeed, the calcium score only increased in coronary segments with 18 F-fluoride uptake (from 95 [30-209] to 148 [61-289] AU; P <0.001) and remained unchanged in segments without 18 F-fluoride uptake (from 46 [16-113] to 49 [20-115] AU; P =0.329). Baseline coronary 18 F-fluoride maximum tissue-to-background ratio correlated with 1-year change in calcium score, calcium volume, and calcium mass (Spearman ρ=0.37, 0.38, and 0.46, respectively; P <0.0001 for all). At the segmental level, baseline 18 F-fluoride activity was an independent predictor of calcium score at 12 months ( P <0.001). However, at the patient level, this was not independent of age, sex, and baseline calcium score ( P =0.50). Conclusions Coronary 18 F-fluoride uptake identifies both patients and individual coronary segments with more rapid progression of coronary calcification, providing important insights into disease activity within the coronary circulation. At the individual patient level, total calcium score remains an important marker of disease burden and progression. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02110303.

The first recorded myringotomy was in 1649. Astley Cooper presented 2 papers to the Royal Society in 1801, based on his observations that myringotomy could improve hearing. Widespread inappropriate use of the procedure followed, with no benefit to patients; this led to it falling from favor for many decades. Hermann Schwartze reintroduced myringotomy later in the 19th century. It had been realized earlier that the tympanic membrane heals spontaneously, and much experimentation took place in attempting to keep the perforation open. The first described grommet was made of gold foil. Other materials were tried, including Politzer's attempts with rubber. Armstrong's vinyl tube effectively reintroduced grommets into current practice last century. There have been many eponymous variants, but the underlying principle of creating a perforation and maintaining it with a ventilation tube has remained unchanged. Recent studies have cast doubt over the long-term benefits of grommet insertion; is this the end of the third era?

Aim: Determine whether plasma omega-7 vaccenic acid and palmitoleic acid levels are related to homeostasis model of insulin resistance scores and incident type II diabetes, and whether race/ethnicity modifies these associations., Methods: Plasma phospholipid fatty acids were measured by gas chromatography with flame-ionization detection in Multi-Ethnic Study of Atherosclerosis participants. Linear regression determined associations of vaccenic acid and palmitoleic acid with log-transformed homeostasis model of insulin resistance scores (n=5689), and Cox regression determined associations with incident type II diabetes (n=5413, 660 cases). Race-interactions were tested., Results: Adjusting for typical risk factors, higher levels of plasma vaccenic acid were found to be inversely associated with insulin resistance scores across all four race/ethnicities, and a significant race-interaction was observed between Hispanics and Caucasians (P for interaction=0.03). Vaccenic acid was related to 17%, 32%, and 39% lower risks of incident type II diabetes in Black, Hispanic, and Chinese American participants, respectively. Differences in associations between races were detected (P for interactions<0.05). By contrast, higher levels of plasma palmitoleic acid were related to greater insulin resistance scores in Blacks (P<0.001) and Hispanics (P<0.001); significant race-based differences between associations were detected (P for interactions<0.05). Palmitoleic acid was correspondingly related to a 21% greater risk of incident type II diabetes in Black individuals., Conclusions: Results suggest that plasma vaccenic acid and palmitoleic acid are markers of metabolic health and dysfunction, respectively. Coupled with previous evidence and the significant race-interactions, our findings have implications for future studies of the race-based differences in omega-7 fatty acids and their regulation in the context of deteriorating metabolic health., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Gold is believed to retain its ambient crystal structure at very high pressures under static and shock compression, enabling its wide use as a pressure marker. Our in situ x-ray diffraction measurements on shock-compressed gold show that it transforms to the body-centered-cubic (bcc) phase, with an onset pressure between 150 and 176 GPa. A liquid-bcc coexistence was observed between 220 and 302 GPa and complete melting occurs by 355 GPa. Our observation of the lower coordination bcc structure in shocked gold is in marked contrast to theoretical predictions and the reported observation of the hexagonal-close-packed structure under static compression.

The Laser Shock Station in the Dynamic Compression Sector (DCS) [Advanced Photon Source (APS), Argonne National Laboratory] links a laser-driven shock compression platform with high energy x-ray pulses from the APS to achieve in situ, time-resolved x-ray measurements (diffraction and imaging) in materials subjected to well-characterized, high stress, short duration shock waves. This station and the other DCS experimental stations provide a unique and versatile facility to study condensed state phenomena subjected to shocks with a wide range of amplitudes (to above ∼350 GPa) and time-durations (∼10 ns-1 µs). The Laser Shock Station uses a 100 J, 5-17 ns, 351 nm frequency tripled Nd:glass laser with programmable pulse shaping and focal profile smoothing for maximum precision. The laser can operate once every 30 min. The interaction chamber has multiple diagnostic ports, a sample holder to expose 14 samples without breaking vacuum, can vary the angle between the x-ray and laser beams by 135°, and can translate to select one of the two types of x-ray beams. The x-ray measurement temporal resolution is ∼90 ps. The system is capable of reproducible, well-characterized experiments. In a series of 10 shots, the absolute variation in shock breakout times was less than 500 ps. The variation in peak particle velocity at the sample/window interface was 4.3%. This paper describes the entire DCS Laser Shock Station, including sample fabrication and diagnostics, as well as experimental results from shock compressed tantalum that demonstrate the facility's capability for acquiring high quality x-ray diffraction data.

Objective: Our aim was to identify drivers of and barriers to help-seeking behaviour of older women with pelvic floor dysfunction (PFD) living independently in Australia ., Methods: Women aged ≥55 years were recruited to this cross-sectional study during July and August 2016. Bladder, bowel, pelvic organ prolapse (POP) and sexual dysfunction were assessed with the Australian Pelvic Floor Questionnaire (APFQ). Drivers and barriers were based on the Barriers to Incontinence Care Seeking Questionnaire. Univariate analyses were used to assess any significant relationships between PFD, age, education level, self-reported PFD, barriers and drivers., Results: Of the 376 study participants [mean, standard deviation (SD) age 68.6 (10.5) years], 67% reported symptoms of PFD and 98.7% scored >0 on the APFQ. Women were more likely to seek help if they scored higher on the APFQ (p < 0.001). The main barrier to seeking help was the perception that PFD was a normal part of ageing (22.4%). Of those who did seek help (50%), the main factor was increased level of symptom bother (51.4%). There was no difference in age or education level between women who did and did not seek help., Conclusion: Women are more likely to seek help for PFD if scoring higher on the APFQ or symptoms are becoming more bothersome. They are less likely to seek help if they view their symptoms as normal. Future direction should be taken to raise awareness of normal pelvic floor function as well as the availability of help for PFD.

Background: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease., Methods: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed., Results: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia., Conclusion: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment., Trial Registration: ClinicalTrials.gov NCT01724580 and NCT02974595., Funding: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18 fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133 xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The Wessex Modified Richmond Sedation Scale (WMRSS) has been developed with the aim of improving the early identification of patients requiring decompressive hemicraniectomy for malignant middle cerebral artery syndrome (MMS). The objective of this study was to evaluate the WMRSS against the Glasgow Coma Scale (GCS)., Methods: A retrospective study was conducted of patients admitted to our unit for observation of MMS. Data were obtained on WMRSS and GCS recordings from admission up to 120-h post-ictus. Patients' meeting inclusion criteria were recommended for theatre based on subsequent deteriorations in consciousness on either WMRSS or GCS from a 6-h post-stroke baseline, after ruling out non-neurological causes., Results: Approximately, 60% of those eligible for monitoring were not recommended for theatre, and none died; however, these patients continued to demonstrate some variability in recorded conscious level. Patients requiring surgical intervention showed earlier drops in WMRSS compared to GCS. Neither the GCS nor the WMRSS on admission predicted the subsequent need for decompressive surgery. There was no increase in mortality with the introduction of WMRSS., Conclusions: WMRSS adds value to monitoring MMS by indicating need for surgery prior to GCS. Early reduction in consciousness may not be sufficient for proceeding to surgical intervention, but subsequent reduction in consciousness may be a more appropriate criterion for surgery.

Kinetic modelling of myocardial perfusion imaging data allows the absolute quantification of myocardial blood flow (MBF) and can improve the diagnosis and clinical assessment of coronary artery disease (CAD). Positron emission tomography (PET) imaging is considered the reference standard technique for absolute quantification, whilst oxygen-15 ( 15 O)-water has been extensively implemented for MBF quantification. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has also been used for MBF quantification and showed comparable diagnostic performance against ( 15 O)-water PET studies. We investigated for the first time the diagnostic performance of two different PET MBF analysis softwares PMOD and Carimas, for obstructive CAD detection against invasive clinical standard methods in 20 patients with known or suspected CAD. Fermi and distributed parameter modelling-derived MBF quantification from DCE-MRI was also compared against ( 15 O)-water PET, in a subgroup of 6 patients. The sensitivity and specificity for PMOD was significantly superior for obstructive CAD detection in both per vessel (0.83, 0.90) and per patient (0.86, 0.75) analysis, against Carimas (0.75, 0.65), (0.81, 0.70), respectively. We showed strong, significant correlations between MR and PET MBF quantifications (r=0.83-0.92). However, DP and PMOD analysis demonstrated comparable and higher haemodynamic differences between obstructive versus (no, minor or non)-obstructive CAD, against Fermi and Carimas analysis. Our MR method assessments against the optimum PET reference standard technique for perfusion analysis showed promising results in per segment level and can support further multi-modality assessments in larger patient cohorts. Further MR against PET assessments may help to determine their comparative diagnostic performance for obstructive CAD detection.

Aim: To assess computed tomography (CT) pulmonary angiography (CTPA) dose and image quality in a large teaching hospital, and subsequently, to optimise the protocol in order to reduce the dose without affecting image quality., Materials and Methods: Dose-length product (DLP), patient size, and objective quality parameters (contrast-to-noise ratio and signal-to-noise ratio on standardised levels) were recorded from 31 patients undergoing CTPA, where also a subjective image quality evaluation was carried out independently by three specialist cardiothoracic consultant radiologists. An equivalent objective and subjective quality assessment was carried out on a cohort of the same size in a different tertiary healthcare centre. Moreover, experimental tests using anthropomorphic chest phantoms were performed, using different scan parameters. In light of the above analysis, two of the scanner settings for CTPA were modified, i.e., the SureExposure pre-set was changed to "Standard" noise level, quantified with standard deviation (SD) of 19, and the minimum amperage setting lowered from 80 to 40 mA. A second cohort of patients using this new protocol was audited, following the same methodology., Results: The average DLP of patients undergoing CTPA was initially found to be higher than both local and national dose reference levels (DRLs; 559 versus 300 mGy·cm and 400 mGy·cm, respectively). The new protocol led to a reduction in average DLP (359 mGy·cm) while the image quality, assessed by three cardiothoracic consultant radiologists, was preserved., Conclusion: The CTPA protocol was implemented in the Royal Infirmary of Edinburgh resulting in significant dose reduction, and is now compliant with national and local DRLs. The image quality was maintained., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: There is little research and no clear guidelines for clinicians to follow when instructing patients with advanced disease about driving., Aims: To investigate current practice in providing advice to patients with advanced disease and identify areas of consensus or variation with the Australian driving guidelines., Methods: An online survey was distributed to Australian members of the Australian and New Zealand Society of Palliative Medicine. Responses were analysed using descriptive statistics., Results: The survey was distributed to 322 Australian and New Zealand Society of Palliative Medicine members and received 92 responses (29% response rate). Most respondents were aware of the driving guidelines (76%) and about half of the respondents had read the driving guidelines (55%). The majority of respondents had been asked to provide advice about driving to their patient or patient's caregiver (91%). Most respondents had asked a patient to stop driving (94%), but only 27% had reported a patient to the Driver Licensing Authority. Only 14% of respondents were in consensus with the guidelines in providing driving advice to a patient with asymptomatic brain metastases. Most doctors (64%) advise patients to refrain temporarily from driving post-short-acting oral morphine, with 4 h (36%) being the most common time period for not driving., Conclusions: This is the first survey investigating the practice of Australian doctors in assessing fitness to drive of patients with advanced disease. The survey found wide variability in practice and substantial discordance with current driving guidelines., (© 2017 Royal Australasian College of Physicians.)

Introduction: CD40 ligand (CD40L) blockade has demonstrated efficacy in experimental autoimmune models. However, clinical trials of hu5c8, an anti-human CD40L IgG1 antibody, in systemic lupus erythematosus (SLE) were halted due to an increased incidence of thrombotic events. This study evaluated CDP7657, a high affinity PEGylated monovalent Fab' anti-CD40L antibody fragment, to assess whether an Fc-deficient molecule retains efficacy while avoiding the increased risk of thrombotic events observed with hu5c8., Methods: The potency and cross-reactivity of CDP7657 was assessed in in vitro assays employing human and non-human primate leukocytes, and the capacity of different antibody formats to activate platelets in vitro was assessed using aggregometry and dense granule release assays. Given the important role CD40L plays in regulating humoral immunity, in vivo efficacy was assessed by investigating the capacity of Cynomolgus monkeys to generate immune responses to the tetanus toxoid antigen while the potential to induce thrombotic events in vivo was evaluated after repeat dosing of antibodies to Rhesus monkeys. A PEGylated anti-mouse CD40L was generated to assess efficacy in the New Zealand Black/White (NZB/W) mouse model of SLE., Results: CDP7657 dose-dependently inhibited antigen-specific immune responses to tetanus toxoid in Cynomolgus monkeys, and in contrast to hu5c8, there was no evidence of pulmonary thrombovasculopathy in Rhesus monkeys. Aglycosyl hu5c8, which lacks Fc receptor binding function, also failed to induce thrombotic events in Rhesus monkeys. In vitro experiments confirmed that antibody constructs lacking an Fc, including CDP7657, did not induce human or monkey platelet activation. A PEGylated monovalent Fab' anti-mouse CD40L antibody also inhibited disease activity in the NZB/W mouse model of SLE after administration using a therapeutic dosing regimen where mice received antibodies only after they had displayed severe proteinuria., Conclusions: These findings demonstrate for the first time that anti-CD40L antibodies lacking a functional Fc region do not induce thrombotic events in Rhesus monkeys and fail to activate platelets in vitro but, nevertheless retain pharmacological activity and support the investigation of CDP7657 as a potential therapy for systemic lupus erythematosus and other autoimmune diseases.

Aim: To assess the feasibility of radiation dose reduction with adaptive iterative dose reduction (AIDR-6 3D) reconstruction in dynamic pulmonary CT perfusion., Materials and Methods: CTP examinations of 10 patients acquired at 100 kVp/50 mAs were reconstructed with filtered back projection (FBP) and AIDR-3D. Artificial noise was added to raw data (pre-reconstruction projection data) to simulate lower tube current scanning. Radiodensity (in Hounsfield units), noise, and perfusion values were compared., Results: There was no significant difference in noise between the full and simulated reduced tube current with AIDR-3D reconstruction (p = 1). There was significantly lower noise in lung tissue with AIDR-3D images when compared to reconstructions without AIDR-3D (p = 0.005) and no significant change in the radiodensity (p = 1; mean difference <6 HU). Mean perfusion values increased significantly at lower tube currents (25 and 12.5 mAs), compared to 50 mAs (p = 0.005). This effect was significantly greater in larger patients compared to thin patients., Conclusion: AIDR-3D produced significantly lower noise images than FBP-based algorithms and maintained consistent noise levels in lung at 12.5 mAs, indicating this algorithm is suitable for reduced dose lung perfusion imaging. Iterative reconstruction allows significant radiation dose reduction of up to fourfold in smaller patients, and up to twofold in the medium/large size patients. The increase in perfusion values at 25% simulated tube currents is attributed to attenuation bias., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Rationale: The relationship between pulmonary artery size with underlying pulmonary hypertension and mortality remains to be determined in COPD. We sought to evaluate the relationships in a cohort of patients with advanced COPD., Methods: A retrospective study of advanced COPD patients evaluated between 1998 and 2012 was conducted at a tertiary care center. Patients with chest computed tomography images and right heart catheterizations formed the study cohort. The diameters of the pulmonary artery and ascending aorta were measured by independent observers and compared to pulmonary artery pressures. Intermediate-term mortality was evaluated for the 24-month period subsequent to the respective studies. Cox proportional hazards model was used to determine independent effects of variables on survival., Results: There were 65 subjects identified, of whom 38 (58%) had pulmonary hypertension. Patients with and without pulmonary hypertension had mean pulmonary artery diameters of 34.4 mm and 29.1 mm, respectively (p = 0.0003). The mean PA:A ratio for those with and without pulmonary hypertension was 1.05 and 0.87, respectively (p = 0.0003). The PA:A ratio was an independent predictor of mortality with a reduced survival in those with a PA:A >1 (p = 0.008)., Conclusions: The PA:A ratio is associated with underlying pulmonary hypertension in patients with COPD and is an independent predictor of mortality. This readily available measurement may be a valuable non-invasive screening tool for underlying pulmonary hypertension in COPD patients and appears to impart important independent prognostic information., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: To assess the cross-centre consistency of iodine enhancement, contrast-to-noise ratio and radiation dose in a multicentre perfusion CT trial of colorectal cancer., Materials and Methods: A cylindrical water phantom containing different iodine inserts was examined on seven CT models in 13 hospitals. The relationship between CT number (Hounsfield units, HU) and iodine concentration (milligrams per millilitre) was established and contrast-to-noise ratios (CNRs) calculated. Radiation doses (CTDIvol, DLP) were compared across all sites., Results: There was a linear relationship between CT number and iodine density. Iodine enhancement varied by a factor of at most 1.10, and image noise by at most 1.5 across the study sites. At an iodine concentration of 1 mg ml(-1) and 100 kV, CNRs ranged from 3.6 to 4.8 in the 220-mm phantom and from 1.4 to 1.9 in the 300-mm phantom. Doses varied by a factor of at most 2.4, but remained within study dose constraints. Iterative reconstruction algorithms did not alter iodine enhancement but resulted in reduced image noise by a factor of at most 2.2, allowing a potential dose decrease of at most 80% compared to filtered back projection (FBP)., Conclusions: Quality control of CT performance across centres indicates that CNR values remain relatively consistent across all sites, giving acceptable image quality within the agreed dose constraints., Key Points: Quality control is essential in a multicentre setting to enable CT quantification. CNRs in a body-sized phantom had the recommended value of at least 1.5. CTDIs and DLPs varied by factors of 1.8 and 2.4 respectively.

The variable proportion of fat in overlying soft tissue is a potential source of error in dual-energy X-ray absorptiometry (DXA) measurements of bone mineral. The effect on spine scanning has previously been assessed from cadaver studies and from computed tomography (CT) scans of soft tissue distribution. We have now applied the latter technique to DXA hip scanning. The CT scans performed for clinical purposes were used to derive mean adipose tissue thicknesses over bone and background areas for total hip and femoral neck. The former was always lower. More importantly, the fat thickness differences varied among subjects. Errors because of bone marrow fat were deduced from CT measurements of marrow thickness and assumed fat proportions of marrow. The effect of these differences on measured bone mineral density was deduced from phantom measurements of the bone equivalence of fat. Uncertainties of around 0.06g/cm(2) are similar to those previously reported for spine scanning and the results from cadaver measurements. They should be considered in assessing the diagnostic accuracy of DXA scanning., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Background: Return to driving is a goal and milestone in the recovery process following acquired brain injury (ABI). Knowledge of whether and when a person is likely to return to driving is important to people with ABI, family members and clinicians., Objective: To determine the rates, timing, correlates, and predictors of return to driving in the first 6 months after discharge from hospital following ABI., Methods: Survey of 212 participants with ABI and 121 family members at discharge and 3 and 6 months later. Participants with ABI were grouped according to driving status (not driving, returned within 3 months, returned within 6 months). Groups were compared on demographics, injury severity, quality of life, functioning, psychosocial integration, depression, and carer well-being., Results: By 6 months post-discharge 62.3% had resumed driving. Between group differences existed on measures of injury severity, and psychosocial integration at 6 months, and carer depression and strain at discharge and 6 months. Whether and when someone returned to driving could be predicted by length of hospital stay, and level of community integration, and pain at discharge., Conclusions: Educating clients about their likelihood and timing of return to driving, and supporting non-drivers and their carers may improve psychosocial outcomes.

Aims: Aspirin achieves its antithrombotic effect through inactivation of cyclo-oxygenase (COX)-1, thereby preventing generation of thromboxane (TX)A2 from arachidonic acid (AA). The reported prevalence of aspirin "resistance" varies significantly and is usually based on platelet function tests (PFTs) that use AA-induced platelet reactivity as a surrogate measure of the effect of aspirin, rather than specific assessment of its effect on its therapeutic target (ie, COX-1 inhibition). The reported rates are not only assay specific but also condition specific, with particularly high rates (up to 70%) previously reported in the stroke population. We investigated whether pharmacological responses to aspirin can be reliably determined from a functional test of AA-induced whole-blood clotting., Methods and Results: A prospective study included 35 patients admitted with ischemic stroke and commenced on 300 mg aspirin. AA-induced whole-blood clotting was measured using short thrombelastography, a previously extensively validated near-patient PFT. Serum TXB2 and inflammatory biomarkers were also measured. The prevalence of apparent aspirin resistance measured using AA was high (range from 49% to 67%). However, serum [TXB2] was consistently low, thereby confirming adequate inhibition of COX-1 by aspirin. Mean inflammatory biomarker levels were elevated throughout., Conclusion: This study demonstrates that although COX-1 activity is adequately and consistently suppressed by aspirin in stroke patients, this effect is not reliably indicated by whole-blood clotting in response to AA. These data help to explain why the reported prevalence of aspirin resistance in stroke from studies employing AA-induced platelet reactivity is high and cast doubt on the veracity of such reports., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Aim: To assess the effect of two iterative reconstruction algorithms (AIDR and AIDR3D) and individualized automatic tube current selection on radiation dose and image quality in computed tomography coronary angiography (CTCA)., Materials and Methods: In a single-centre cohort study, 942 patients underwent electrocardiogram-gated CTCA using a 320-multidetector CT system. Images from group 1 (n = 228) were reconstructed with a filtered back projection algorithm (Quantum Denoising Software, QDS+). Iterative reconstruction was used for group 2 (AIDR, n = 379) and group 3 (AIDR3D, n = 335). Tube current was selected based on body mass index (BMI) for groups 1 and 2, and selected automatically based on scout image attenuation for group 3. Subjective image quality was graded on a four-point scale (1 = excellent, 4 = non-diagnostic)., Results: There were no differences in age (p = 0.975), body mass index (p = 0.435), or heart rate (p = 0.746) between the groups. Image quality improved with iterative reconstruction and automatic tube current selection [1.3 (95% confidence intervals (CI): 1.2-1.4), 1.2 (1.1-1.2) and 1.1 (1-1.2) respectively; p < 0.001] and radiation dose decreased [274 (260-290), 242 (230-253) and 168 (156-180) mGy cm, respectively; p < 0.001]., Conclusion: The application of the latest iterative reconstruction algorithm and individualized automatic tube current selection can substantially reduce radiation dose whilst improving image quality in CTCA., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chevalier Jackson was one of the greatest pioneers of otolaryngology. He was a pioneer of oesophagoscopy, bronchoscopy and the removal of foreign bodies. He changed the mortality rate for an airway foreign body from 98 per cent to a survival rate of 98 per cent. He became distressed by the number of preventable injuries in children from the ingestion of caustic substances, most commonly household lye. His experiences of children with oesophageal stricturing secondary to caustic ingestion moved him to start a campaign to force manufacturers to label all poisonous substances as such. This took him from the American Senate to the House of Representatives and back again; the Federal Caustic Poisons Act (1927) is still enforced today. In a career with over 400 publications, written during exacerbations of his pulmonary tuberculosis, his life story is a remarkable one, only part of which is widely known.

Background: The course of idiopathic pulmonary fibrosis (IPF) is characterized by variable patterns of disease progression. The red cell distribution width (RDW) is a parameter that is routinely reported with all CBC counts. We sought to test the prognostic usefulness of this parameter in a well-defined cohort of patients with IPF., Methods: CBCs, demographics, and pulmonary function data from patients with IPF evaluated between January 1997 and June 2011 were collated. Patient outcomes were ascertained from the program's database and the Social Security Death Index., Results: There were 319 patients with IPF evaluated in whom baseline CBCs were available. The range in the RDW was 11.9 to 21.9 (median 14.1). There were 228 subjects with RDW values ≤ 15 (normal) and 91 patients with RDW values &gt; 15. Patients with normal RDW values had a median survival of 43.1 months compared with 16.3 months for those whose RDW was &gt; 15 (P = .001). There were 198 patients with available serial RDW data. Those patients who had a change in the RDW of less or greater than +0.010/mo had median survivals of 43.0 and 23.9 months, respectively (P = .0246)., Conclusions: The RDW is a readily available laboratory test result that may provide important, independent prognostic information at baseline and follow-up in patients with IPF. Further studies are warranted to validate this as a biomarker for IPF outcomes, as well as to define the biologic basis for this association.

Background: Although 1 in 5 adults will develop heart failure (HF) in their lifetime, data on the effect of plasma omega-6 (n-3) PUFAs on risk of HF are currently sparse., Objectives: We investigated whether plasma phospholipid omega-6 concentrations are associated with risk of HF in US male physicians. In a secondary analysis, we evaluated whether such an association differs between HF with and without previous myocardial infarction (MI)., Design: With the use of a nested case-control design, this ancillary study comprised 788 cases and 788 matched controls from the Physicians' Health Study. Plasma omega-6 PUFAs were measured by using gas chromatography., Results: The mean age of subjects was 58.7 y with a mean follow-up time of 17.1 y. We did not show any evidence of a statistically significant relation between total omega-6 PUFAs and HF [OR (95% CI): 1.00; 0.85 (0.63, 1.14); 0.84 (0.63, 1.13); and 0.87 (0.63, 1.20) across consecutive quartiles of omega-6 PUFAs; P-linear trend = 0.39]. Results were similar for HF with and without previous MI., Conclusion: Our data showed no significant association between total plasma omega-6 PUFAs and risk of developing HF.

Objective: MRI at 3 T is said to be more accurate than 1.5 T MR, but costs and other practical differences mean that it is unclear which to use., Methods: We systematically reviewed studies comparing diagnostic accuracy at 3 T with 1.5 T. We searched MEDLINE, EMBASE and other sources from 1 January 2000 to 22 October 2010 for studies comparing diagnostic accuracy at 1.5 and 3 T in human neuroimaging. We extracted data on methodology, quality criteria, technical factors, subjects, signal-to-noise, diagnostic accuracy and errors according to QUADAS and STARD criteria., Results: Amongst 150 studies (4,500 subjects), most were tiny, compared old 1.5 T with new 3 T technology, and only 22 (15 %) described diagnostic accuracy. The 3 T images were often described as "crisper", but we found little evidence of improved diagnosis. Improvements were limited to research applications [functional MRI (fMRI), spectroscopy, automated lesion detection]. Theoretical doubling of the signal-to-noise ratio was not confirmed, mostly being 25 %. Artefacts were worse and acquisitions took slightly longer at 3 T., Conclusion: Objective evidence to guide MRI purchasing decisions and routine diagnostic use is lacking. Rigorous evaluation accuracy and practicalities of diagnostic imaging technologies should be the routine, as for pharmacological interventions, to improve effectiveness of healthcare., Key Points: • Higher field strength MRI may improve image quality and diagnostic accuracy. • There are few direct comparisons of 1.5 and 3 T MRI. • Theoretical doubling of the signal-to-noise ratio in practice was only 25 %. • Objective evidence of improved routine clinical diagnosis is lacking. • Other aspects of technology improved images more than field strength.

Background: Sildenafil was the only phosphodiesterase-5 inhibitor available for the treatment of pulmonary arterial hypertension (PAH) until the approval and availability of once-daily tadalafil. Since no direct comparative study is likely to be performed between these agents, we sought to evaluate the feasibility of transitioning stable PAH patients from sildenafil to tadalafil., Methods: The primary end point was continuation on tadalafil without clinical deterioration. A functional outcome through an evaluation of serial change in the 6-min walk test distance (6MWD) was also performed., Results: Thirty-five patients on sildenafil qualified for the analysis, of which 85.7 % (30/35) were successfully transitioned. The remaining 14.3 % (5/30) (failure group) were switched back to sildenafil due to worsening symptoms. The mean pretransition 6MWD was 363 m, with an average change in the success group of +16.4 m (range = -64 to +140 m) compared to -45 m (range = -123 to +32 m) in the failure group at 1-3 months post switch (p = 0.02). All 30 patients in the success group remained on tadalafil, with an average improvement in the 6MWD of +37.04 m (range = -36.5 to +236.5 m) at 12 months post switch. The failure group had a higher daily sildenafil dose (180 vs. 115.5 mg; p = 0.06), with 42.8 % of patients at the highest sildenafil dose failing the transition., Conclusion: The transition from sildenafil to tadalafil is safe and generally well tolerated. Patients with more severe disease and those on higher doses of sildenafil are more likely to fail the transition and should be monitored closely post switch.

Background: The characteristics of long-term survivors with idiopathic pulmonary fibrosis (IPF) have never been fully elucidated. We sought to illustrate the attenuated mortality and describe the characteristics of patients with IPF who survived at least 5 years beyond their initial presentation., Methods: Patients with IPF evaluated between 1997 and 2006 were identified through the clinic database. Patients who survived beyond 5 years from the time of their evaluation were compared with those who died or underwent lung transplantation within 5 years. Survival analyses were performed from the time of initial evaluation and contingent on annualized survival thereafter., Results: Eighty-seven patients who survived at least 5 years formed the comparator group to whom other patients were contrasted. These patients had a higher BMI, FVC % predicted, FEV1 % predicted, total lung capacity % predicted, and diffusing capacity of lung for carbon monoxide % predicted, but a lower FEV1/FVC ratio and lower mean pulmonary artery pressures. More than one-half of these patients had moderate or severe disease at the time of presentation. Our annualized contingent survival analyses revealed a progressively increasing median survival dependent on the duration of the disease., Conclusions: Although we were able to demonstrate differences in our 5-year survivors, rather than being a distinct group, these patients appear to exist within a continuum of improving survival dependent on prior disease duration. This progressively improving time-dependent prognosis mandates the serial reevaluation of an individual patient’s projected outcomes. The implementation of dynamic counseling is an important concept in more accurately predicting life expectancy for patients with IPF who are frequently haunted by the prospects of a dismal survival.

Cardiac CT is a rapidly advancing technology. Non-invasive CT coronary angiography is an established technique for assessing coronary heart disease with accuracy similar to invasive coronary angiography. CT myocardial perfusion imaging can now identify perfusion defects in animal models and humans. MRI is the current 'gold standard' for the assessment of myocardial viability, but it is now also possible to assess delayed enhancement by CT. This has led to the possibility of a 'one-stop shop' for cardiovascular imaging that would provide information on anatomy, function, perfusion and viability in one rapid diagnostic test at a radiation dose equivalent to contemporary nuclear medicine imaging. This review discusses the current status of 'one-stop shop' cardiac CT assessment, clinical utility and directions for future research.

The American Thoracic Society and European Respiratory Society guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) have been published recently. However, the influence, practical application, and utility of the prior consensus statement for IPF have never been evaluated. Demographics, diagnostic criteria, pulmonary function data, and disposition of patients with IPF evaluated at an interstitial lung disease center between 2000 and 2009 were analyzed. Enrollment in clinical drug trials, lung transplantation, and mortality also were assessed. A total of 521 patients with IPF were evaluated, with pulmonary function testing available in 446. In the 64% of patients without surgical lung biopsy, the most common major criterion not fulfilled was bronchoscopy. Lung transplantation was performed in 16.1% of patients, whereas 27.4% of prescreened patients were enrolled in a prospective drug study. Patients with mild, moderate, and severe disease categorized by FVC % predicted had median survivals of 55.6, 38.7, and 27.4 months, respectively. The attrition rate of patients who survived beyond 5 years was attenuated in subsequent years. IPF remains a deadly disease with a poor prognosis. Bronchoscopy does not appear to be required for an accurate diagnosis. A minority of patients were accommodated within a clinical trial or with transplantation. Categorization by baseline FVC % predicted effectively discriminates groups with different long-term outcomes. Our analysis supports the view that the value of statements also can be realized in the subsequent demonstration of their impact on patient management, which might enable further refinements in a continuous, iterative rediscovery process.