Joint shape/texture representation learning for cardiovascular disease diagnosis from magnetic resonance imaging.

Aims: Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cardiac image and mesh are two primary modalities to present the shape and structure of the heart and have been demonstrated to be efficient in CVD prediction and diagnosis. However, previous research has been generally focussed on a single modality (image or mesh), and few of them have tried to jointly consider the image and mesh representations of heart. To obtain efficient and explainable biomarkers for CVD prediction and diagnosis, it is needed to jointly consider both representations. Methods and results: We design a novel multi-channel variational auto-encoder, mesh-image variational auto-encoder, to learn joint representation of paired mesh and image. After training, the shape-aware image representation (SAIR) can be learned directly from the raw images and applied for further CVD prediction and diagnosis. We demonstrate our method on data from UK Biobank study and two other datasets via extensive experiments. In acute myocardial infarction prediction, SAIR achieves 81.43% accuracy, significantly higher than traditional biomarkers like metadata and clinical indices (left ventricle and right ventricle clinical indices of cardiac function like chamber volume, mass, and ejection fraction). Conclusion: Our mesh-image variational auto-encoder provides a novel approach for 3D cardiac mesh reconstruction from images. The extraction of SAIR is fast and without need of segmentation masks, and its focussing can be visualized in the corresponding cardiac meshes. SAIR archives better performance than traditional biomarkers and can be applied as an efficient supplement to them, which is of significant potential in CVD analysis.

Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop.

The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging 'pipelines', and integrating advanced imaging with 'omics', lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds.

COSTA: A Multi-center TOF-MRA Dataset and A Style Self-Consistency Network for Cerebrovascular Segmentation.

Time-of-flight magnetic resonance angiography (TOF-MRA) is the least invasive and ionizing radiation-free approach for cerebrovascular imaging, but variations in imaging artifacts across different clinical centers and imaging vendors result in inter-site and inter-vendor heterogeneity, making its accurate and robust cerebrovascular segmentation challenging. Moreover, the limited availability and quality of annotated data pose further challenges for segmentation methods to generalize well to unseen datasets. In this paper, we construct the largest and most diverse TOF-MRA dataset (COSTA) from 8 individual imaging centers, with all the volumes manually annotated. Then we propose a novel network for cerebrovascular segmentation, namely CESAR, with the ability to tackle feature granularity and image style heterogeneity issues. Specifically, a coarse-to-fine architecture is implemented to refine cerebrovascular segmentation in an iterative manner. An automatic feature selection module is proposed to selectively fuse global long-range dependencies and local contextual information of cerebrovascular structures. A style self-consistency loss is then introduced to explicitly align diverse styles of TOF-MRA images to a standardized one. Extensive experimental results on the COSTA dataset demonstrate the effectiveness of our CESAR network against state-of-the-art methods. We have made 6 subsets of COSTA with the source code online available, in order to promote relevant research in the community.

Multi-centre benchmarking of deep learning models for COVID-19 detection in chest x-rays.

Introduction: This study is a retrospective evaluation of the performance of deep learning models that were developed for the detection of COVID-19 from chest x-rays, undertaken with the goal of assessing the suitability of such systems as clinical decision support tools. Methods: Models were trained on the National COVID-19 Chest Imaging Database (NCCID), a UK-wide multi-centre dataset from 26 different NHS hospitals and evaluated on independent multi-national clinical datasets. The evaluation considers clinical and technical contributors to model error and potential model bias. Model predictions are examined for spurious feature correlations using techniques for explainable prediction. Results: Models performed adequately on NHS populations, with performance comparable to radiologists, but generalised poorly to international populations. Models performed better in males than females, and performance varied across age groups. Alarmingly, models routinely failed when applied to complex clinical cases with confounding pathologies and when applied to radiologist defined "mild" cases. Discussion: This comprehensive benchmarking study examines the pitfalls in current practices that have led to impractical model development. Key findings highlight the need for clinician involvement at all stages of model development, from data curation and label definition, to model evaluation, to ensure that all clinical factors and disease features are appropriately considered during model design. This is imperative to ensure automated approaches developed for disease detection are fit-for-purpose in a clinical setting.

Retinal imaging for the assessment of stroke risk: a systematic review.

BACKGROUND: Stroke is a leading cause of morbidity and mortality. Retinal imaging allows non-invasive assessment of the microvasculature. Consequently, retinal imaging is a technology which is garnering increasing attention as a means of assessing cardiovascular health and stroke risk. METHODS: A biomedical literature search was performed to identify prospective studies that assess the role of retinal imaging derived biomarkers as indicators of stroke risk. RESULTS: Twenty-four studies were included in this systematic review. The available evidence suggests that wider retinal venules, lower fractal dimension, increased arteriolar tortuosity, presence of retinopathy, and presence of retinal emboli are associated with increased likelihood of stroke. There is weaker evidence to suggest that narrower arterioles and the presence of individual retinopathy traits such as microaneurysms and arteriovenous nicking indicate increased stroke risk. Our review identified three models utilizing artificial intelligence algorithms for the analysis of retinal images to predict stroke. Two of these focused on fundus photographs, whilst one also utilized optical coherence tomography (OCT) technology images. The constructed models performed similarly to conventional risk scores but did not significantly exceed their performance. Only two studies identified in this review used OCT imaging, despite the higher dimensionality of this data. CONCLUSION: Whilst there is strong evidence that retinal imaging features can be used to indicate stroke risk, there is currently no predictive model which significantly outperforms conventional risk scores. To develop clinically useful tools, future research should focus on utilization of deep learning algorithms, validation in external cohorts, and analysis of OCT images.

A Generative Shape Compositional Framework to Synthesize Populations of Virtual Chimeras.

Generating virtual organ populations that capture sufficient variability while remaining plausible is essential to conduct in silico trials (ISTs) of medical devices. However, not all anatomical shapes of interest are always available for each individual in a population. The imaging examinations and modalities used can vary between subjects depending on their individualized clinical pathways. Different imaging modalities may have various fields of view and are sensitive to signals from other tissues/organs, or both. Hence, missing/partially overlapping anatomical information is often available across individuals. We introduce a generative shape model for multipart anatomical structures, learnable from sets of unpaired datasets, i.e., where each substructure in the shape assembly comes from datasets with missing or partially overlapping substructures from disjoint subjects of the same population. The proposed generative model can synthesize complete multipart shape assemblies coined virtual chimeras (VCs). We applied this framework to build VCs from databases of whole-heart shape assemblies that each contribute samples for heart substructures. Specifically, we propose a graph neural network-based generative shape compositional framework, which comprises two components, a part-aware generative shape model that captures the variability in shape observed for each structure of interest in the training population and a spatial composition network that assembles/composes the structures synthesized by the former into multipart shape assemblies (i.e., VCs). We also propose a novel self-supervised learning scheme that enables the spatial composition network to be trained with partially overlapping data and weak labels. We trained and validated our approach using shapes of cardiac structures derived from cardiac magnetic resonance (MR) images in the UK Biobank (UKBB). When trained with complete and partially overlapping data, our approach significantly outperforms a principal component analysis (PCA)-based shape model (trained with complete data) in terms of generalizability and specificity. This demonstrates the superiority of the proposed method, as the synthesized cardiac virtual populations are more plausible and capture a greater degree of shape variability than those generated by the PCA-based shape model.

Unsupervised ensemble-based phenotyping enhances discoverability of genes related to left-ventricular morphology.

Recent genome-wide association studies have successfully identified associations between genetic variants and simple cardiac morphological parameters derived from cardiac magnetic resonance images. However, the emergence of large databases, including genetic data linked to cardiac magnetic resonance facilitates the investigation of more nuanced patterns of cardiac shape variability than those studied so far. Here we propose a framework for gene discovery coined unsupervised phenotype ensembles. The unsupervised phenotype ensemble builds a redundant yet highly expressive representation by pooling a set of phenotypes learnt in an unsupervised manner, using deep learning models trained with different hyperparameters. These phenotypes are then analysed via genome-wide association studies, retaining only highly confident and stable associations across the ensemble. We applied our approach to the UK Biobank database to extract geometric features of the left ventricle from image-derived three-dimensional meshes. We demonstrate that our approach greatly improves the discoverability of genes that influence left ventricle shape, identifying 49 loci with study-wide significance and 25 with suggestive significance. We argue that our approach would enable more extensive discovery of gene associations with image-derived phenotypes for other organs or image modalities.

Beyond images: an integrative multi-modal approach to chest x-ray report generation.

Image-to-text radiology report generation aims to automatically produce radiology reports that describe the findings in medical images. Most existing methods focus solely on the image data, disregarding the other patient information accessible to radiologists. In this paper, we present a novel multi-modal deep neural network framework for generating chest x-rays reports by integrating structured patient data, such as vital signs and symptoms, alongside unstructured clinical notes. We introduce a conditioned cross-multi-head attention module to fuse these heterogeneous data modalities, bridging the semantic gap between visual and textual data. Experiments demonstrate substantial improvements from using additional modalities compared to relying on images alone. Notably, our model achieves the highest reported performance on the ROUGE-L metric compared to relevant state-of-the-art models in the literature. Furthermore, we employed both human evaluation and clinical semantic similarity measurement alongside word-overlap metrics to improve the depth of quantitative analysis. A human evaluation, conducted by a board-certified radiologist, confirms the model's accuracy in identifying high-level findings, however, it also highlights that more improvement is needed to capture nuanced details and clinical context.

Accelerated simulation methodologies for computational vascular flow modelling.

Vascular flow modelling can improve our understanding of vascular pathologies and aid in developing safe and effective medical devices. Vascular flow models typically involve solving the nonlinear Navier-Stokes equations in complex anatomies and using physiological boundary conditions, often presenting a multi-physics and multi-scale computational problem to be solved. This leads to highly complex and expensive models that require excessive computational time. This review explores accelerated simulation methodologies, specifically focusing on computational vascular flow modelling. We review reduced order modelling (ROM) techniques like zero-/one-dimensional and modal decomposition-based ROMs and machine learning (ML) methods including ML-augmented ROMs, ML-based ROMs and physics-informed ML models. We discuss the applicability of each method to vascular flow acceleration and the effectiveness of the method in addressing domain-specific challenges. When available, we provide statistics on accuracy and speed-up factors for various applications related to vascular flow simulation acceleration. Our findings indicate that each type of model has strengths and limitations depending on the context. To accelerate real-world vascular flow problems, we propose future research on developing multi-scale acceleration methods capable of handling the significant geometric variability inherent to such problems.

Deep segmentation of OCTA for evaluation and association of changes of retinal microvasculature with Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Optical coherence tomography angiography (OCTA) enables fast and non-invasive high-resolution imaging of retinal microvasculature and is suggested as a potential tool in the early detection of retinal microvascular changes in Alzheimer's Disease (AD). We developed a standardised OCTA analysis framework and compared their extracted parameters among controls and AD/mild cognitive impairment (MCI) in a cross-section study. METHODS: We defined and extracted geometrical parameters of retinal microvasculature at different retinal layers and in the foveal avascular zone (FAZ) from segmented OCTA images obtained using well-validated state-of-the-art deep learning models. We studied these parameters in 158 subjects (62 healthy control, 55 AD and 41 MCI) using logistic regression to determine their potential in predicting the status of our subjects. RESULTS: In the AD group, there was a significant decrease in vessel area and length densities in the inner vascular complexes (IVC) compared with controls. The number of vascular bifurcations in AD is also significantly lower than that of healthy people. The MCI group demonstrated a decrease in vascular area, length densities, vascular fractal dimension and the number of bifurcations in both the superficial vascular complexes (SVC) and the IVC compared with controls. A larger vascular tortuosity in the IVC, and a larger roundness of FAZ in the SVC, can also be observed in MCI compared with controls. CONCLUSION: Our study demonstrates the applicability of OCTA for the diagnosis of AD and MCI, and provides a standard tool for future clinical service and research. Biomarkers from retinal OCTA images can provide useful information for clinical decision-making and diagnosis of AD and MCI.

Simultaneous Hip Implant Segmentation and Gruen Landmarks Detection.

The assessment of implant status and complications of Total Hip Replacement (THR) relies mainly on the clinical evaluation of the X-ray images to analyse the implant and the surrounding rigid structures. Current clinical practise depends on the manual identification of important landmarks to define the implant boundary and to analyse many features in arthroplasty X-ray images, which is time-consuming and could be prone to human error. Semantic segmentation based on the Convolutional Neural Network (CNN) has demonstrated successful results in many medical segmentation tasks. However, these networks cannot define explicit properties that lead to inaccurate segmentation, especially with the limited size of image datasets. Our work integrates clinical knowledge with CNN to segment the implant and detect important features simultaneously. This is instrumental in the diagnosis of complications of arthroplasty, particularly for loose implant and implant-closed bone fractures, where the location of the fracture in relation to the implant must be accurately determined. In this work, we define the points of interest using Gruen zones that represent the interface of the implant with the surrounding bone to build a Statistical Shape Model (SSM). We propose a multitask CNN that combines regression of pose and shape parameters constructed from the SSM and semantic segmentation of the implant. This integrated approach has improved the estimation of implant shape, from 74% to 80% dice score, making segmentation realistic and allowing automatic detection of Gruen zones. To train and evaluate our method, we generated a dataset of annotated hip arthroplasty X-ray images that will be made available.

A generalised deep meta-learning model for automated quality control of cardiovascular magnetic resonance images.

BACKGROUND AND OBJECTIVES: Cardiovascular magnetic resonance (CMR) imaging is a powerful modality in functional and anatomical assessment for various cardiovascular diseases. Sufficient image quality is essential to achieve proper diagnosis and treatment. A large number of medical images, the variety of imaging artefacts, and the workload of imaging centres are amongst the factors that reveal the necessity of automatic image quality assessment (IQA). However, automated IQA requires access to bulk annotated datasets for training deep learning (DL) models. Labelling medical images is a tedious, costly and time-consuming process, which creates a fundamental challenge in proposing DL-based methods for medical applications. This study aims to present a new method for CMR IQA when there is limited access to annotated datasets. METHODS: The proposed generalised deep meta-learning model can evaluate the quality by learning tasks in the prior stage and then fine-tuning the resulting model on a small labelled dataset of the desired tasks. This model was evaluated on the data of over 6,000 subjects from the UK Biobank for five defined tasks, including detecting respiratory motion, cardiac motion, Aliasing and Gibbs ringing artefacts and images without artefacts. RESULTS: The results of extensive experiments show the superiority of the proposed model. Besides, comparing the model's accuracy with the domain adaptation model indicates a significant difference by using only 64 annotated images related to the desired tasks. CONCLUSION: The proposed model can identify unknown artefacts in images with acceptable accuracy, which makes it suitable for medical applications and quality assessment of large cohorts. CODE AVAILABILITY: https://github.com/HosseinSimchi/META-IQA-CMRImages.

Hemodynamics of thrombus formation in intracranial aneurysms: An in silico observational study.

How prevalent is spontaneous thrombosis in a population containing all sizes of intracranial aneurysms? How can we calibrate computational models of thrombosis based on published data? How does spontaneous thrombosis differ in normo- and hypertensive subjects? We address the first question through a thorough analysis of published datasets that provide spontaneous thrombosis rates across different aneurysm characteristics. This analysis provides data for a subgroup of the general population of aneurysms, namely, those of large and giant size (>10 mm). Based on these observed spontaneous thrombosis rates, our computational modeling platform enables the first in silico observational study of spontaneous thrombosis prevalence across a broader set of aneurysm phenotypes. We generate 109 virtual patients and use a novel approach to calibrate two trigger thresholds: residence time and shear rate, thus addressing the second question. We then address the third question by utilizing this calibrated model to provide new insight into the effects of hypertension on spontaneous thrombosis. We demonstrate how a mechanistic thrombosis model calibrated on an intracranial aneurysm cohort can help estimate spontaneous thrombosis prevalence in a broader aneurysm population. This study is enabled through a fully automatic multi-scale modeling pipeline. We use the clinical spontaneous thrombosis data as an indirect population-level validation of a complex computational modeling framework. Furthermore, our framework allows exploration of the influence of hypertension in spontaneous thrombosis. This lays the foundation for in silico clinical trials of cerebrovascular devices in high-risk populations, e.g., assessing the performance of flow diverters in aneurysms for hypertensive patients.

Measuring cardiomyocyte cellular characteristics in cardiac hypertrophy using diffusion-weighted MRI.

PURPOSE: This paper presents a hierarchical modeling approach for estimating cardiomyocyte major and minor diameters and intracellular volume fraction (ICV) using diffusion-weighted MRI (DWI) data in ex vivo mouse hearts. METHODS: DWI data were acquired on two healthy controls and two hearts 3 weeks post transverse aortic constriction (TAC) using a bespoke diffusion scheme with multiple diffusion times ( Δ $$ \Delta $$ ), q-shells and diffusion encoding directions. Firstly, a bi-exponential tensor model was fitted separately at each diffusion time to disentangle the dependence on diffusion times from diffusion weightings, that is, b-values. The slow-diffusing component was attributed to the restricted diffusion inside cardiomyocytes. ICV was then extrapolated at Δ = 0 $$ \Delta =0 $$ using linear regression. Secondly, given the secondary and the tertiary diffusion eigenvalue measurements for the slow-diffusing component obtained at different diffusion times, major and minor diameters were estimated assuming a cylinder model with an elliptical cross-section (ECS). High-resolution three-dimensional synchrotron X-ray imaging (SRI) data from the same specimen was utilized to evaluate the biophysical parameters. RESULTS: Estimated parameters using DWI data were (control 1/control 2 vs. TAC 1/TAC 2): major diameter-17.4 µ $$ \mu $$ m/18.0 µ $$ \mu $$ m versus 19.2 µ $$ \mu $$ m/19.0 µ $$ \mu $$ m; minor diameter-10.2 µ $$ \mu $$ m/9.4 µ $$ \mu $$ m versus 12.8 µ $$ \mu $$ m/13.4 µ $$ \mu $$ m; and ICV-62%/62% versus 68%/47%. These findings were consistent with SRI measurements. CONCLUSION: The proposed method allowed for accurate estimation of biophysical parameters suggesting cardiomyocyte diameters as sensitive biomarkers of hypertrophy in the heart.

Fully Automatic initialization and segmentation of left and right ventricles for large-scale cardiac MRI using a deeply supervised network and 3D-ASM.

BACKGROUND AND OBJECTIVE: The sheer volume of data generated by population imaging studies is unparalleled by current capabilities to extract objective and quantitative cardiac phenotypes; subjective and time-consuming manual image analysis remains the gold standard. Automated image analytics to compute quantitative imaging biomarkers of cardiac function are desperately needed. Data volumes and their variability pose a challenge to most state-of-the-art methods for endo- and epicardial contours, which lack robustness when applied to very large datasets. Our aim is to develop an analysis pipeline for the automatic quantification of cardiac function from cine magnetic resonance imaging data. METHOD: This work adopt 4,638 cardiac MRI cases coming from UK Biobank with ground truth available for left and RV contours. A hybrid and robust algorithm is proposed to improve the accuracy of automatic left and right ventricle segmentation by harnessing the localization accuracy of deep learning and the morphological accuracy of 3D-ASM (three-dimensional active shape models). The contributions of this paper are three-fold. First, a fully automatic method is proposed for left and right ventricle initialization and cardiac MRI segmentation by taking full advantage of spatiotemporal constraint. Second, a deeply supervised network is introduced to train and segment the heart. Third, the 3D-ASM image search procedure is improved by combining image intensity models with convolutional neural network (CNN) derived distance maps improving endo- and epicardial edge localization. RESULTS: The proposed architecture outperformed the state of the art for cardiac MRI segmentation from UK Biobank. The statistics of RV landmarks detection errors for Triscuspid valve and RV apex are 4.17 mm and 5.58 mm separately. The overlap metric, mean contour distance, Hausdorff distance and cardiac functional parameters are calculated for the LV (Left Ventricle) and RV (Right Ventricle) contour segmentation. Bland-Altman analysis for clinical parameters shows that the results from our automated image analysis pipelines are in good agreement with results from expert manual analysis. CONCLUSIONS: Our hybrid scheme combines deep learning and statistical shape modeling for automatic segmentation of the LV/RV from cardiac MRI datasets is effective and robust and can compute cardiac functional indexes from population imaging.

Virtual high-resolution MR angiography from non-angiographic multi-contrast MRIs: synthetic vascular model populations for in-silico trials.

Despite success on multi-contrast MR image synthesis, generating specific modalities remains challenging. Those include Magnetic Resonance Angiography (MRA) that highlights details of vascular anatomy using specialised imaging sequences for emphasising inflow effect. This work proposes an end-to-end generative adversarial network that can synthesise anatomically plausible, high-resolution 3D MRA images using commonly acquired multi-contrast MR images (e.g. T1/T2/PD-weighted MR images) for the same subject whilst preserving the continuity of vascular anatomy. A reliable technique for MRA synthesis would unleash the research potential of very few population databases with imaging modalities (such as MRA) that enable quantitative characterisation of whole-brain vasculature. Our work is motivated by the need to generate digital twins and virtual patients of cerebrovascular anatomy for in-silico studies and/or in-silico trials. We propose a dedicated generator and discriminator that leverage the shared and complementary features of multi-source images. We design a composite loss function for emphasising vascular properties by minimising the statistical difference between the feature representations of the target images and the synthesised outputs in both 3D volumetric and 2D projection domains. Experimental results show that the proposed method can synthesise high-quality MRA images and outperform the state-of-the-art generative models both qualitatively and quantitatively. The importance assessment reveals that T2 and PD-weighted images are better predictors of MRA images than T1; and PD-weighted images contribute to better visibility of small vessel branches towards the peripheral regions. In addition, the proposed approach can generalise to unseen data acquired at different imaging centres with different scanners, whilst synthesising MRAs and vascular geometries that maintain vessel continuity. The results show the potential for use of the proposed approach to generating digital twin cohorts of cerebrovascular anatomy at scale from structural MR images typically acquired in population imaging initiatives.

Toxicity Prediction in Pelvic Radiotherapy Using Multiple Instance Learning and Cascaded Attention Layers.

Modern radiotherapy delivers treatment plans optimised on an individual patient level, using CT-based 3D models of patient anatomy. This optimisation is fundamentally based on simple assumptions about the relationship between radiation dose delivered to the cancer (increased dose will increase cancer control) and normal tissue (increased dose will increase rate of side effects). The details of these relationships are still not well understood, especially for radiation-induced toxicity. We propose a convolutional neural network based on multiple instance learning to analyse toxicity relationships for patients receiving pelvic radiotherapy. A dataset comprising of 315 patients were included in this study; with 3D dose distributions, pre-treatment CT scans with annotated abdominal structures, and patient-reported toxicity scores provided for each participant. In addition, we propose a novel mechanism for segregating the attentions over space and dose/imaging features independently for a better understanding of the anatomical distribution of toxicity. Quantitative and qualitative experiments were performed to evaluate the network performance. The proposed network could predict toxicity with 80% accuracy. Attention analysis over space demonstrated that there was a significant association between radiation dose to the anterior and right iliac of the abdomen and patient-reported toxicity. Experimental results showed that the proposed network had outstanding performance for toxicity prediction, localisation and explanation with the ability of generalisation for an unseen dataset.

RecON: Online learning for sensorless freehand 3D ultrasound reconstruction.

Sensorless freehand 3D ultrasound (US) reconstruction based on deep networks shows promising advantages, such as large field of view, relatively high resolution, low cost, and ease of use. However, existing methods mainly consider vanilla scan strategies with limited inter-frame variations. These methods thus are degraded on complex but routine scan sequences in clinics. In this context, we propose a novel online learning framework for freehand 3D US reconstruction under complex scan strategies with diverse scanning velocities and poses. First, we devise a motion-weighted training loss in training phase to regularize the scan variation frame-by-frame and better mitigate the negative effects of uneven inter-frame velocity. Second, we effectively drive online learning with local-to-global pseudo supervisions. It mines both the frame-level contextual consistency and the path-level similarity constraint to improve the inter-frame transformation estimation. We explore a global adversarial shape before transferring the latent anatomical prior as supervision. Third, we build a feasible differentiable reconstruction approximation to enable the end-to-end optimization of our online learning. Experimental results illustrate that our freehand 3D US reconstruction framework outperformed current methods on two large, simulated datasets and one real dataset. In addition, we applied the proposed framework to clinical scan videos to further validate its effectiveness and generalizability.