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Despite the fact that ∼70% of bladder cancers are non-invasive and have high recurrence rates, early stage disease is understudied. The relative lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. While mutations inPIK3CAare frequent in human bladder cancer, anin vivomodel for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, aUpk2-Cre/Pik3caH1047Rmouse model expressing one or twoR26-Pik3caH1047Ralleles in a urothelium-specific manner was created.Pik3caH1047Rfunctionality was confirmed by quantifying Akt phosphorylation and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. At 6 months,Pik3caH1047Rmice developed increased urothelial thickness and nuclear atypia, however, at 12 months,Pik3caH1047Rmice did not exhibit progressive disease. Immunohistochemistry shows urothelium maintained luminal differentiation characterized by high Foxa1 and Pparγ expression. In addition, mice were subjected to low-dose carcinogen exposure (N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN)). Surprisingly,Pik3caH1047Rmice exhibited no significant differences after exposure relative to mice without exposure. Furthermore, ssGSEA analysis of invasive human tumors showed those with mutantPIK3CAdo not exhibit significantly increased PI3K/AKT pathway activity compared to wildtypePIK3CAtumors. Overall, these data suggest thatPik3caH1047Rcan elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.

Accurate detection of the hepatic fibrosis stage is essential to estimate the outcome of patients with non-alcoholic fatty liver disease (NAFLD). Many formulas, biomarkers, and imaging tests are being developed to predict advanced liver fibrosis without performing a liver biopsy. However, these tests do not have high efficiency in detecting early-stage hepatic fibrosis. Therefore, we aimed to detect the presence of hepatic fibrosis (≥F1) merely by using only standard clinical markers.A total of 436 patients with NAFLD who underwent liver biopsy were retrospectively enrolled as the discovery cohort (316 patients) and the validation cohort (120 patients). Liver biopsy and laboratory data were matched to extract simple parameters for identifying ≥F1.We developed a novel simplified ≥F1 detecting system, designated as 2-Step PLT16-AST44 method, where (1) PLT of 16 × 10We propose the 2-Step PLT16-AST44 method as a simple and beneficial early-stage hepatic fibrosis detection system.

Early response prediction for locally advanced rectal cancer (LARC) provides an opportunity for response-tailored treatment management. The goal of this review is to summarize recent advances in applying functional MRI, such as diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI), to predict treatment response for LARC patients, as well as to discuss the associated limitations and future directions. Many recent studies incorporated advanced data analysis methods, such as radiomics and deep learning, to enhance prediction performance. Multi-parametric imaging has also become a trend that utilizes complementary information from each technique. However, there are wide variations in patient enrollment, imaging time points, scan parameters, and treatment response endpoint definitions, which leads to a range of findings among these studies. Moreover, small sample size and lack of independent validation of most studies also weaken conclusions. Functional MRI has been shown as a potential early biomarker for rectal cancer treatment response estimation. To incorporate functional MRI into clinical workflow, future work with large standardized data are warranted.

John Busby,1 David Price,2– 4 Riyad Al-Lehebi,5 Sinthia Bosnic-Anticevich,6– 8 Job FM van Boven,9 Benjamin Emmanuel,10 J Mark FitzGerald,11 Mina Gaga,12 Susanne Hansen,13,14 Mark Hew,15,16 Takashi Iwanaga,17 Désirée Larenas Linnemann,18 Bassam Mahboub,19,20 Patrick Mitchell,21 Daniela Morrone,22 Jonathan Pham,15,23 Celeste Porsbjerg,14 Nicolas Roche,24,25 Eileen Wang,26,27 Neva Eleangovan,2,3 Liam G Heaney28 1Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland; 2Optimum Patient Care, Cambridge, UK; 3Observational and Pragmatic Research Institute, Singapore, Singapore; 4Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 5Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia; 6Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; 7Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia; 8Central Sydney Local Area Health District, Sydney, Australia; 9Department of Clinical Pharmacy & Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 10BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 11Department of Medicine, The University of British Columbia, Vancouver, Canada; 12 7th Respiratory Medicine Department and Asthma Centre, Athens Chest Hospital, Athens, Greece; 13Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; 14Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark; 15Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, Australia; 16Public Health and Preventive Medicine, Monash University, Melbourne, Australia; 17Center for General Medical Education and Clinical Training, Kindai University Hospital, Osakasayama, Japan; 18Directora Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico; 19College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 20Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates; 21Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 22Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy; 23Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Melbourne, Australia; 24Respiratory Medicine, Cochin Hospital, APHP.Centre, Paris, France; 25University of Paris, Cochin Institute (UMR1016), Paris, France; 26Division of Allergy & Clinical Immunology, Department of Medicine, National Jewish Health, Denver, CO, USA; 27Division of Allergy & Clinical Immunology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 28Wellcome-Wolfson Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern IrelandCorrespondence: David PriceCentre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, AB25 2ZD, UKTel +65 6962 3627Email dprice@opri.sgIntroduction: Asthma morbidity and health-care utilization are known to exhibit a steep socioeconomic gradient. Further investigation into the modulators of this effect is required to identify potentially modifiable factors.Methods: We identified a cohort of patients with asthma from the Optimum Patient Care Research Database (OPCRD). We compared demographics, clinical variables, and health-care utilization by quintile of the UK 2011 Indices of Multiple Deprivation based on the location of the patients’ general practice. Multivariable analyses were conducted using generalized linear models adjusting for year, age, and sex. We conducted subgroup analyses and interaction tests to investigate the impact of deprivation by age, sex, ethnicity, and treatment step.Results: Our analysis included 127,040 patients with asthma. Patients from the most deprived socio-economic status (SES) quintile were more likely to report uncontrolled disease (OR: 1.54, 95% CI: 1.16, 2.05) and to have an exacerbation during follow-up (OR: 1.27, 95% CI: 1.13, 1.42) than the least deprived quintile. They had higher blood eosinophils (ratio: 1.03; 95% CI: 1.00, 1.06) and decreased peak flow (ratio: 0.95, 95% CI: 0.94, 0.97) when compared to those in the least deprived quintile. The effect of deprivation on asthma control was greater among those aged over 75 years (OR = 1.81, 95% CI: 1.20, 2.73) compared to those aged less than 35 years (OR: 1.22, 95% CI: 0.85, 1.74; pinteraction=0.019). Similarly, socioeconomic disparities in exacerbations were larger among those from ethnic minority groups (OR: 1.94, 95% CI: 1.40, 2.68) than white patients (OR: 1.24, 95% CI: 1.10, 1.39; pinteraction=0.012).Conclusion: We found worse disease control and increased exacerbation rates among patients with asthma from more deprived areas. There was evidence that the magnitude of socioeconomic disparities was elevated among older patients and those from ethnic minority groups. The drivers of these differences require further exploration.Keywords: asthma, socioeconomic status, disparities

Information on inappropriate dosing of direct oral anticoagulants (DOACs) is scarce in the Australian context.To describe the prevalence and potential predictors of inappropriate dosing of DOACs.Patients who received DOACs during admission under a general medical unit over a 2-year period (from January 2017 to December 2018) were retrospectively studied. Appropriateness of the dosing regimen was verified against the recommendations of the Therapeutic Goods Administration of Australia. Data were obtained from medical records and analysed in univariate and multivariate logistic regression models. The variables associated with under- and overdosing were also determined.A total of 203 (mean age 71.6 ± 14.5 years, females 52%) patients were studied. Inappropriate dosing occurred in 44 (22%) patients: underdosing 27 (13%) and overdosing 17 (8%). Age ≥75 years (P 0.01), lower estimated creatinine clearance (CrCl) (P 0.01), prescription of DOAC prior to index admission (P 0.01) and higher Charlson Comorbidity Index (P 0.01), HAS-BLED (P 0.01) and CHAInappropriate dosing of DOACs, especially underdosing, is common in clinical practice. Clinicians should exercise due diligence when prescribing DOACs to patients with renal impairment and in outpatient settings.

Treatment of elderly patients with lung cancer is significantly hindered by concerns about treatment tolerability, toxicity and limited clinical trial data in the elderly; potentially giving rise to treatment nihilism amongst clinicians. This study aims to describe survival in elderly patients with lung cancer and explore potential causes for excess mortality. Patients diagnosed with lung cancer in the Victorian Lung Cancer Registry between 2011–2018 were analysed (n=3481). Patients were age-categorised and compared using Cox-regression modelling to determine mortality risk, after adjusting for confounding. Probability of being offered cancer treatments was also determined, further stratified by disease stage. The eldest patients (≥80 years old) had significantly shorter median survival compared with younger age groups (, Treatment strongly determines lung cancer survival, yet nihilism may threaten treatment provision and survival outcomes. Older patients in this cohort had reduced multidisciplinary presentation, less treatment (OR 0.24) and 28% increased mortality risk. https://bit.ly/2ZGotj0

ImportanceMagnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial.ObjectiveTo determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance.Design, Setting, and ParticipantsThis phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up.InterventionsPatients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions.Main Outcomes and MeasuresThe primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03–based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)–based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)–based outcomes.ResultsBetween May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month.Conclusions and RelevanceIn this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist.Trial RegistrationClinicalTrials.gov Identifier: NCT04384770

We propose svMorph, a framework for interactive virtual sculpting of patient-specific vascular anatomic models. Our framework includes three tools for the creation of tortuosity, aneurysms, and stenoses in tubular vascular geometries. These shape edits are performed via geometric operations on the surface mesh and vessel centerline curves of the input model. The tortuosity tool also uses the physics-based Oriented Particles method, coupled with linear blend skinning, to achieve smooth, elastic-like deformations. Our tools can be applied separately or in combination to produce simulation-suitable morphed models. They are also compatible with popular vascular modeling software, such as simvascular. To illustrate our tools, we morph several image-based, patient-specific models to create a range of shape changes and simulate the resulting hemodynamics via three-dimensional, computational fluid dynamics. We also demonstrate the ability to quickly estimate the hemodynamic effects of the shape changes via the automated generation of associated zero-dimensional lumped-parameter models.

Accurate delineation of the urethra is a prerequisite for urethral dose reduction in prostate radiotherapy. However, even in magnetic resonance-guided radiation therapy (MRgRT), consistent delineation of the urethra is challenging, particularly in online adaptive radiotherapy. This paper presented a fully automatic MRgRT-based prostatic urethra segmentation framework.Twenty-eight prostate cancer patients were included in this study. In-house 3D half fourier single-shot turbo spin-echo (HASTE) and turbo spin echo (TSE) sequences were used to image the Foley-free urethra on a 0.35 T MRgRT system. The segmentation pipeline uses 3D nnU-Net as the base and innovatively combines ground truth and its corresponding radial distance (RD) map during training supervision. Additionally, we evaluate the benefit of incorporating a convolutional long short term memory (LSTM-Conv) layer and spatial recurrent convolution layer (RCL) into nnU-Net. A novel slice-by-slice simple exponential smoothing (SEPS) method specifically for tubular structures was used to post-process the segmentation results.The experimental results show that nnU-Net trained using a combination of Dice, cross-entropy and RD achieved a Dice score of 77.1 ± 2.3% in the testing dataset. With SEPS, Hausdorff distance (HD) and 95% HD were reduced to 2.95 ± 0.17 mm and 1.84 ± 0.11 mm, respectively. LSTM-Conv and RCL layers only minimally improved the segmentation precision.We present the first Foley-free MRgRT-based automated urethra segmentation study. Our method is built on a data-driven neural network with novel cost functions and a post-processing step designed for tubular structures. The performance is consistent with the need for online and offline urethra dose reduction in prostate radiotherapy.

Background A large number of CT brain (CTB) scans are ordered in the ED for older patients with a confirmed or possible head strike but no ongoing symptoms of a head injury. This study aimed to evaluate the effect of the Canadian CT head rule supplemented by the original published minimum inclusion criteria to assist clinician assessment of the need for CTB following minimal trauma fall in patients presenting from residential aged care facilities to a major metropolitan emergency department (ED). Methods This study was conducted as a pre- and post-intervention retrospective audit. The intervention involved implementation of a decision support tool to help clinicians assess patients presenting to the ED following a fall. The tool integrated the Canadian CT Head Rule (CCHR) in conjunction with a simplified set of inclusion criteria to help clinicians define a minimum threshold for a “minor head injury”. Outcome data pertaining to CT brain ordering practices and results were compared over symmetrical 3-month time periods pre- and post-intervention in 2 consecutive years. Results The study included 233 patients in the pre-intervention arm and 241 in the post-intervention arm. Baseline demographics and clinical characteristics were similar in both groups. There was a 20% reduction in the total number of CTB scans ordered following tool implementation, with 134 (57.0%) scans in the pre-intervention group and 90 (37.3%) in the post-intervention group (p p = 0.52). No variation was observed in medical management between groups, and no patients in either group underwent neurosurgical intervention. Conclusions Use of the CCHR supplemented by the original published minimum inclusion criteria appeared to safely reduce the number of CTB scans performed in residential aged care facility residents presenting to an ED after a fall, with no associated adverse outcomes. A larger study across multiple centres is required to determine widespread efficacy and safety of this tool.

Introduction: The definition of pulmonary hypertension relies on the invasive measurement of increased pulmonary arterial pressures (PAPs). The systolic PAP can be non-invasively estimated from the maximal velocity (Vmax) of tricuspid regurgitation (TR) Doppler signals. However, the accuracy of this method is conditioned by the quality of the TR signal. It is also subject to high interobserver variability. To address these issues, we developed an automated, machine-learning framework to analyze TR signals. We hypothesize our method can accurately predict Vmax and velocity time integral (VTI) for any TR signal. Methods: We analyzed 306 TR Doppler signals consisting of high and intermediate signal qualities from 65 patients (median 50 [21, 86] years old). Our method combines a U-Net convolutional neural network with OpenCV, an image processing tool. The U-Net performs semantic image segmentation on an input TR Doppler signal. OpenCV then deduces the Vmax and VTI of the curve. We compared our predictions against expert assessments of the TR signal, Vmax, and VTI. We used 230/56 signals for training/validation to determine the optimal parameters in our U-Net and 20 signals for testing to obtain an unbiased measure of performance. Results: As shown in the figure, our framework accurately predicts Vmax with a bias of 0.06 m/s and 95% limits of agreement of [-0.50, 0.63] m/s, and VTI with a bias of 0.01 m and 95% limits of agreement of [-0.22, 0.23] m. Two signals proved difficult to trace due to noisy images. Our framework takes about 5 seconds to predict Vmax and VTI for each TR signal. Conclusions: The accuracy of the predicted Vmax and VTI is heavily influenced by the quality of the input TR signal. We can solve this issue by training our U-Net on a larger dataset and leveraging other computer-vision techniques or flagging these signals for user intervention. Automation of signal analysis opens the door for more detailed curve analysis on larger clinical cohorts.

INTRODUCTION AND OBJECTIVE:Prior studies using nationwide databases have implicated an increased incidence of renal cell carcinoma (RCC) over time. Granular data, however, may highlight potential g...

In this paper, we demonstrate an easy-to-use and inexpensive stamping method that can be used to generate hydrophobic paraffin surface patterns on a variety of materials and surface geometries, including flat and curved surfaces. In this method, a waxy Parafilm sheet is placed on the back of a polydimethylsiloxane (PDMS) stamp containing microscale surface features; when heated above the melting temperature, the paraffin liquefies and diffuses into the stamp, which functions as a paraffin reservoir. The directional diffusion of the paraffin allows only a thin layer of liquid to be present at the micropatterned stamp surface. Hence, when it is put into contact with a target surface, it transfers a paraffin pattern with submicron lateral resolution and sub-100 nm thickness. By using XPS analysis to track paraffin diffusion process within the PDMS stamp, the diffusion coefficient in PDMS is estimated to be 5.3 x 10-11 m2/s at 65°C. In addition to improved patterning, the paraffin-saturated PDMS stamp removes the need for re-inking for consecutive patterning. In general, our process allows for rapid deposition of complex, multi-layer paraffin patterns on a variety of surfaces.

Simple Summary Stereotactic body radiation therapy (SBRT) has become a standard of care option for prostate cancer patients, utilizing large fractionated dose to shorten treatment times. However, genitourinary (GU) toxicity associated with urethral injury remains prevalent due to non-trivial urethra delineation and sparing at treatment planning and treatment delivery. The aim of our study was to evaluate two optimized urethral MRI sequences (3D HASTE and 3D TSE) with a 0.35T MR-guided radiotherapy (MRgRT) system for urethral visibility and delineation. Among 11 prostate cancer patients, a radiation oncologist qualitatively scored MRgRT 3D HASTE as having the best urethra visibility, superior to CT, clinical MRgRT 3D bSSFP, MRgRT 3D TSE, and similar to diagnostic 3T (2D/3D) T2-weighetd MRI. Moreover, urethra contours from different imaging and clinical workflows demonstrated significant urethra localization variability. Optimized 3D MRgRT HASTE can provide urethral visualization and delineation within an MRgRT workflow for urethral sparing, avoiding cross-modality/system registration errors. Abstract Purpose: To evaluate urethral contours from two optimized urethral MRI sequences with an MR-guided radiotherapy system (MRgRT). Methods: Eleven prostate cancer patients were scanned on a MRgRT system using optimized urethral 3D HASTE and 3D TSE. A resident radiation oncologist contoured the prostatic urethra on the patients’ planning CT, diagnostic 3T T2w MRI, and both urethral MRIs. An attending radiation oncologist reviewed/edited the resident’s contours and additionally contoured the prostatic urethra on the clinical planning MRgRT MRI (bSSFP). For each image, the resident radiation oncologist, attending radiation oncologist, and a senior medical physicist qualitatively scored the prostatic urethra visibility. Using MRgRT 3D HASTE-based contouring workflow as baseline, prostatic urethra contours drawn on CT, diagnostic MRI, clinical bSSFP and 3D TSE were evaluated relative to the contour on 3D HASTE using 95th percentile Hausdorff distance (HD95), mean-distance-to-agreement (MDA), and DICE coefficient. Additionally, prostatic urethra contrast-to-noise-ratios (CNR) were calculated for all images. Results: For two out of three observers, the urethra visibility score for 3D HASTE was significantly higher than CT, and clinical bSSFP, but was not significantly different from diagnostic MRI. The mean HD95/MDA/DICE values were 11.35 ± 3.55 mm/5.77 ± 2.69 mm/0.07 ± 0.08 for CT, 7.62 ± 2.75 mm/3.83 ± 1.47 mm/0.12 ± 0.10 for CT + diagnostic MRI, 5.49 ± 2.32 mm/2.18 ± 1.19 mm/0.35 ± 0.19 for 3D TSE, and 6.34 ± 2.89 mm/2.65 ± 1.31 mm/0.21 ± 0.12 for clinical bSSFP. The CNR for 3D HASTE was significantly higher than CT, diagnostic MRI, and clinical bSSFP, but was not significantly different from 3D TSE. Conclusion: The urethra’s visibility scores showed optimized urethral MRgRT 3D HASTE was superior to the other tested methodologies. The prostatic urethra contours demonstrated significant variability from different imaging and workflows. Urethra contouring uncertainty introduced by cross-modality registration and sub-optimal imaging contrast may lead to significant treatment degradation when urethral sparing is implemented to minimize genitourinary toxicity.

Three-dimensional cardiovascular fluid dynamics simulations typically require computation of several cardiac cycles before they reach a periodic solution, rendering them computationally expensive. Furthermore, there is currently no standardized method to determine whether a simulation has yet reached that periodic state. In this work, we propose the use of an asymptotic error measurement to quantify the difference between simulation results and their ideal periodic state using open-loop lumped-parameter modeling. We further show that initial conditions are crucial in reducing computational time and develop an automated framework to generate appropriate initial conditions from a one-dimensional model of blood flow. We demonstrate the performance of our initialization method using six patient-specific models from the Vascular Model Repository. In our examples, our initialization protocol achieves periodic convergence within one or two cardiac cycles, leading to a significant reduction in computational cost compared to standard methods. All computational tools used in this work are implemented in the open-source software platform SimVascular. Automatically generated initial conditions have the potential to significantly reduce computation time in cardiovascular fluid dynamics simulations.

Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.

A dessin d’enfant or dessin is a bicolored graph embedded into a Riemann surface. Acyclic dessins can be described analytically by preimages of Shabat polynomials and algebraically by their monodromy groups. We determine the Shabat polynomials and monodromy groups of planar acyclic dessins that are uniquely determined by their ramification types.

GOAL The goal of this study was to determine the financial impact of adopting the US Multi-Society Task Force (USMSTF) polypectomy guidelines on physician reimbursement and disposable equipment costs for gastroenterologists in the academic medical center and community practice settings. BACKGROUND In 2020, USMSTF guidelines on polypectomy were introduced with a strong recommendation for cold snare rather than cold forceps technique for removing diminutive and small polyps. Polypectomy with snare technique reimburses physicians at a higher rate compared with cold forceps and also requires different disposable equipment. The financial implications of adopting these guidelines is unknown. MATERIALS AND METHODS Patients that underwent screening colonoscopy where polypectomy was performed at an academic medical center (Loma Linda University Medical Center) and community practice medical center (Ascension Providence Hospital) between July 2018 and July 2019 were identified. The polypectomy technique performed during each procedure was determined (forceps alone, snare alone, forceps plus snare) along with the number and size of polyps as well as disposable equipment. Actual and projected provider reimbursement and disposable equipment costs were determined based on applying the new polypectomy guidelines. RESULTS A total of 1167 patients underwent colonoscopy with polypectomy. Adhering to new guidelines would increase estimated physician reimbursement by 5.6% and 12.5% at academic and community practice sites, respectively. The mean increase in physician reimbursement per procedure was significantly higher at community practice compared with the academic setting ($29.50 vs. $14.13, P

The purpose of the present work is to examine, on a clinically diverse population of older adults (N = 46) sleeping at home, the performance of two actigraphy-based sleep tracking algorithms (i.e., Actigraphy-based Sleep algorithm, ACT-S1 and Sadeh's algorithm) compared to manually scored electroencephalography-based PSG (PSG-EEG). ACT-S1 allows for a fully automatic identification of sleep period time (SPT) and within the identified sleep period, the sleep-wake classification. SPT detected by ACT-S1 did not differ statistically from using PSG-EEG (bias = -9.98 min; correlation 0.89). In sleep-wake classification on 30-s epochs within the identified sleep period, the new ACT-S1 presented similar or slightly higher accuracy (83-87%), precision (86-89%) and F1 score (90-92%), significantly higher specificity (39-40%), and significantly lower, but still high, sensitivity (96-97%) compared to Sadeh's algorithm, which achieved 99% sensitivity as the only measure better than ACT-S1's. Total sleep times (TST) estimated with ACT-S1 and Sadeh's algorithm were higher, but still highly correlated to PSG-EEG's TST. Sleep quality metrics of sleep period efficiency and wake-after-sleep-onset computed by ACT-S1 were not significantly different from PSG-EEG, while the same sleep quality metrics derived by Sadeh's algorithm differed significantly from PSG-EEG. Agreement between ACT-S1 and PSG-EEG reached was highest when analyzing the subset of subjects with least disrupted sleep (N = 28). These results provide evidence of promising performance of a full-automation of the sleep tracking procedure with ACT-S1 on older adults. Future longitudinal validations across specific medical conditions are needed. The algorithm's performance may further improve with integrating multi-sensor information.

Friction and wear are important phenomena occurring in all devices with moving parts. While their origin and the way they evolve over time are not fully understood, they are both intimately linked to surface roughness. Guided by pin-on-disc experiments, we present the steps giving rise to the formation of surface roughness on silica, first by the creation of roughly spherical wear particles whose size is related to a critical length scale governing the transition between ductile and brittle behavior, then by the accumulation of these small particles into a larger third body layer, or gouge. We show that, for the explored range of loading conditions, the surface roughness evolves toward a common steady state under unlubricated wear regardless of the initial surface roughness, hinting toward the possible predictability of roughness evolution in wearing components. The friction coefficient is shown to be related to the surface roughness and its time evolution is discussed as well., 12 pages, 10 figures, published in Wear

AIM Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients. METHODS One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays. RESULTS Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P

Background The predictors of clinically significant bleeding events (CSBEs) associated with direct oral anticoagulants (DOACs) are poorly characterised in literature. Aim To determine the incidence and predictors of CSBEs in patients receiving DOACs. Methods Patients who received DOACs during admission under a general medical unit over a two-year period were retrospectively studied. Following index admission, patients were followed for 12 months or for the duration of treatment (if the latter was less than 12 months). The relevant data were obtained by review of medical records. Results A total of 203 patients were studied over a mean follow-up period of 293 (±81) days. The incidence of CSBE was 13.7 (95%CI 9.5-21.1) per 100 person-years. Age ≥ 75 years (P=0.01), concurrent use of antiplatelet medications (P=0.02) and lower estimated creatinine clearance (CrCl) (P=0.03) had a significant univariate association with CSBEs. However, in the multivariate logistic regression only concurrent use of antiplatelet medications remained significantly associated with CSBEs (adjusted OR3.6, 95%CI:1.4-9.6, P=0.01). Concurrent use of antiplatelet medications was also independently associated with major bleeding events (MBEs) (adjusted OR4.9, 95%CI:1.1-21.4, P=0.04). Although 39 (19.2%) patients received antiplatelet medications, the indications for concurrent antiplatelet use complied with current guidelines in only 3 (7.7%) patients. Conclusion Caution should be exercised when prescribing antiplatelet medications with DOACs, as this combination is a potential risk factor for both major and non-major clinically significant bleeding events. In most patients, the concurrent use of antiplatelet medications was discordant with the current consensus guidelines. This article is protected by copyright. All rights reserved.

Introduction Bronchiolitis obliterans syndrome (BOS) after allogeneic haemopoietic stem cell transplant (HSCT) is an under-recognised and difficult to treat disease. This occurs in the context of limited clinical research and inconsistent diagnostic criteria. Method Retrospective data was collected on 275 patients who underwent allogeneic HSCT at an Australian tertiary hospital between 2007 and 2017. The prevalence of BOS, defined by 2014 National Institute of Health criteria, as well as predictors for BOS and mortality were determined. Treatment outcomes, using serial spirometry, were compared between patients who received early versus late immunosuppression for BOS. Results The prevalence of BOS was 9.1%. Myeloablative conditioning (OR: 2.7, 95%CI: 1.13–6.50, p = 0.03) and extra-pulmonary chronic graft-versus-host disease (OR 2.62, 95% CI: 1.04–6.60, p = 0.04) were associated with BOS. There was reduced median survival in the BOS group compared with the non-BOS group, but this was not statistically significant (4.1years (IQR: 2.8, 6.8) versus 4.6years (IQR: 2.4, 7.8), respectively, p = 0.33). The vast majority (87.5%) of BOS patients failed to attain improvement in FEV1 at 12 months, regardless of treatment strategy. Patients who underwent a late immunosuppression strategy had worse mean FEV1 decline compared to those who received early immunosuppression (−36.3% versus −1.6%, respectively, p = 0.03). Conclusion BOS is a common and progressive disease following HSCT and is largely refractory to current treatment strategies. Compared to late immunosuppression, early augmentation of immunosuppression may slow lung function deterioration in the short term. However, further research is urgently needed to identify effective prevention and treatment strategies for BOS.

PURPOSE To evaluate two distortion correction techniques for diffusion-weighted single-shot echo-planar imaging (DW-ssEPI) on a 0.35 T magnetic resonance-guided radiotherapy (MRgRT) system. METHODS The effects of sequence optimization through enabling parallel imaging (PI) and selecting appropriate bandwidth on spatial distortion were first evaluated on the 0.35 T MRgRT system using a spatial integrity phantom. Field map (FM) and reversed gradient (RG) corrections were then performed on the optimized protocol to further reduce distortion. An open-source toolbox was used to quantify the spatial displacement before and after distortion correction. To evaluate ADC accuracy and repeatability of the optimized protocol, as well as impacts of distortion correction on ADC values, the optimized protocol was scanned twice on a diffusion phantom. The calculated ADC values were compared with reference ADCs using paired t-test. Intraclass correlation coefficient (ICC) between the two repetitions, as well as between before and after FM/RG correction was calculated to evaluate ADC repeatability and effects of distortion correction. Six patients were recruited to assess the in-vivo performance. The optimal distortion correction technique was identified by visual assessment. To quantify distortion reduction, tumor and critical structures were contoured on the turbo spin echo (TSE) image (reference image), the DW-ssEPI image, and the distortion corrected images independently by two radiation oncologists. Mean distance to agreement (MDA) and DICE coefficient between contours on the reference images and the diffusion images were calculated. Tumor apparent diffusion coefficient (ADC) values from the original DW-ssEPI images and the distortion corrected images were compared using Bland-Altman analysis. RESULTS Sequence optimization played a vital role in improving the spatial integrity, and spatial distortion was proportional to the total readout time. Before the correction, distortion of the optimized protocol (PI and high bandwidth) was 1.50 ± 0.89 mm in a 100 mm radius and 2.21 ± 1.39 mm in a 175 mm radius for the central plane. FM corrections reduced the distortions to 0.42 ± 0.27 mm and 0.67 ± 0.49 mm respectively, and RG reduced distortion to 0.40 ± 0.22 mm and 0.64 ± 0.47 mm, respectively. The optimized protocol provided accurate and repeatable ADC quantification on the diffusion phantom. The calculated ADC values were consistent before and after FM/RG correction. For the patient study, the FM correction was unable to reduce chemical shift artifacts whereas the RG method successfully mitigated the chemical shift. MDA reduced from 2.52 ± 1.29 mm to 1.11 ± 0.72 mm after the RG correction. The DICE coefficient increased from 0.80 ± 0.13 to 0.91 ± 0.06. A Bland-Altman plot showed that there was a good agreement between ADC measurements before and after application of the RG correction. CONCLUSION Two distortion correction techniques were evaluated on a commercial low-field MRgRT system. Overall, the RG correction was able to drastically improve spatial distortion and preserve ADC accuracy.

Rationale Patients with epilepsy experience frequent episodes of fragmented sleep which may contribute to chronic sleep loss. Enhancing sleep patterns might lead to improved quality of life in these patients. Currently, unlike some other antiepileptic drugs (AEDs), there are no data on the effects of clobazam, a novel AED on sleep. Therefore, we tested the hypothesis that patients with epilepsy will have longer, more consolidated sleep after treatment with clobazam. Methods In this prospective study, we included adults with drug-resistant epilepsy who were being considered for treatment with clobazam. Patients with known untreated moderate/severe sleep apnea or with major circadian rhythm disorders were excluded. We tested a set of the following subjective sleep measures: Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS), Karolinska Sleepiness Scale (KSS), Insomnia Severity Index (ISI), and Quality of Life in Epilepsy (QOLIE) prior to starting the treatment, as well as after achieving a stable clobazam dose. We also measured sleep pattern using wrist actigraphy – before starting therapy and after achieving stable dose. Results A total of 12 participants completed all parts of the study. After treatment, a lower number of awakenings and less wake after sleep onset (WASO) were seen, as well as a lower number of seizures. Average pretreatment bedtime was 23:45, and average wake time was 8:24. A higher seizure frequency significantly correlated with all subjective sleep measures, as well as with a higher amount actigraphy measured WASO and less total sleep time (TST) measured both by sleep log and by actigraphy. Those with higher baseline WASO by actigraphy also had more depressive symptoms, worse quality of life, longer duration of epilepsy, and a higher seizure frequency. Conclusion Both objective and subjective sleep metrics correlate with depressive symptoms and quality of life. After treatment, there were fewer awakenings as well as fewer seizures.

A 65-year-old man who had diabetes mellitus was referred to our hospital due to fever and back pain. Laboratory findings showed liver dysfunction and C-reactive protein (CRP) elevation. Enhanced computed tomography (CT) showed multiple liver abscesses, hepatic vein and inferior vena cava thrombosis, and spondylodiscitis in the fourth lumbar vertebrae. Based on several detections of Klebsiella pneumoniae (K. pneumoniae) in blood culture, he was diagnosed as having invasive liver abscess syndrome (ILAS), which is characterized by liver abscess and metastatic infection caused by K. pneumoniae. Despite the prompt improvement of liver abscess and thrombosis, after administering antibiotics and anticoagulant, spondylodiscitis worsened. Additionally, iliopsoas abscess emerged on repeated CT imaging. Lumbar laminectomy was needed as a radical treatment. We reviewed 12 cases of ILAS representing spondylodiscitis, and surgical treatments for spondylodiscitis were required in 7 of these cases (58%). When encountering patients with liver abscess and spondylodiscitis, we should consider the possibility of invasive disseminated K. pneumoniae infection, which is hard to treat with antibiotics alone and sometimes requires surgical treatments for spondylodiscitis.

Purpose of review In asthma, there is an increasing focus on personalizing treatment by targeting treatable traits. Ethnicity has effects on many biological and behavioural traits, and so is an important consideration when personalizing asthma care. This review has particular relevance in light of current patterns of international migration, which are leading to unprecedented levels of ethnic heterogeneity in many geographic regions. Recent findings This review examines the effect of ethnicity on three key domains - biological traits, behavioural traits and health system behaviour. Ethnicity influences asthma biology by affecting biomarker reference ranges, response to drug therapy and asthma phenotypes. Ethnicity impacts behavioural traits through its effects on psychosocial well being, adherence and asthma self-management. Ethnic minorities are often disadvantaged with regards to healthcare access and healthcare interactions. Summary Concerted action is needed to address current issues around behavioural traits and healthcare behaviour, which are influenced by ethnicity. More research is required to understand the impact of ethnicity on asthma biology, especially the interplay between genetic and environmental influences on asthma, and the differential response to asthma therapies.

The Chinese population has a comparable prevalence of obstructive sleep apnea (OSA) compared to their Caucasian counterparts, but are notably less obese. Given this difference in body weight, Chinese patients could have a distinct OSA phenotype. We aimed to compare the characteristics of obstructive events in Chinese and Caucasian individuals matched for OSA severity. Chinese and Caucasian subjects with moderate-to-severe OSA (apnea–hypopnea index (AHI) ≥ 20events/h) were included in the study (n = 90) and matched for age, gender and AHI. Data were analysed to identify differences in event type, effect of sleep state and body position, degree of hypoxemia, and prevalence of metabolic risk factors. Data presented are Mean ± SEM or Median (IQR). Chinese subjects had a significantly lower body mass index (BMI) compared to AHI-matched Caucasian counterparts [27 (25–30) versus 34 (30–39) kg/m2, p

Benign prostatic hyperplasia is the most common proliferative abnormality of the prostate. All men experience some prostatic growth as they age, but the rate of growth varies among individuals. Steroid 5α-reductase 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Previous work indicates that one-third of adult prostatic samples do not express SRD5A2, secondary to epigenetic modifications. Here we show that the level of oestradiol is dramatically elevated, concomitant with significant upregulation of oestrogen response genes, in prostatic samples with methylation at the SRD5A2 promoter. The phosphorylation of oestrogen receptor-α in prostatic stroma is upregulated when SRD5A2 expression is absent. We show that tumour necrosis factor (TNF)-α suppresses SRD5A2 mRNA and protein expression, and simultaneously promotes expression of aromatase, the enzyme responsible for conversion of testosterone to oestradiol. Concomitant suppression of SRD5A2 and treatment with TNF-α synergistically upregulate the aromatase levels. The data suggest that, in the absence of prostatic SRD5A2, there is an androgenic to oestrogenic switch. These findings have broad implications for choosing appropriate classes of medications for the management of benign and malignant prostatic diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The development of highly swollen, strong, conductive hydrogel materials is necessary for the advancement of edible device research. Using a gellan gum/gelatin ionic-covalent entanglement (ICE) hydrogel, a simple method of producing conductive, edible hydrogels is described. ICE gels containing NaCl or CsCl were developed which exhibited conductivities of 200 ± 20 mS cm−1 and 380 ± 30 mS cm−1, respectively. Furthermore, the potential of food grade products for use as edible electrodes was examined by analysing the electrical properties of alginate–gelatin hydrogels, Vegemite, Marmite, jelly and gold leaf. Lastly, these edible ICE gels were used to demonstrate a capacitive pressure sensor from consumable materials, which displayed a sensitivity of 0.80 ± 0.06 pF kPa−1 for a range of 4–20 kPa. The pressure exerted by the GI tract on its contents is standardly 0.7 kPa to 6.3 kPa. This suggests potential for application in the detection of digestive pressure abnormalities such as intestinal motility disorders.