A computational framework for generating patient-specific vascular models and assessing uncertainty from medical images

Patient-specific computational modeling is a popular, non-invasive method to answer medical questions. Medical images are used to extract geometric domains necessary to create these models, providing a predictive tool for clinicians. However, in vivo imaging is subject to uncertainty, impacting vessel dimensions essential to the mathematical modeling process. While there are numerous programs available to provide information about vessel length, radii, and position, there is currently no exact way to determine and calibrate these features. This raises the question, if we are building patient-specific models based on uncertain measurements, how accurate are the geometries we extract and how can we best represent a patient's vasculature? In this study, we develop a novel framework to determine vessel dimensions using change points. We explore the impact of uncertainty in the network extraction process on hemodynamics by varying vessel dimensions and segmenting the same images multiple times. Our analyses reveal that image segmentation, network size, and minor changes in radius and length have significant impacts on pressure and flow dynamics in rapidly branching structures and tapering vessels. Accordingly, we conclude that it is critical to understand how uncertainty in network geometry propagates to fluid dynamics, especially in clinical applications.Comment: 21 pages, 9 figure

Aspirations and accommodations for students with disability to equitably access higher education: a systematic scoping review

IntroductionSeveral international conventions have recognized the importance of equal access to higher education on the basis of ‘capacity’. However, inequalities persist for various groups. This paper presents a systematic scoping review of studies on the aspirations and access needs of students with disability, medical and mental health conditions to equitably participate in tertiary education.MethodsA search of ERIC, PsycINFO and Web of Science databases identified 133 relevant research articles from across the world covering the experiences of students with all types of disability. These were subjected to thematic analysis.ResultsThree main themes were identified. Firstly, the findings showed that a crucial component of the student higher education experience was the development of their own self-identity, addressing stigma and enhancing self-advocacy skills, autonomy, and career prospects. Secondly, the studies described how students struggled for full membership in the university community, calling for a transformation of university physical, social and teaching environments for them to access and participate in academic and social activities. Thirdly, the analysis showed that students valued individual accommodations in both coursework and assessment.DiscussionThese findings constitute a newly comprehensive framework for inclusive tertiary education systems and individual accommodations which is grounded in empirical research from a wide variety of contexts. This can serve higher education institutions to develop policy and procedures to ensure equitable participation of students with disability

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Numerical predictions of shear stress and cyclic stretch in pulmonary hypertension due to left heart failure

Isolated post-capillary pulmonary hypertension (Ipc-PH) occurs due to left heart failure, which contributes to 1 out of every 9 deaths in the United States. In some patients, through unknown mechanisms, Ipc-PH transitions to combined pre-/post-capillary PH (Cpc-PH) and is associated with a dramatic increase in mortality. Altered mechanical forces and subsequent biological signaling in the pulmonary vascular bed likely contribute to the transition from Ipc-PH to Cpc-PH. However, even in a healthy pulmonary circulation, the mechanical forces in the smallest vessels (the arterioles, capillary bed, and venules) have not been quantitatively defined. This study is the first to examine this question via a computational fluid dynamics model of the human pulmonary arteries, arterioles, venules, and veins. Using this model, we predict temporal and spatial dynamics of cyclic stretch and wall shear stress with healthy and diseased hemodynamics. In the normotensive case for large vessels, numerical simulations show that large arteries have higher pressure and flow than large veins, as well as more pronounced changes in area throughout the cardiac cycle. In the microvasculature, shear stress increases and cyclic stretch decreases as vessel radius decreases. When we impose an increase in left atrial pressure to simulate Ipc-PH, shear stress decreases and cyclic stretch increases as compared to the healthy case. Overall, this model predicts pressure, flow, shear stress, and cyclic stretch that providing a way to analyze and investigate hypotheses related to disease progression in the pulmonary circulation

Gallium-68 complex of a macrobicyclic cage amine chelator tethered to two integrin-targeting peptides for diagnostic tumor imaging

Michelle T. Ma, Oliver C. Neels, Delphine Denoyer, Peter Roselt, John A. Karas, Denis B. Scanlon, Jonathan M. White, Rodney J. Hicks, and Paul S. Donnell

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88–1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. US National Institutes of Health and Operation Warp Spee