Citations

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) present a major health burden to society. Changes in brain structure and cognition are generally only observed at the late stage of the disease. Although advanced magnetic resonance imaging (MRI) techniques such as diffusion imaging may allow identification of biomarkers at earlier stages of neurodegeneration, early diagnosis is still challenging. Magnetic resonance elastography (MRE) is a noninvasive MRI technique for studying the mechanical properties of tissues by measuring the wave propagation induced in the tissues using a purpose‐built actuator. Here, we present a systematic review of preclinical and clinical studies in which MRE has been applied to study neurodegenerative diseases. Actuator systems for data acquisition, inversion algorithms for data analysis, and sample demographics are described and tissue stiffness measures obtained for the whole brain and internal structures are summarized. A total of six animal studies and eight human studies have been published. The animal studies refer to 123 experimental animals (68 AD and 55 PD) and 121 wild‐type animals, while the human studies refer to 142 patients with neurodegenerative disease (including 56 AD and 17 PD) and 166 controls. The animal studies are consistent in the reporting of decreased stiffness of the hippocampal region in AD mice. However, in terms of disease progression, although consistent decreases in either storage modulus or shear modulus magnitude are reported for whole brain, there is variation in the results reported for the hippocampal region. The clinical studies are consistent in reports of a significant decrease in either whole brain storage modulus or shear modulus magnitude, in both AD and PD and with different brain structures affected in different neurodegenerative diseases. MRE studies of neurodegenerative diseases are still in their infancy, and in future it will be interesting to investigate potential relationships between brain mechanical properties and clinical measures, which may help elucidate the mechanisms underlying onset and progression of neurodegenerative diseases.Evidence Level1.Technical EfficacyStage 2.

Infectious diseases contribute significantly to the global disease burden. Sensitive and accurate screening methods are some of the most effective means of identifying sources of infection and controlling infectivity. Conventional detecting strategies such as quantitative polymerase chain reaction (qPCR), DNA sequencing, and mass spectrometry typically require bulky equipment and well-trained personnel. Therefore, mass screening of a large population using conventional strategies during pandemic periods often requires additional manpower, resources, and time, which cannot be guaranteed in resource-limited settings. Recently, emerging microfluidic technologies have shown the potential to replace conventional methods in performing point-of-care detection because they are automated, miniaturized, and integrated. By exploiting the spatial separation of detection sites, microfluidic platforms can enable the multiplex detection of infectious diseases to reduce the possibility of misdiagnosis and incomplete diagnosis of infectious diseases with similar symptoms. This review presents the recent advances in microfluidic platforms used for multiplex detection of infectious diseases, including microfluidic immunosensors and microfluidic nucleic acid sensors. As representative microfluidic platforms, lateral flow immunoassay (LFIA) platforms, polymer-based chips, paper-based devices, and droplet-based devices will be discussed in detail. In addition, the current challenges, commercialization, and prospects are proposed to promote the application of microfluidic platforms in infectious disease detection.

Objectives: The development and evaluation of percutaneous thrombectomy devices for pulmonary embolism (PE) pose a need for standardized large in vivo models with representative anatomical and physiological conditions and clots analogs. In this study, we present a swine model of PE model employing human-derived clot analogs. Material and Methods: Baseline angiographic and physiological pressure measurements were obtained in six adult Yorkshire pigs (45–65 kg) and results were benchmarked for interspecies comparison with published human data using fluoroscopic examinations, intra-arterial pressure measurements, and histologic studies. Then, clot analogs were created ex vivo employing banked human blood and a subset incubated in iodinated contrast for fluoroscopic visualization. Clot analogs were then embolized via a femoral venous access and angiographic/physiological consequences were evaluated. Results: The main, right, and left pulmonary artery diameters were 24 ± 1.1 mm, 16.5 ± 0.8 mm, and 12.6 ± 1.2 mm, respectively. The angle between the main pulmonary artery at the bifurcation point was approximately 90–95°. The clot analogs were heterogeneous and had increased fibrin content along the clot length. The overall composition was 96.63% red blood cell (RBC)/3.37% fibrin in the initial section, 48.85% RBC/51.15% fibrin in the intermediate section, and 3.44% RBC/96.56% fibrin in the final section. Embolization of the clot analogs resulted in distal occlusion of the right and left pulmonary arteries. Conclusions: This swine model coupled with clot analog is able to accurately mimic human anatomical and physiological conditions in PE making it feasible for the evaluation of pulmonary thrombectomy devices.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

PurposeTo improve calibrationless parallel imaging using pre‐learned subspaces of coil sensitivity functions.Theory and MethodsA subspace‐based joint sensitivity estimation and image reconstruction method was developed for improved parallel imaging with no calibration data. Specifically, we proposed to use a probabilistic subspace model to capture prior information of the coil sensitivity functions from previous scans acquired using the same receiver system. Both the subspace basis and coefficient distributions were learned from a small set of training data. The learned subspace model was then incorporated into the regularized reconstruction formalism that includes a sparsity prior. The nonlinear optimization problem was solved using alternating minimization algorithm. Public fastMRI brain dataset was retrospectively undersampled by different schemes for performance evaluation of the proposed method.ResultsWith no calibration data, the proposed method consistently produced the most accurate coil sensitivity estimation and highest quality image reconstructions at all acceleration factors tested in comparison with state‐of‐the‐art methods including JSENSE, DeepSENSE, P‐LORAKS, and Sparse BLIP. Our results are comparable to or even better than those from SparseSENSE, which used calibration data for sensitivity estimation. The work also demonstrated that the probabilistic subspace model learned from T2w data can be generalized to aiding the reconstruction of FLAIR data acquired from the same receiver system.ConclusionA subspace‐based method named JSENSE‐Pro has been proposed for accelerated parallel imaging without the acquisition of companion calibration data. The method is expected to further enhance the practical utility of parallel imaging, especially in applications where calibration data acquisition is not desirable or limited.

Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish ( Danio rerio ) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart’s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411 , in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.

Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered.

Abstract Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability to respond to physical stresses (resilience) and, ultimately, organismal death. Cellular senescence, a self-defensive mechanism activated in response to intrinsic stimuli and/or exogenous stress, is one of the central hallmarks of aging. Senescent cells cease to proliferate, while remaining metabolically active and secreting numerous extracellular factors, a feature known as the senescence-associated secretory phenotype. Senescence is physiologically important for embryonic development, tissue repair, and wound healing, and prevents carcinogenesis. However, chronic accumulation of persisting senescent cells contributes to a host of pathologies including age-related morbidities. By paracrine and endocrine mechanisms, senescent cells can induce inflammation locally and systemically, thereby causing tissue dysfunction, and organ degeneration. Agents including those targeting damaging components of the senescence-associated secretory phenotype or inducing apoptosis of senescent cells exhibit remarkable benefits in both preclinical models and early clinical trials for geriatric conditions. Here we summarize features of senescent cells and outline strategies holding the potential to be developed as clinical interventions. In the long run, there is an increasing demand for safe, effective, and clinically translatable senotherapeutics to address healthcare needs in current settings of global aging.

Abstract Background Nearly half of patients with hidradenitis suppurativa (HS) report dissatisfaction with their treatment. However, factors related to treatment satisfaction have not been explored. Objectives To measure associations between treatment satisfaction and clinical and treatment-related characteristics among patients with HS. Methods Treatment satisfaction was evaluated utilizing data from a cross-sectional global survey of patients with HS recruited from 27 institutions, mainly HS referral centres, in 14 different countries from October 2017 to July 2018. The primary outcome was patients’ self-reported overall satisfaction with their current treatments for HS, rated on a five-point scale from ‘very dissatisfied’ to ‘very satisfied’. Results The final analysis cohort comprised 1418 patients with HS, most of whom were European (55%, 780 of 1418) or North American (38%, 542 of 1418), and female (85%, 1210 of 1418). Overall, 45% (640 of 1418) of participants were either dissatisfied or very dissatisfied with their current medical treatment. In adjusted analysis, patients primarily treated by a dermatologist for HS had 1·99 [95% confidence interval (CI) 1·62–2·44, P < 0·001] times the odds of being satisfied with current treatment than participants not primarily treated by a dermatologist. Treatment with biologics was associated with higher satisfaction [odds ratio (OR) 2·36, 95% CI 1·74–3·19, P < 0·001] relative to treatment with nonbiologic systemic medications. Factors associated with lower treatment satisfaction included smoking (OR 0·78, 95% CI 0·62–0·99; active vs. never), depression (OR 0·69, 95% CI 0·54–0·87), increasing number of comorbidities (OR 0·88 per comorbidity, 95% CI 0·81–0·96) and increasing flare frequency. Conclusions There are several factors that appear to positively influence satisfaction with treatment among patients with HS, including treatment by a dermatologist and treatment with a biologic medication. Factors that appear to lower treatment satisfaction include active smoking, depression, accumulation of comorbid conditions and increasing flare frequency. Awareness of these factors may support partnered decision making with the goal of improving treatment outcomes. What is already known about this topic? Nearly half of patients with hidradenitis suppurativa report dissatisfaction with their treatments. What does this study add? Satisfaction with treatment is increased by receiving care from a dermatologist and treatment with biologics.Satisfaction with treatment is decreased by tobacco smoking, accumulation of comorbid conditions including depression, and higher flare frequency. What are the clinical implications of this work? Awareness of the identified factors associated with poor treatment satisfaction may support partnered decision making and improve treatment outcomes.