Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial.

Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.

Aboriginal young people's experiences of type 2 diabetes diagnosis, management and support: A qualitative study in the Kimberley region of Western Australia.

ISSUES ADDRESSED: In Australia, Aboriginal and Torres Strait Islander young people in remote settings are most-affected by young onset type 2 diabetes (T2D). It is necessary to understand young people's experiences, including factors impacting on self-management, to improve models of care. METHODS: A phenomenological methodology underpinned this qualitative study in Western Australia's Kimberley region. Two Aboriginal Community Controlled Health Services supported recruitment of seven Aboriginal young people aged 12-24 with T2D, who participated in interviews. A carer and health professional of one young person in each site were also interviewed and relevant medical record data reviewed to assist with triangulation of data. De-identified transcripts were inductively coded and a coding structure developed with oversight by a Kimberley Aboriginal researcher. RESULTS: Young people reported varied experiences and emotions relating to a T2D diagnosis. Most recounted this was upsetting and some reported current negative impact on emotional wellbeing. Challenges with understanding and managing diabetes were highlighted, particularly regarding healthy eating, physical activity and medication. Family are a prominent source of self-management support, with the intergenerational impact of diabetes being evident for each participant. Positive relationships with health professionals, entailing continuity of care, were valued. CONCLUSIONS: There are significant emotional and medical challenges for young people with T2D and their families. Recommendations from this work will contribute to the development of local resources and initiatives to improve diabetes-related support. SO WHAT?: Alongside broader efforts to support good health at the societal level, enhanced health education and family-oriented support structures including Aboriginal clinical staff for young people with T2D are needed.

Oral glucose tolerance test-The imperfect gold standard for gestational diabetes screening: A qualitative study involving clinicians in regional, rural and remote areas of Western Australia.

ISSUE ADDRESSED: The oral glucose tolerance test is the 'gold standard' for detecting gestational diabetes in Australian and International guidelines. Test completion in regional, rural and remote regions may be as low as 50%. We explored challenges and enablers for regional, rural and remote antenatal clinicians providing gestational diabetes screening to better understand low oral glucose tolerance test completion. METHODS: We conducted a qualitative descriptive study using semi-structured interviews. Participants eligible for the study were doctors or midwives providing antenatal care in regional, rural and remote Western Australia, between August 2019 and November 2020. Interviews were recorded digitally and transcribed into a Word document. We conducted a thematic analysis after initial categorisation and deduction of themes through workshops involving the research team. RESULTS: We found a diversity of viewpoints on oral glucose tolerance test reliability for detecting gestational diabetes. Themes that emerged were; good collaboration between antenatal clinicians is required for successful screening; screening occurs throughout pregnancy using various tests; clinicians make significant efforts to address barriers; clinicians prioritise therapeutic relationships. CONCLUSIONS: Effective universal screening for gestational diabetes in regional, rural and remote Western Australia is difficult and more complex in practice than guidelines imply. Detecting gestational diabetes requires creative solutions, early identification of at risk women and trust and collaboration between clinicians and women. SO WHAT?: Detection of gestational diabetes in regional, rural and remote Western Australia remains poorly completed. New strategies are required to adequately identify women at risk of adverse birth outcomes relating to hyperglycaemia in pregnancy.

High-resolution MR Angiographic Cerebrovascular Findings in a Tri-Ethnic Population.

BACKGROUND AND PURPOSE: Incidental findings on brain MR and variation of the circle of Willis (CoW) are relatively common among the general population. Ethnic differences have been described before, but few studies have explored the prevalence of incidental intracranial cerebrovascular findings and CoW variants in the setting of a single multi-ethnic cohort. The purpose of this investigation is to describe both incidental cerebrovascular findings and the morphology of the CoW on high-resolution 3T time-of-flight MR angiography (ToF MRA) in a UK tri-ethnic population-based cohort and to present updated prevalence estimates and morphologic reference values. MATERIALS AND METHODS: We studied participants from the UK Southall and Brent Revisited (SABRE) study who underwent 3T brain MRI between 2014-2018. ToF MRA images were assessed for the presence of incidental cerebrovascular imaging findings and used to determine CoW anatomy. RESULTS: 750 participants (mean age: 71.28 ± 6.46 years, range [46-90], 337 female), 322 White Europeans, 253 South Asians, and 175 African Caribbeans, were included. Incidental cerebrovascular findings were observed in 84 subjects (11.2%, 95% CI [9.0-13.7]; 38 women, 45.24%, 95% CI [34.34-56.48]), cerebral aneurysms being the most frequent, followed by intracranial arterial stenoses (ICAS) with highest prevalence among South Asians compared to White European (OR: 2.72, 95% CI [1.22-6.08], p = .015) and African Caribbean subjects (OR: 2.79, 95% CI [1.00-7.82], p = .051). Other findings included arteriovenous malformations and infundibula. The CoW was found to be more often complete in women than in men (25.22% compared to 18.41%, p = .024), and in African Caribbean (34.86%), compared to White European (19.19%), and South Asian (14.23%) subjects (p <0.001 each). CONCLUSIONS: ICAS were independently associated with ethnicity after adjusting for vascular risk factors, having the highest prevalence among South Asians. The prevalence of aneurysms was higher than in previous population-based studies. We observed anatomical differences in the CoW configuration between women, men, and ethnicities. ABBREVIATIONS: BP = Blood pressure; ICAS = Intracranial arterial stenoses; CoW = Circle of Willis; CVM = Cerebral vascular malformations; OR = Odds ratio; ToF MRA = Time-of-flight MR angiography.

ssVERDICT: Self-supervised VERDICT-MRI for enhanced prostate tumor characterization.

PURPOSE: Demonstrating and assessing self-supervised machine-learning fitting of the VERDICT (vascular, extracellular and restricted diffusion for cytometry in tumors) model for prostate cancer. METHODS: We derive a self-supervised neural network for fitting VERDICT (ssVERDICT) that estimates parameter maps without training data. We compare the performance of ssVERDICT to two established baseline methods for fitting diffusion MRI models: conventional nonlinear least squares and supervised deep learning. We do this quantitatively on simulated data by comparing the Pearson's correlation coefficient, mean-squared error, bias, and variance with respect to the simulated ground truth. We also calculate in vivo parameter maps on a cohort of 20 prostate cancer patients and compare the methods' performance in discriminating benign from cancerous tissue via Wilcoxon's signed-rank test. RESULTS: In simulations, ssVERDICT outperforms the baseline methods (nonlinear least squares and supervised deep learning) in estimating all the parameters from the VERDICT prostate model in terms of Pearson's correlation coefficient, bias, and mean-squared error. In vivo, ssVERDICT shows stronger lesion conspicuity across all parameter maps, and improves discrimination between benign and cancerous tissue over the baseline methods. CONCLUSION: ssVERDICT significantly outperforms state-of-the-art methods for VERDICT model fitting and shows, for the first time, fitting of a detailed multicompartment biophysical diffusion MRI model with machine learning without the requirement of explicit training labels.

Responses of intraspecific metabolic scaling to temperature and activity differ between water- and air-breathing ectothermic vertebrates.

Metabolism underpins all life-sustaining processes and varies profoundly with body size, temperature and locomotor activity. A current theory explains some of the size-dependence of metabolic rate (its mass exponent, b) through changes in metabolic level (L). We propose two predictive advances that: (a) combine the above theory with the evolved avoidance of oxygen limitation in water-breathers experiencing warming, and (b) quantify the overall magnitude of combined temperatures and degrees of locomotion on metabolic scaling across air- and water-breathers. We use intraspecific metabolic scaling responses to temperature (523 regressions) and activity (281 regressions) in diverse ectothermic vertebrates (fish, reptiles and amphibians) to show that b decreases with temperature-increased L in water-breathers, supporting surface area-related avoidance of oxygen limitation, whereas b increases with activity-increased L in air-breathers, following volume-related influences. This new theoretical integration quantitatively incorporates different influences (warming, locomotion) and respiration modes (aquatic, terrestrial) on animal energetics.

Prevalence of functional limitations in older remote-living Aboriginal Australians.

INTRODUCTION: To better tailor prevention and care strategies, there is a need to identify modifiable factors associated with functional impairment in older Aboriginal people, and related service needs. OBJECTIVE: To investigate the prevalence and associated factors for functional impairment in older Aboriginal people, and related service needs. DESIGN: Cross-sectional survey of 289 Aboriginal people aged ≥45 years living in the remote Kimberley region of Western Australia. Factors associated with functional impairment were explored with logistic regression. FINDINGS: 41.2% (95% CI 35.6%-47.0%) of participants required assistance with at least one I/ADL, and 26.0% (95% CI 21.2%-31.3%) required assistance with two or more I/ADLs. A core activity limitation (required assistance with showering, dressing or cooking) was reported by 15.9% (95% CI 12.1%-20.6%). In multivariable logistic regression analyses, older age, diabetes, difficulty walking, head injury, higher depression score and worse cognition were associated with needing help with two or more I/ADLs, while older age, history of stroke, higher depression score and worse cognition were associated with the presence of a core activity limitation. The proportion of participants receiving support with I/ADLs ranged from 71.2% to 97.6%. Support was generally provided by family and friends rather than service providers. DISCUSSION: The key modifiable factors associated with functional impairment in older Aboriginal people living in remote regions are diabetes, depression and cognitive impairment. Services required are transport and socio-cultural activities, and ensuring support for family providing the majority of care. CONCLUSIONS: This study highlights the need for holistic prevention strategies and care for older Aboriginal people with functional limitations and their families.

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021.

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.

Combiner and HyperCombiner networks: Rules to combine multimodality MR images for prostate cancer localisation.

One of the distinct characteristics of radiologists reading multiparametric prostate MR scans, using reporting systems like PI-RADS v2.1, is to score individual types of MR modalities, including T2-weighted, diffusion-weighted, and dynamic contrast-enhanced, and then combine these image-modality-specific scores using standardised decision rules to predict the likelihood of clinically significant cancer. This work aims to demonstrate that it is feasible for low-dimensional parametric models to model such decision rules in the proposed Combiner networks, without compromising the accuracy of predicting radiologic labels. First, we demonstrate that either a linear mixture model or a nonlinear stacking model is sufficient to model PI-RADS decision rules for localising prostate cancer. Second, parameters of these combining models are proposed as hyperparameters, weighing independent representations of individual image modalities in the Combiner network training, as opposed to end-to-end modality ensemble. A HyperCombiner network is developed to train a single image segmentation network that can be conditioned on these hyperparameters during inference for much-improved efficiency. Experimental results based on 751 cases from 651 patients compare the proposed rule-modelling approaches with other commonly-adopted end-to-end networks, in this downstream application of automating radiologist labelling on multiparametric MR. By acquiring and interpreting the modality combining rules, specifically the linear-weights or odds ratios associated with individual image modalities, three clinical applications are quantitatively presented and contextualised in the prostate cancer segmentation application, including modality availability assessment, importance quantification and rule discovery.

Medications and cognitive risk in Aboriginal primary care: a cross-sectional study.

BACKGROUND: Aboriginal and Torres Strait Islander people are ageing with high rates of comorbidity, yet little is known about suboptimal prescribing in this population. AIM: The prevalence of potentially suboptimal prescribing and associated risk factors were investigated among older patients attending primary care through Aboriginal Community Controlled Health Services (ACCHSs). METHODS: Medical records of 420 systematically selected patients aged ≥50 years attending urban, rural and remote health services were audited. Polypharmacy (≥ 5 prescribed medications), potentially inappropriate medications (PIMs) as per Beers Criteria and anticholinergic burden (ACB) were estimated and associated risk factors were explored with logistic regression. RESULTS: The prevalence of polypharmacy, PIMs and ACB score ≥3 was 43%, 18% and 12% respectively. In multivariable logistic regression analyses, polypharmacy was less likely in rural (odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.24-0.77) compared to urban patients, and more likely in those with heart disease (OR = 2.62, 95% CI = 1.62-4.25), atrial fibrillation (OR = 4.25, 95% CI = 1.08-16.81), hypertension (OR = 2.14, 95% CI = 1.34-3.44), diabetes (OR = 2.72, 95% CI = 1.69-4.39) or depression (OR = 1.91, 95% CI = 1.19-3.06). PIMs were more frequent in females (OR = 1.88, 95% CI = 1.03-3.42) and less frequent in rural (OR = 0.41, 95% CI = 0.19-0.85) and remote (OR = 0.58, 95% CI = 0.29-1.18) patients. Factors associated with PIMs were kidney disease (OR = 2.60, 95% CI = 1.37-4.92), urinary incontinence (OR = 3.00, 95% CI = 1.02-8.83), depression (OR = 2.67, 95% CI = 1.50-4.77), heavy alcohol use (OR = 2.83, 95% CI = 1.39-5.75) and subjective cognitive concerns (OR = 2.69, 95% CI = 1.31-5.52). High ACB was less common in rural (OR = 0.10, 95% CI = 0.03-0.34) and remote (OR = 0.51, 95% CI = 0.25-1.04) patients and more common in those with kidney disease (OR = 3.07, 95% CI = 1.50-6.30) or depression (OR = 3.32, 95% CI = 1.70-6.47). CONCLUSION: Associations between potentially suboptimal prescribing and depression or cognitive concerns highlight the importance of considering medication review and deprescribing for these patients.

First-in-human in-vivo depiction of paraganglioma metabolism by hyperpolarised 13C-magnetic resonance.

Phaeochromocytomas (PCC) and paragangliomas (PGL), cumulatively referred to as PPGLs, are neuroendocrine tumours arising from neural crest-derived cells in the sympathetic and parasympathetic nervous systems. Predicting future tumour behaviour and the likelihood of metastatic disease remains problematic as genotype-phenotype correlations are limited, the disease has variable penetrance and, to date, no reliable molecular, cellular or histological markers have emerged. Tumour metabolism quantification can be considered as a method to delineating tumour aggressiveness by utilising hyperpolarised 13 C-MR (HP-MR). The technique may provide an opportunity to non-invasively characterise disease behaviour. Here, we present the first instance of the analysis of PPGL metabolism via HP-MR in a single case.

Use of super resolution reconstruction MRI for surgical planning in Placenta accreta spectrum disorder: Case series.

INTRODUCTION: Comprehensive imaging using ultrasound and MRI of placenta accreta spectrum (PAS) aims to prevent catastrophic haemorrhage and maternal death. Standard MRI of the placenta is limited by between-slice motion which can be mitigated by super-resolution reconstruction (SRR) MRI. We applied SRR in suspected PAS cases to determine its ability to enhance anatomical placental assessment and predict adverse maternal outcome. METHODS: Suspected PAS patients (n = 22) underwent MRI at a gestational age (weeks + days) of (32+3±3+2, range (27+1-38+6)). SRR of the placental-myometrial-bladder interface involving rigid motion correction of acquired MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume, was achieved in twelve. 2D MRI or SRR images alone, and paired data were assessed by four radiologists in three review rounds. All radiologists were blinded to results of the ultrasound, original MR image reports, case outcomes, and PAS diagnosis. A Random Forest Classification model was used to highlight the most predictive pathological MRI markers for major obstetric haemorrhage (MOH), bladder adherence (BA), and placental attachment depth (PAD). RESULTS: At delivery, four patients had placenta praevia with no abnormal attachment, two were clinically diagnosed with PAS, and six had histopathological PAS confirmation. Pathological MRI markers (T2-dark intraplacental bands, and loss of retroplacental T2-hypointense line) predicting MOH were more visible using SRR imaging (accuracy 0.73), in comparison to 2D MRI or paired imaging. Bladder wall interruption, predicting BA, was only easily detected by paired imaging (accuracy 0.72). Better detection of certain pathological markers predicting PAD was found using 2D MRI (placental bulge and myometrial thinning (accuracy 0.81)), and SRR (loss of retroplacental T2-hypointense line (accuracy 0.82)). DISCUSSION: The addition of SRR to 2D MRI potentially improved anatomical assessment of certain pathological MRI markers of abnormal placentation that predict maternal morbidity which may benefit surgical planning.

The Importance of Person-Centered Approaches to Managing Behavioral and Psychological Symptoms of Dementia: A Case Report.

Behavioral and psychological symptoms of dementia (BPSD) are common and associated with increased morbidity and mortality in dementia. In this report, we describe a patient with severe BPSD who was effectively managed with a variety of non-pharmacologic strategies. A 70-year-old Navy veteran and retired commercial flooring business owner with a history of dementia was admitted to the hospital with aggressive behavior. He was no longer manageable by his family. He required intermittent use of restraints and multiple antipsychotics during hospitalization. He spent much of his time crawling on the floor, "working" on floor tiles, which was often difficult for staff to safely accommodate. However, with time, interprofessional staff identified signs of distress and developed strategies to safely engage the patient's current perception of his situation. This case highlights how BPSD may be driven by a person's identities and roles from earlier stages of life. Approaching and managing these symptoms flexibly can enhance dementia care.

Antidepressant Strategies for Treatment of Acute Depressive Episodes Among Veterans.

OBJECTIVE: The 2016 VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder offers consensus-based recommendations when response to the initial antidepressant medication is suboptimal; however, little is known about "real-world" pharmacological strategies used by providers treating depression in the Veterans Affairs Health Care System (VAHCS). METHODS: We extracted pharmacy and administrative records of patients diagnosed with a depressive disorder and treated at the Minneapolis VAHCS between January 1, 2010 and May 11, 2021. Patients with bipolar disorder, psychosis-spectrum, or dementia diagnoses were excluded. An algorithm was developed to identify antidepressant strategies: monotherapy (MONO); optimization (OPM); switching (SWT); combination (COM); and augmentation (AUG). Additional data extracted included demographics, service utilization, other psychiatric diagnoses, and clinical risk for hospitalization and mortality. RESULTS: The sample consisted of 1298 patients, 11.3% of whom were female. The mean age of the sample was 51 years. Half of the patients received MONO, with 40% of those patients receiving inadequate doses. OPM was the most common next-step strategy. SWT and COM/AUG were used for 15.9% and 2.6% of patients, respectively. Overall, patients who received COM/AUG were younger. OPM, SWT, and COM/AUG occurred more frequently in psychiatric services settings and required a greater number of outpatient visits. The association between antidepressant strategies and risk of mortality became nonsignificant after accounting for age. CONCLUSIONS: Most of the veterans with acute depression were treated with a single antidepressant, while COM and AUG were rarely used. The age of the patient, and not necessarily greater medical risks, appeared to be a major factor in decisions about antidepressant strategies. Future studies should evaluate whether implementation of underutilized COM and AUG strategies early in the course of depression treatment are feasible.

A pilot study to develop assessment tools for Group A Streptococcus surveillance studies.

Introduction: Group A Streptococcus (GAS) causes pharyngitis (sore throat) and impetigo (skin sores) GAS pharyngitis triggers rheumatic fever (RF) with epidemiological evidence supporting that GAS impetigo may also trigger RF in Australian Aboriginal children. Understanding the concurrent burden of these superficial GAS infections is critical to RF prevention. This pilot study aimed to trial tools for concurrent surveillance of sore throats and skins sore for contemporary studies of RF pathogenesis including development of a sore throat checklist for Aboriginal families and pharynx photography. Methods: Yarning circle conversations and semi-structured interviews were performed with Aboriginal caregivers and used to develop the language and composition of a sore throat checklist. The sore throat story checklist was combined with established methods of GAS pharyngitis and impetigo surveillance (examination, bacteriological culture, rapid antigen detection and serological tests) and new technologies (photography) and used for a pilot cross-sectional surveillance study of Aboriginal children attending their health clinic for a routine appointment. Feasibility, acceptability, and study costs were compiled. Results: Ten Aboriginal caregivers participated in the sore-throat yarning circles; a checklist was derived from predominant symptoms and their common descriptors. Over two days, 21 Aboriginal children were approached for the pilot surveillance study, of whom 17 were recruited; median age was 9 years [IQR 5.5-13.5], 65% were female. One child declined throat swabbing and three declined finger pricks; all other surveillance elements were completed by each child indicating high acceptability of surveillance assessments. Mean time for screening assessment was 19 minutes per child. Transport of clinical specimens enabled gold standard microbiological and serological testing for GAS. Retrospective examination of sore throat photography concorded with assessments performed on the day. Conclusion: Yarning circle conversations were effective in deriving culturally appropriate sore throat questionnaires for GAS pharyngitis surveillance. New and established tools were feasible, practical and acceptable to participants and enable surveillance to determine the burden of superficial GAS infections in communities at high risk of RF. Surveillance of GAS pharyngitis and impetgio in remote Australia informs primary RF prevention with potential global translation.

Joint estimation of relaxation and diffusion tissue parameters for prostate cancer with relaxation-VERDICT MRI.

This work presents a biophysical model of diffusion and relaxation MRI for prostate called relaxation vascular, extracellular and restricted diffusion for cytometry in tumours (rVERDICT). The model includes compartment-specific relaxation effects providing T1/T2 estimates and microstructural parameters unbiased by relaxation properties of the tissue. 44 men with suspected prostate cancer (PCa) underwent multiparametric MRI (mp-MRI) and VERDICT-MRI followed by targeted biopsy. We estimate joint diffusion and relaxation prostate tissue parameters with rVERDICT using deep neural networks for fast fitting. We tested the feasibility of rVERDICT estimates for Gleason grade discrimination and compared with classic VERDICT and the apparent diffusion coefficient (ADC) from mp-MRI. The rVERDICT intracellular volume fraction fic discriminated between Gleason 3 + 3 and 3 + 4 (p = 0.003) and Gleason 3 + 4 and ≥ 4 + 3 (p = 0.040), outperforming classic VERDICT and the ADC from mp-MRI. To evaluate the relaxation estimates we compare against independent multi-TE acquisitions, showing that the rVERDICT T2 values are not significantly different from those estimated with the independent multi-TE acquisition (p > 0.05). Also, rVERDICT parameters exhibited high repeatability when rescanning five patients (R2 = 0.79-0.98; CV = 1-7%; ICC = 92-98%). The rVERDICT model allows for accurate, fast and repeatable estimation of diffusion and relaxation properties of PCa sensitive enough to discriminate Gleason grades 3 + 3, 3 + 4 and ≥ 4 + 3.

Human apoA-I[Lys107del] mutation affects lipid surface behavior of apoA-I and its ability to form large nascent HDL.

Population studies have found that a natural human apoA-I variant, apoA-I[K107del], is strongly associated with low HDL-C but normal plasma apoA-I levels. We aimed to reveal properties of this variant that contribute to its unusual phenotype associated with atherosclerosis. Our oil-drop tensiometry studies revealed that compared to WT, recombinant apoA-I[K107del] adsorbed to surfaces of POPC-coated triolein drops at faster rates, remodeled the surfaces to a greater extent, and was ejected from the surfaces at higher surface pressures on compression of the lipid drops. These properties may drive increased binding of apoA-I[K107del] to and its better retention on large triglyceride-rich lipoproteins, thereby increasing the variant's content on these lipoproteins. While K107del did not affect apoA-I capacity to promote ABCA1-mediated cholesterol efflux from J774 cells, it impaired the biogenesis of large nascent HDL particles resulting in the formation of predominantly smaller nascent HDL. Size-exclusion chromatography of spontaneously reconstituted 1,2-dimyristoylphosphatidylcholine-apoA-I complexes showed that apoA-I[K107del] had a hampered ability to form larger complexes but formed efficiently smaller-sized complexes. CD analysis revealed a reduced ability of apoA-I[K107del] to increase α-helical structure on binding to 1,2-dimyristoylphosphatidylcholine or in the presence of trifluoroethanol. This property may hinder the formation of large apoA-I[K107del]-containing discoidal and spherical HDL but not smaller HDL. Both factors, the increased content of apoA-I[K107del] on triglyceride-rich lipoproteins and the impaired ability of the variant to stabilize large HDL particles resulting in reduced lipid:protein ratios in HDL, may contribute to normal plasma apoA-I levels along with low HDL-C and increased risk for CVD.

Quantification of Prostate Cancer Metabolism Using 3D Multiecho bSSFP and Hyperpolarized [1-13 C] Pyruvate: Metabolism Differs Between Tumors of the Same Gleason Grade.

BACKGROUND: Three-dimensional (3D) multiecho balanced steady-state free precession (ME-bSSFP) has previously been demonstrated in preclinical hyperpolarized (HP) 13 C-MRI in vivo experiments, and it may be suitable for clinical metabolic imaging of prostate cancer (PCa). PURPOSE: To validate a signal simulation framework for the use of sequence parameter optimization. To demonstrate the feasibility of ME-bSSFP for HP 13 C-MRI in patients. To evaluate the metabolism in PCa measured by ME-bSSFP. STUDY TYPE: Retrospective single-center cohort study. PHANTOMS/POPULATION: Phantoms containing aqueous solutions of [1-13 C] lactate (2.3 M) and [13 C] urea (8 M). Eight patients (mean age 67 ± 6 years) with biopsy-confirmed Gleason 3 + 4 (n = 7) and 4 + 3 (n = 1) PCa. FIELD STRENGTH/SEQUENCES: 1 H MRI at 3 T with T2 -weighted turbo spin-echo sequence used for spatial localization and spoiled dual gradient-echo sequence used for B0 -field measurement. ME-bSSFP sequence for 13 C MR spectroscopic imaging with retrospective multipoint IDEAL metabolite separation. ASSESSMENT: The primary endpoint was the analysis of pyruvate-to-lactate conversion in PCa and healthy prostate regions of interest (ROIs) using model-free area under the curve (AUC) ratios and a one-directional kinetic model (kP ). The secondary objectives were to investigate the correlation between simulated and experimental ME-bSSFP metabolite signals for HP 13 C-MRI parameter optimization. STATISTICAL TESTS: Pearson correlation coefficients with 95% confidence intervals and paired t-tests. The level of statistical significance was set at P < 0.05. RESULTS: Strong correlations between simulated and empirical ME-bSSFP signals were found (r > 0.96). Therefore, the simulation framework was used for sequence optimization. Whole prostate metabolic HP 13 C-MRI, observing the conversion of pyruvate into lactate, with a temporal resolution of 6 seconds was demonstrated using ME-bSSFP. Both assessed metrics resulted in significant differences between PCa (mean ± SD) (AUC = 0.33 ± 012, kP  = 0.038 ± 0.014) and healthy (AUC = 0.15 ± 0.10, kP  = 0.011 ± 0.007) ROIs. DATA CONCLUSION: Metabolic HP 13 C-MRI in the prostate using ME-bSSFP allows for differentiation between aggressive PCa and healthy tissue. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Integrative Approaches to Understanding Organismal Responses to Aquatic Deoxygenation.

AbstractOxygen bioavailability is declining in aquatic systems worldwide as a result of climate change and other anthropogenic stressors. For aquatic organisms, the consequences are poorly known but are likely to reflect both direct effects of declining oxygen bioavailability and interactions between oxygen and other stressors, including two-warming and acidification-that have received substantial attention in recent decades and that typically accompany oxygen changes. Drawing on the collected papers in this symposium volume ("An Oxygen Perspective on Climate Change"), we outline the causes and consequences of declining oxygen bioavailability. First, we discuss the scope of natural and predicted anthropogenic changes in aquatic oxygen levels. Although modern organisms are the result of long evolutionary histories during which they were exposed to natural oxygen regimes, anthropogenic change is now exposing them to more extreme conditions and novel combinations of low oxygen with other stressors. Second, we identify behavioral and physiological mechanisms that underlie the interactive effects of oxygen with other stressors, and we assess the range of potential organismal responses to oxygen limitation that occur across levels of biological organization and over multiple timescales. We argue that metabolism and energetics provide a powerful and unifying framework for understanding organism-oxygen interactions. Third, we conclude by outlining a set of approaches for maximizing the effectiveness of future work, including focusing on long-term experiments using biologically realistic variation in experimental factors and taking truly cross-disciplinary and integrative approaches to understanding and predicting future effects.

Controversial Roles of Oxygen in Organismal Responses to Climate Warming.

AbstractDespite the global ecological importance of climate change, controversy surrounds how oxygen affects the fate of aquatic ectotherms under warming. Disagreements extend to the nature of oxygen bioavailability and whether oxygen usually limits growth under warming, explaining smaller adult size. These controversies affect two influential hypotheses: gill oxygen limitation and oxygen- and capacity-limited thermal tolerance. Here, we promote deeper integration of physiological and evolutionary mechanisms. We first clarify the nature of oxygen bioavailability in water, developing a new mass-transfer model that can be adapted to compare warming impacts on organisms with different respiratory systems and flow regimes. By distinguishing aerobic energy costs of moving oxygen from environment to tissues from costs of all other functions, we predict a decline in energy-dependent fitness during hypoxia despite approximately constant total metabolic rate before reaching critically low environmental oxygen. A new measure of oxygen bioavailability that keeps costs of generating water convection constant predicts a higher thermal sensitivity of oxygen uptake in an amphipod model than do previous oxygen supply indices. More importantly, by incorporating size- and temperature-dependent costs of generating water flow, we propose that oxygen limitation at different body sizes and temperatures can be modeled mechanistically. We then report little evidence for oxygen limitation of growth and adult size under benign warming. Yet occasional oxygen limitation, we argue, may, along with other selective pressures, help maintain adaptive plastic responses to warming. Finally, we discuss how to overcome flaws in a commonly used growth model that undermine predictions of warming impacts.