Symptoms before and after COVID-19: a population and case-control study using prospective data.

BACKGROUND: Some individuals experience prolonged illness after acute coronavirus disease 2019 (COVID-19). We assessed whether pre-infection symptoms affected post-acute COVID illness duration. METHODS: Survival analysis was performed in adults (n=23 452) with community-managed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prospectively self-logging data through the ZOE COVID Symptom Study app, at least weekly, from 8 weeks before to 12 weeks after COVID-19 onset, conditioned on presence versus absence of baseline symptoms (4-8 weeks before COVID-19). A case-control study was performed in 1350 individuals with long illness (≥8 weeks, including 906 individuals (67.1%) with illness ≥12 weeks), matched 1:1 (for age, sex, body mass index, testing week, prior infection, vaccination, smoking, index of multiple deprivation) with 1350 individuals with short illness (<4 weeks). Baseline symptoms were compared between the two groups, and against post-COVID symptoms. RESULTS: Individuals reporting baseline symptoms had longer COVID-related symptom duration (median 15 days versus 10 days for individuals without baseline symptoms) with baseline fatigue nearly doubling duration. Two-thirds (910 (67.4%) of 1350) of individuals with long illness were asymptomatic beforehand. However, 440 (32.6%) had baseline symptoms, versus 255 (18.9%) of 1350 individuals with short illness (p<0.0001). Baseline symptoms doubled the odds ratio for long illness (2.14, 95% CI 1.78-2.57). Prior comorbidities were more common in individuals with long versus short illness. In individuals with long illness, baseline symptomatic (versus asymptomatic) individuals were more likely to be female, younger, and have prior comorbidities; and baseline and post-acute symptoms, and symptom burden, correlated strongly. CONCLUSIONS: Individuals experiencing symptoms before COVID-19 had longer illness duration and increased odds of long illness. However, many individuals with long illness were well before SARS-CoV-2 infection.

Radiogenomic biomarkers for immunotherapy in glioblastoma: A systematic review of magnetic resonance imaging studies.

Background: Immunotherapy is an effective "precision medicine" treatment for several cancers. Imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients may serve as preoperative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the advances in bioinformatics and machine learning make such developments plausible. We performed a systematic review to determine the extent of development and validation of immune-related radiogenomic biomarkers for glioblastoma. Methods: A systematic review was performed following PRISMA guidelines using the PubMed, Medline, and Embase databases. Qualitative analysis was performed by incorporating the QUADAS 2 tool and CLAIM checklist. PROSPERO registered: CRD42022340968. Extracted data were insufficiently homogenous to perform a meta-analysis. Results: Nine studies, all retrospective, were included. Biomarkers extracted from magnetic resonance imaging volumes of interest included apparent diffusion coefficient values, relative cerebral blood volume values, and image-derived features. These biomarkers correlated with genomic markers from tumor cells or immune cells or with patient survival. The majority of studies had a high risk of bias and applicability concerns regarding the index test performed. Conclusions: Radiogenomic immune biomarkers have the potential to provide early treatment options to patients with glioblastoma. Targeted immunotherapy, stratified by these biomarkers, has the potential to allow individualized neo-adjuvant precision treatment options in clinical trials. However, there are no prospective studies validating these biomarkers, and interpretation is limited due to study bias with little evidence of generalizability.

Glioblastoma and radiotherapy: A multicenter AI study for Survival Predictions from MRI (GRASP study).

BACKGROUND: The aim was to predict survival of glioblastoma at 8 months after radiotherapy (a period allowing for completing a typical course of adjuvant temozolomide), by applying deep learning to the first brain MRI after radiotherapy completion. METHODS: Retrospective and prospective data were collected from 206 consecutive glioblastoma, isocitrate dehydrogenase -wildtype patients diagnosed between March 2014 and February 2022 across 11 UK centers. Models were trained on 158 retrospective patients from 3 centers. Holdout test sets were retrospective (n = 19; internal validation), and prospective (n = 29; external validation from 8 distinct centers). Neural network branches for T2-weighted and contrast-enhanced T1-weighted inputs were concatenated to predict survival. A nonimaging branch (demographics/MGMT/treatment data) was also combined with the imaging model. We investigated the influence of individual MR sequences; nonimaging features; and weighted dense blocks pretrained for abnormality detection. RESULTS: The imaging model outperformed the nonimaging model in all test sets (area under the receiver-operating characteristic curve, AUC P = .038) and performed similarly to a combined imaging/nonimaging model (P > .05). Imaging, nonimaging, and combined models applied to amalgamated test sets gave AUCs of 0.93, 0.79, and 0.91. Initializing the imaging model with pretrained weights from 10 000s of brain MRIs improved performance considerably (amalgamated test sets without pretraining 0.64; P = .003). CONCLUSIONS: A deep learning model using MRI images after radiotherapy reliably and accurately determined survival of glioblastoma. The model serves as a prognostic biomarker identifying patients who will not survive beyond a typical course of adjuvant temozolomide, thereby stratifying patients into those who might require early second-line or clinical trial treatment.

CrossMoDA 2021 challenge: Benchmark of cross-modality domain adaptation techniques for vestibular schwannoma and cochlea segmentation.

Domain Adaptation (DA) has recently been of strong interest in the medical imaging community. While a large variety of DA techniques have been proposed for image segmentation, most of these techniques have been validated either on private datasets or on small publicly available datasets. Moreover, these datasets mostly addressed single-class problems. To tackle these limitations, the Cross-Modality Domain Adaptation (crossMoDA) challenge was organised in conjunction with the 24th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2021). CrossMoDA is the first large and multi-class benchmark for unsupervised cross-modality Domain Adaptation. The goal of the challenge is to segment two key brain structures involved in the follow-up and treatment planning of vestibular schwannoma (VS): the VS and the cochleas. Currently, the diagnosis and surveillance in patients with VS are commonly performed using contrast-enhanced T1 (ceT1) MR imaging. However, there is growing interest in using non-contrast imaging sequences such as high-resolution T2 (hrT2) imaging. For this reason, we established an unsupervised cross-modality segmentation benchmark. The training dataset provides annotated ceT1 scans (N=105) and unpaired non-annotated hrT2 scans (N=105). The aim was to automatically perform unilateral VS and bilateral cochlea segmentation on hrT2 scans as provided in the testing set (N=137). This problem is particularly challenging given the large intensity distribution gap across the modalities and the small volume of the structures. A total of 55 teams from 16 countries submitted predictions to the validation leaderboard. Among them, 16 teams from 9 different countries submitted their algorithm for the evaluation phase. The level of performance reached by the top-performing teams is strikingly high (best median Dice score - VS: 88.4%; Cochleas: 85.7%) and close to full supervision (median Dice score - VS: 92.5%; Cochleas: 87.7%). All top-performing methods made use of an image-to-image translation approach to transform the source-domain images into pseudo-target-domain images. A segmentation network was then trained using these generated images and the manual annotations provided for the source image.

Detection of cerebral aneurysms using artificial intelligence: a systematic review and meta-analysis.

BACKGROUND: Subarachnoid hemorrhage from cerebral aneurysm rupture is a major cause of morbidity and mortality. Early aneurysm identification, aided by automated systems, may improve patient outcomes. Therefore, a systematic review and meta-analysis of the diagnostic accuracy of artificial intelligence (AI) algorithms in detecting cerebral aneurysms using CT, MRI or DSA was performed. METHODS: MEDLINE, Embase, Cochrane Library and Web of Science were searched until August 2021. Eligibility criteria included studies using fully automated algorithms to detect cerebral aneurysms using MRI, CT or DSA. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis: Diagnostic Test Accuracy (PRISMA-DTA), articles were assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Meta-analysis included a bivariate random-effect model to determine pooled sensitivity, specificity, and area under the receiver operator characteristic curve (ROC-AUC). PROSPERO: CRD42021278454. RESULTS: 43 studies were included, and 41/43 (95%) were retrospective. 34/43 (79%) used AI as a standalone tool, while 9/43 (21%) used AI assisting a reader. 23/43 (53%) used deep learning. Most studies had high bias risk and applicability concerns, limiting conclusions. Six studies in the standalone AI meta-analysis gave (pooled) 91.2% (95% CI 82.2% to 95.8%) sensitivity; 16.5% (95% CI 9.4% to 27.1%) false-positive rate (1-specificity); 0.936 ROC-AUC. Five reader-assistive AI studies gave (pooled) 90.3% (95% CI 88.0% - 92.2%) sensitivity; 7.9% (95% CI 3.5% to 16.8%) false-positive rate; 0.910 ROC-AUC. CONCLUSION: AI has the potential to support clinicians in detecting cerebral aneurysms. Interpretation is limited due to high risk of bias and poor generalizability. Multicenter, prospective studies are required to assess AI in clinical practice.

Toward semi-automatic biologically effective dose treatment plan optimisation for Gamma Knife radiosurgery.

Objective.Dose-rate effects in Gamma Knife radiosurgery treatments can lead to varying biologically effective dose (BED) levels for the same physical dose. The non-convex BED model depends on the delivery sequence and creates a non-trivial treatment planning problem. We investigate the feasibility of employing inverse planning methods to generate treatment plans exhibiting desirable BED characteristics using the per iso-centre beam-on times and delivery sequence.Approach.We implement two dedicated optimisation algorithms. One approach relies on mixed-integer linear programming (MILP) using a purposely developed convex underestimator for the BED to mitigate local minima issues at the cost of computational complexity. The second approach (local optimisation) is faster and potentially usable in a clinical setting but more prone to local minima issues. It sequentially executes the beam-on time (quasi-Newton method) and sequence optimisation (local search algorithm). We investigate the trade-off between time to convergence and solution quality by evaluating the resulting treatment plans' objective function values and clinical parameters. We also study the treatment time dependence of the initial and optimised plans using BED95(BED delivered to 95% of the target volume) values.Main results.When optimising the beam-on times and delivery sequence, the local optimisation approach converges several orders of magnitude faster than the MILP approach (minutes versus hours-days) while typically reaching within 1.2% (0.02-2.08%) of the final objective function value. The quality parameters of the resulting treatment plans show no meaningful difference between the local and MILP optimisation approaches. The presented optimisation approaches remove the treatment time dependence observed in the original treatment plans, and the chosen objectives successfully promote more conformal treatments.Significance.We demonstrate the feasibility of using an inverse planning approach within a reasonable time frame to ensure BED-based objectives are achieved across varying treatment times and highlight the prospect of further improvements in treatment plan quality.

Automated image curation in diabetic retinopathy screening using deep learning.

Diabetic retinopathy (DR) screening images are heterogeneous and contain undesirable non-retinal, incorrect field and ungradable samples which require curation, a laborious task to perform manually. We developed and validated single and multi-output laterality, retinal presence, retinal field and gradability classification deep learning (DL) models for automated curation. The internal dataset comprised of 7743 images from DR screening (UK) with 1479 external test images (Portugal and Paraguay). Internal vs external multi-output laterality AUROC were right (0.994 vs 0.905), left (0.994 vs 0.911) and unidentifiable (0.996 vs 0.680). Retinal presence AUROC were (1.000 vs 1.000). Retinal field AUROC were macula (0.994 vs 0.955), nasal (0.995 vs 0.962) and other retinal field (0.997 vs 0.944). Gradability AUROC were (0.985 vs 0.918). DL effectively detects laterality, retinal presence, retinal field and gradability of DR screening images with generalisation between centres and populations. DL models could be used for automated image curation within DR screening.

Emerging Treatments for Disorders of Consciousness in Paediatric Age.

The number of paediatric patients living with a prolonged Disorder of Consciousness (DoC) is growing in high-income countries, thanks to substantial improvement in intensive care. Life expectancy is extending due to the clinical and nursing management achievements of chronic phase needs, including infections. However, long-known pharmacological therapies such as amantadine and zolpidem, as well as novel instrumental approaches using direct current stimulation and, more recently, stem cell transplantation, are applied in the absence of large paediatric clinical trials and rigorous age-balanced and dose-escalated validations. With evidence building up mainly through case reports and observational studies, there is a need for well-designed paediatric clinical trials and specific research on 0-4-year-old children. At such an early age, assessing residual and recovered abilities is most challenging due to the early developmental stage, incompletely learnt motor and cognitive skills, and unreliable communication; treatment options are also less explored in early age. In middle-income countries, the lack of rehabilitation services and professionals focusing on paediatric age hampers the overall good assistance provision. Young and fast-evolving health insurance systems prevent universal access to chronic care in some countries. In low-income countries, rescue networks are often inadequate, and there is a lack of specialised and intensive care, difficulty in providing specific pharmaceuticals, and lower compliance to intensive care hygiene standards. Despite this, paediatric cases with DoC are reported, albeit in fewer numbers than in countries with better-resourced healthcare systems. For patients with a poor prospect of recovery, withdrawal of care is inhomogeneous across countries and still heavily conditioned by treatment costs as well as ethical and cultural factors, rather than reliant on protocols for assessment and standardised treatments. In summary, there is a strong call for multicentric, international, and global health initiatives on DoC to devote resources to the paediatric age, as there is now scope for funders to invest in themes specific to DoC affecting the early years of the life course.

Imaging Biomarkers of Glioblastoma Treatment Response: A Systematic Review and Meta-Analysis of Recent Machine Learning Studies.

OBJECTIVE: Monitoring biomarkers using machine learning (ML) may determine glioblastoma treatment response. We systematically reviewed quality and performance accuracy of recently published studies. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis: Diagnostic Test Accuracy, we extracted articles from MEDLINE, EMBASE and Cochrane Register between 09/2018-01/2021. Included study participants were adults with glioblastoma having undergone standard treatment (maximal resection, radiotherapy with concomitant and adjuvant temozolomide), and follow-up imaging to determine treatment response status (specifically, distinguishing progression/recurrence from progression/recurrence mimics, the target condition). Using Quality Assessment of Diagnostic Accuracy Studies Two/Checklist for Artificial Intelligence in Medical Imaging, we assessed bias risk and applicability concerns. We determined test set performance accuracy (sensitivity, specificity, precision, F1-score, balanced accuracy). We used a bivariate random-effect model to determine pooled sensitivity, specificity, area-under the receiver operator characteristic curve (ROC-AUC). Pooled measures of balanced accuracy, positive/negative likelihood ratios (PLR/NLR) and diagnostic odds ratio (DOR) were calculated. PROSPERO registered (CRD42021261965). RESULTS: Eighteen studies were included (1335/384 patients for training/testing respectively). Small patient numbers, high bias risk, applicability concerns (particularly confounding in reference standard and patient selection) and low level of evidence, allow limited conclusions from studies. Ten studies (10/18, 56%) included in meta-analysis gave 0.769 (0.649-0.858) sensitivity [pooled (95% CI)]; 0.648 (0.749-0.532) specificity; 0.706 (0.623-0.779) balanced accuracy; 2.220 (1.560-3.140) PLR; 0.366 (0.213-0.572) NLR; 6.670 (2.800-13.500) DOR; 0.765 ROC-AUC. CONCLUSION: ML models using MRI features to distinguish between progression and mimics appear to demonstrate good diagnostic performance. However, study quality and design require improvement.

Disentangling post-vaccination symptoms from early COVID-19.

BACKGROUND: Identifying and testing individuals likely to have SARS-CoV-2 is critical for infection control, including post-vaccination. Vaccination is a major public health strategy to reduce SARS-CoV-2 infection globally. Some individuals experience systemic symptoms post-vaccination, which overlap with COVID-19 symptoms. This study compared early post-vaccination symptoms in individuals who subsequently tested positive or negative for SARS-CoV-2, using data from the COVID Symptom Study (CSS) app. METHODS: We conducted a prospective observational study in 1,072,313 UK CSS participants who were asymptomatic when vaccinated with Pfizer-BioNTech mRNA vaccine (BNT162b2) or Oxford-AstraZeneca adenovirus-vectored vaccine (ChAdOx1 nCoV-19) between 8 December 2020 and 17 May 2021, who subsequently reported symptoms within seven days (N=362,770) (other than local symptoms at injection site) and were tested for SARS-CoV-2 (N=14,842), aiming to differentiate vaccination side-effects per se from superimposed SARS-CoV-2 infection. The post-vaccination symptoms and SARS-CoV-2 test results were contemporaneously logged by participants. Demographic and clinical information (including comorbidities) were recorded. Symptom profiles in individuals testing positive were compared with a 1:1 matched population testing negative, including using machine learning and multiple models considering UK testing criteria. FINDINGS: Differentiating post-vaccination side-effects alone from early COVID-19 was challenging, with a sensitivity in identification of individuals testing positive of 0.6 at best. Most of these individuals did not have fever, persistent cough, or anosmia/dysosmia, requisite symptoms for accessing UK testing; and many only had systemic symptoms commonly seen post-vaccination in individuals negative for SARS-CoV-2 (headache, myalgia, and fatigue). INTERPRETATION: Post-vaccination symptoms per se cannot be differentiated from COVID-19 with clinical robustness, either using symptom profiles or machine-derived models. Individuals presenting with systemic symptoms post-vaccination should be tested for SARS-CoV-2 or quarantining, to prevent community spread. FUNDING: UK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK National Institute for Health Research, UK Medical Research Council and British Heart Foundation, Chronic Disease Research Foundation, Zoe Limited.

The impact of unscheduled gaps and iso-centre sequencing on the biologically effective dose in Gamma Knife radiosurgery.

PURPOSE: Establish the impact of iso-centre sequencing and unscheduled gaps in Gamma Knife® (GK) radiosurgery on the biologically effective dose (BED). METHODS: A BED model was used to study BED values on the prescription iso-surface of patients treated with GK Perfexion™ (Vestibular Schwannoma). The effect of a 15 min gap, simulated at varying points in the treatment delivery, and adjustments to the sequencing of iso-centre delivery, based on average dose-rate, was quantified in terms of the impact on BED. RESULTS: Depending on the position of the gap and the average dose-rate profiles, the mean BED values were decreased by 0.1% to 9.9% of the value in the original plan. A heuristic approach to iso-centre sequencing showed variations in BED of up to 14.2%, relative to the mean BED of the original sequence. CONCLUSION: The treatment variables, like the iso-centre sequence and unscheduled gaps, should be considered during GK radiosurgery treatments.

A Position Statement on the Utility of Interval Imaging in Standard of Care Brain Tumour Management: Defining the Evidence Gap and Opportunities for Future Research.

OBJECTIV E: To summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics. METHODS: Experts in 'interval imaging' (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed. RESULTS: Meningioma and glioma were identified as priorities for interval imaging utility analysis. The "monitoring biomarkers" most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value. CONCLUSION: Evidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management.

Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people.

BACKGROUND: The association between current tobacco smoking, the risk of developing symptomatic COVID-19 and the severity of illness is an important information gap. METHODS: UK users of the Zoe COVID-19 Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, and were asked to log their condition daily. Participants who reported that they did not feel physically normal were then asked by the app to complete a series of questions, including 14 potential COVID-19 symptoms and about hospital attendance. The main study outcome was the development of 'classic' symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness and their association with current smoking. The number of concurrent COVID-19 symptoms was used as a proxy for severity and the pattern of association between symptoms was also compared between smokers and non-smokers. RESULTS: Between 24 March 2020 and 23 April 2020, data were available on 2 401 982 participants, mean (SD) age 43.6 (15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834 437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to report symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR (95% CI) 1.14 (1.10 to 1.18); >5 symptoms 1.29 (1.26 to 1.31); >10 symptoms 1.50 (1.42 to 1.58). The pattern of association between reported symptoms did not vary between smokers and non-smokers. INTERPRETATION: These data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19.

Feasibility Randomized Trial for an Intensive Memory-Focused Training Program for School-Aged Children with Acquired Brain Injury.

(1) Background: Memory deficits are common sequelae of pediatric Acquired Brain Injury (ABI). Only methods for non-focused cognitive remediation are available to the pediatric field. The aims of this feasibility trial are the description, implementation, and test of an intensive program specific to the training and re-adaptation of memory function in children, called Intensive Memory-Focused Training Program (IM-FTP); (2) Methods: Eleven children and adolescents with ABI (mean age at injury = 12.2 years, brain tumor survivors excluded) were clinically assessed and rehabilitated over 1-month through IM-FTP, including physio-kinesis/occupational, speech, and neuropsychology treatments. Each patient received a psychometric evaluation and a brain functional MRI at enrollment and at discharge. Ten pediatric controls with ABI (mean age at injury = 13.8 years) were clinically assessed, and rehabilitated through a standard program; (3) Results: After treatment, both groups had marked improvement in both immediate and delayed recall. IM-FTP was associated with better learning of semantically related and unrelated words, and larger improvement in immediate recall in prose memory. Imaging showed functional modification in the left frontal inferior cortex; (4) Conclusions: We described an age-independent reproducible multidisciplinary memory-focused rehabilitation protocol, which can be adapted to single patients while preserving inter-subject comparability, and is applicable up to a few months after injury. IM-FTP will now be employed in a powered clinical trial.

Evaluation of MRI to Ultrasound Registration Methods for Brain Shift Correction: The CuRIOUS2018 Challenge.

In brain tumor surgery, the quality and safety of the procedure can be impacted by intra-operative tissue deformation, called brain shift. Brain shift can move the surgical targets and other vital structures such as blood vessels, thus invalidating the pre-surgical plan. Intra-operative ultrasound (iUS) is a convenient and cost-effective imaging tool to track brain shift and tumor resection. Accurate image registration techniques that update pre-surgical MRI based on iUS are crucial but challenging. The MICCAI Challenge 2018 for Correction of Brain shift with Intra-Operative UltraSound (CuRIOUS2018) provided a public platform to benchmark MRI-iUS registration algorithms on newly released clinical datasets. In this work, we present the data, setup, evaluation, and results of CuRIOUS 2018, which received 6 fully automated algorithms from leading academic and industrial research groups. All algorithms were first trained with the public RESECT database, and then ranked based on a test dataset of 10 additional cases with identical data curation and annotation protocols as the RESECT database. The article compares the results of all participating teams and discusses the insights gained from the challenge, as well as future work.

Associations Between Vascular Risk Across Adulthood and Brain Pathology in Late Life: Evidence From a British Birth Cohort.

Importance: Midlife vascular risk burden is associated with late-life dementia. Less is known about if and how risk exposure in early adulthood influences late-life brain health. Objective: To determine the associations between vascular risk in early adulthood, midlife, and late life with late-life brain structure and pathology using measures of white matter-hyperintensity volume, ß-amyloid load, and whole-brain and hippocampal volumes. Design, Setting, and Participants: This prospective longitudinal cohort study, Insight 46, is part of the Medical Research Council National Survey of Health and Development, which commenced in 1946. Participants had vascular risk factors evaluated at ages 36 years (early adulthood), 53 years (midlife), and 69 years (early late life). Participants were assessed with multimodal magnetic resonance imaging and florbetapir-amyloid positron emission tomography scans between May 2015 and January 2018 at University College London. Participants with at least 1 available imaging measure, vascular risk measurements at 1 or more points, and no dementia were included in analyses. Exposures: Office-based Framingham Heart study-cardiovascular risk scores (FHS-CVS) were derived at ages 36, 53, and 69 years using systolic blood pressure, antihypertensive medication usage, smoking, diabetic status, and body mass index. Analysis models adjusted for age at imaging, sex, APOE genotype, socioeconomic position, and, where appropriate, total intracranial volume. Main Outcomes and Measures: White matter-hyperintensity volume was generated from T1/fluid-attenuated inversion recovery scans using an automated technique and whole-brain volume and hippocampal volume were generated from automated in-house pipelines; ß-amyloid status was determined using a gray matter/eroded subcortical white matter standardized uptake value ratio threshold of 0.61. Results: A total of 502 participants were assessed as part of Insight 46, and 463 participants (236 male [51.0%]) with at least 1 available imaging measure (mean [SD] age at imaging, 70.7 [0.7] years; 83 ß-amyloid positive [18.2%]) who fulfilled eligibility criteria were included. Among them, FHS-CVS increased with age (36 years: median [interquartile range], 2.7% [1.5%-3.6%]; 53 years: 10.9% [6.7%-15.6%]; 69 years: 24.3% [14.9%-34.9%]). At all points, these scores were associated with smaller whole-brain volumes (36 years: ß coefficient per 1% increase, -3.6 [95% CI, -7.0 to -0.3]; 53 years: -0.8 [95% CI, -1.5 to -0.08]; 69 years: -0.6 [95% CI, -1.1 to -0.2]) and higher white matter-hyperintensity volume (exponentiated coefficient: 36 years, 1.09 [95% CI, 1.01-1.18]; 53 years, 1.02 [95% CI, 1.00-1.04]; 69 years, 1.01 [95% CI, 1.00-1.02]), with largest effect sizes at age 36 years. At no point were FHS-CVS results associated with ß-amyloid status. Conclusions and Relevance: Higher vascular risk is associated with smaller whole-brain volume and greater white matter-hyperintensity volume at age 69 to 71 years, with the strongest association seen with early adulthood vascular risk. There was no evidence that higher vascular risk influences amyloid deposition, at least up to age 71 years. Reducing vascular risk with appropriate interventions should be considered from early adulthood to maximize late-life brain health.

GAS: A genetic atlas selection strategy in multi-atlas segmentation framework.

Multi-Atlas based Segmentation (MAS) algorithms have been successfully applied to many medical image segmentation tasks, but their success relies on a large number of atlases and good image registration performance. Choosing well-registered atlases for label fusion is vital for an accurate segmentation. This choice becomes even more crucial when the segmentation involves organs characterized by a high anatomical and pathological variability. In this paper, we propose a new genetic atlas selection strategy (GAS) that automatically chooses the best subset of atlases to be used for segmenting the target image, on the basis of both image similarity and segmentation overlap. More precisely, the key idea of GAS is that if two images are similar, the performances of an atlas for segmenting each image are similar. Since the ground truth of each atlas is known, GAS first selects a predefined number of similar images to the target, then, for each one of them, finds a near-optimal subset of atlases by means of a genetic algorithm. All these near-optimal subsets are then combined and used to segment the target image. GAS was tested on single-label and multi-label segmentation problems. In the first case, we considered the segmentation of both the whole prostate and of the left ventricle of the heart from magnetic resonance images. Regarding multi-label problems, the zonal segmentation of the prostate into peripheral and transition zone was considered. The results showed that the performance of MAS algorithms statistically improved when GAS is used.

Weakly-supervised convolutional neural networks for multimodal image registration.

One of the fundamental challenges in supervised learning for multimodal image registration is the lack of ground-truth for voxel-level spatial correspondence. This work describes a method to infer voxel-level transformation from higher-level correspondence information contained in anatomical labels. We argue that such labels are more reliable and practical to obtain for reference sets of image pairs than voxel-level correspondence. Typical anatomical labels of interest may include solid organs, vessels, ducts, structure boundaries and other subject-specific ad hoc landmarks. The proposed end-to-end convolutional neural network approach aims to predict displacement fields to align multiple labelled corresponding structures for individual image pairs during the training, while only unlabelled image pairs are used as the network input for inference. We highlight the versatility of the proposed strategy, for training, utilising diverse types of anatomical labels, which need not to be identifiable over all training image pairs. At inference, the resulting 3D deformable image registration algorithm runs in real-time and is fully-automated without requiring any anatomical labels or initialisation. Several network architecture variants are compared for registering T2-weighted magnetic resonance images and 3D transrectal ultrasound images from prostate cancer patients. A median target registration error of 3.6 mm on landmark centroids and a median Dice of 0.87 on prostate glands are achieved from cross-validation experiments, in which 108 pairs of multimodal images from 76 patients were tested with high-quality anatomical labels.

Issues in quantification of registered respiratory gated PET/CT in the lung.

PET/CT quantification of lung tissue is limited by several difficulties: the lung density and local volume changes during respiration, the anatomical mismatch between PET and CT and the relative contributions of tissue, air and blood to the PET signal (the tissue fraction effect). Air fraction correction (AFC) has been shown to improve PET image quantification in the lungs. Methods to correct for the movement and anatomical mismatch involve respiratory gating and image registration techniques. While conventional registration methods only account for spatial mismatch, the Jacobian determinant of the deformable registration transformation field can be used to estimate local volume changes and could therefore potentially be used to correct (i.e. Jacobian Correction, JC) the PET signal for changes in concentration due to local volume changes. This work aims to investigate the relationship between variations in the lung due to respiration, specifically density, tracer concentration and local volume changes. In particular, we study the effect of AFC and JC on PET quantitation after registration of respiratory gated PET/CT patient data. Six patients suffering from lung cancer with solitary pulmonary nodules underwent [Formula: see text]F-FDG PET/cine-CT. The PET data were gated into six respiratory gates using displacement gating based on a real-time position management (RPM) signal and reconstructed with matched gated CT. The PET tracer concentration and tissue density were extracted from registered gated PET and CT images before and after corrections (AFC or JC) and compared to the values from the reference images. Before correction, we observed a linear correlation between the PET tracer concentration values and density. Across all gates and patients, the maximum relative change in PET tracer concentration before (after) AFC was found to be 16.2% (4.1%) and the maximum relative change in tissue density and PET tracer concentration before (after) JC was found to be 17.1% (5.5%) and 16.2% (6.8%) respectively. Overall our results show that both AFC or JC largely explain the observed changes in PET tracer activity over the respiratory cycle. We also speculate that a second order effect is related to change in fluid content but this needs further investigation. Consequently, either AFC or JC is recommended when combining lung PET images from different gates to reduce noise.