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Articular cartilage damage and degeneration are among hallmark manifestations of joint injuries and arthritis, classically osteoarthritis. Cartilage compositional MRI (Cart-C MRI), a quantitative technique, which aims to detect early-stage cartilage matrix changes that precede macroscopic alterations, began development in the 1990s. However, despite the significant advancements over the past three decades, Cart-C MRI remains predominantly a research tool, hindered by various technical and clinical hurdles. This paper will review the technical evolution of Cart-C MRI, delve into its clinical applications, and conclude by identifying the existing gaps and challenges that need to be addressed to enable even broader clinical application of Cart-C MRI.

BACKGROUND: The polyarticular nature of Osteoarthritis (OA) tends to manifest in multi-joints. Associations between cartilage health in connected joints can help identify early degeneration and offer the potential for biomechanical intervention. Such associations between hip and knee cartilages remain understudied. PURPOSE: To investigate T1p associations between hip-femoral and acetabular-cartilage subregions with Intra-limb and Inter-limb patellar cartilage; whole and deep-medial (DM), deep-lateral (DL), superficial-medial (SM), superficial-lateral (SL) subregions. STUDY TYPE: Prospective. SUBJECTS: Twenty-eight subjects (age 55.1 ± 12.8 years, 15 females) with none-to-moderate hip-OA while no radiographic knee-OA. FIELD STRENGTH/SEQUENCE: 3-T, bilateral hip, and knee: 3D-proton-density-fat-saturated (PDFS) Cube and Magnetization-Prepared-Angle-Modulated-Partitioned-k-Space-Spoiled-Gradient-Echo-Snapshots (MAPSS). ASSESSMENT: Ages of subjects were categorized into Group-1 (≤40), Group-2 (41-50), Group-3 (51-60), Group-4 (61-70), Group-5 (71-80), and Group-6 (≥81). Hip T1p maps, co-registered to Cube, underwent an atlas-based algorithm to quantify femoral and acetabular subregional (R2-R7) cartilage T1p. For knee Cube, a combination of V-Net architectures was used to segment the patellar cartilage and subregions (DM, DL, SM, SL). T1p values were computed from co-registered MAPSS. STATISTICAL TESTS: For Intra-and-Inter-limb, 5 optimum predictors out of 13 (Hip subregional T1p, age group, gender) were selected by univariate linear-regression, to predict outcome (patellar T1p). The top five predictors were stepwise added to six linear mixed-effect (LME) models. In all LME models, we assume the data come from the same subject sharing the same random effect. The best-performing models (LME-modelbest) selected via ANOVA, were tested with DM, SM, SL, and DL subregional-mean T1p. LME assumptions were verified (normality of residuals, random-effects, and posterior-predictive-checks). RESULTS: LME-modelbest (Intra-limb) had significant negative and positive fixed-effects of femoral-R5 and acetabular-R2 T1p, respectively (conditional-R2 = 0.581). LME-modelbest (Inter-limb) had significant positive fixed-effects of femoral-R3 T1p (conditional-R2 = 0.26). DATA CONCLUSION: Significant positive and negative T1p associations were identified between load-bearing hip cartilage-subregions vs. ipsilateral and contralateral patellar cartilages respectively. The effects were localized on medial subregions of Inter-limb, in particular. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

PurposeHigh quality scan prescription that optimally covers the area of interest with scan planes aligned to relevant anatomical structures is crucial for error-free radiologic interpretation. The goal of this project was to develop a machine learning pipeline for oblique scan prescription that could be trained on localizer images and metadata from previously acquired MR exams.MethodsA novel Multislice Rotational Region-based Convolutional Neural Network (MS-R2CNN) architecture was developed. Based on this architecture, models for automated prescription sagittal lumbar spine acquisitions from axial, sagittal, and coronal localizer slices were trained. The automated prescription pipeline was integrated with the scanner console software and evaluated in experiments with healthy volunteers (N = 3) and patients with lower-back pain (N = 20).ResultsExperiments in healthy volunteers demonstrated high accuracy of automated prescription in all subjects. There was good agreement between alignment and coverage of manual and automated prescriptions, as well as consistent views of the lumbar spine at different positions of the subjects within the scanner bore. In patients with lower-back pain, the generated prescription was applied in 18 cases (90% of the total number). None of the cases required major adjustment, while in 11 cases (55%) there were minor manual adjustments to the generated prescription.ConclusionsThis study demonstrates the ability of oriented object detection-based models to be trained to prescribe oblique lumbar spine MRI acquisitions without the need of manual annotation or feature engineering and the feasibility of using machine learning-based pipelines on the scanner for automated prescription of MRI acquisitions.

ConspectusBase excision repair (BER) enzymes are genomic superheroes that stealthily and accurately identify and remove chemically modified DNA bases. DNA base modifications erode the informational content of DNA and underlie many disease phenotypes, most conspicuously, cancer. The OG of oxidative base damage, 8-oxo-7,8-dihydroguanine (OG), is particularly insidious due to its miscoding ability that leads to the formation of rare, pro-mutagenic OG:A mismatches. Thwarting mutagenesis relies on the capture of OG:A mismatches prior to DNA replication and removal of the mis-inserted adenine by MutY glycosylases to initiate BER. The threat of OG and the importance of its repair are underscored by the association between inherited dysfunctional variants of the MutY human homologue (MUTYH) and colorectal cancer, known as MUTYH-associated polyposis (MAP). Our functional studies of the two founder MUTYH variants revealed that both have compromised activity and a reduced affinity for OG:A mismatches. Indeed, these studies underscored the challenge of the recognition of OG:A mismatches that are only subtly structurally different than T:A base pairs. Since the original discovery of MAP, many MUTYH variants have been reported, with most considered to be variants of uncertain significance. To reveal features associated with damage recognition and adenine excision by MutY and MUTYH, we have developed a multipronged chemical biology approach combining enzyme kinetics, X-ray crystallography, single-molecule visualization, and cellular repair assays. In this review, we highlight recent work in our laboratory where we defined MutY structure-activity relationship (SAR) studies using synthetic analogs of OG and A in cellular and in vitro assays. Our studies revealed the 2-amino group of OG as the key distinguishing feature of OG:A mismatches. Indeed, the unique position of the 2-amino group in the major groove of OGsyn:Aanti mismatches provides a means for its rapid detection among a large excess of highly abundant and structurally similar canonical base pairs. Furthermore, site-directed mutagenesis and structural analysis showed that a conserved C-terminal domain β-hairpin FSH loop is critical for OG recognition with the His serving as the lesion detector. Notably, MUTYH variants located within and near the FSH loop have been associated with different forms of cancer. Uncovering the role(s) of this loop in lesion recognition provided a detailed understanding of the search and repair process of MutY. Such insights are also useful to identify mutational hotspots and pathogenic variants, which may improve the ability of physicians to diagnose the likelihood of disease onset and prognosis. The critical importance of the FSH loop in lesion detection suggests that it may serve as a unique locus for targeting probes or inhibitors of MutY/MUTYH to provide new chemical biology tools and avenues for therapeutic development.

BackgroundParaspinal muscle fat infiltration is associated with spinal degeneration and low back pain, however, quantifying muscle fat using clinical magnetic resonance imaging (MRI) techniques continues to be a challenge. Advanced MRI techniques, including chemical-shift encoding (CSE) based water-fat MRI, enable accurate measurement of muscle fat, but such techniques are not widely available in routine clinical practice.MethodsTo facilitate assessment of paraspinal muscle fat using clinical imaging, we compared four thresholding approaches for estimating muscle fat fraction (FF) using T1- and T2-weighted images, with measurements from water-fat MRI as the ground truth: Gaussian thresholding, Otsu's method, K-mean clustering, and quadratic discriminant analysis. Pearson's correlation coefficients (r), mean absolute errors, and mean bias errors were calculated for FF estimates from T1- and T2-weighted MRI with water-fat MRI for the lumbar multifidus (MF), erector spinae (ES), quadratus lumborum (QL), and psoas (PS), and for all muscles combined.ResultsWe found that for all muscles combined, FF measurements from T1- and T2-weighted images were strongly positively correlated with measurements from the water-fat images for all thresholding techniques (r = 0.70-0.86, p

Embolization of de novo pulmonary arteriovenous malformations (PAVMs) using high-volume detachable non-fibered (HVDNF) coils was compared to traditional non-HVDNF coils. Persistent-occlusion rates were evaluated. A total of 272 de novo (previously untreated) PAVM treatments were retrospectively stratified into those treated with non-HVDNF coils only (n = 192) and those treated with HVDNF coils with or without other coils (n = 80). Propensity score matching, followed by survival analysis and cost analysis, was performed. The overall persistent-occlusion rate was 86.0% (234/272). Persistent occlusion was achieved in 81.8% of PAVMs using non-HVDNF coils, compared with 96.3% using HVDNF coils (p = 0.0017). The mean follow-up was 30.7 ± 31.9 months versus 14.7 ± 13.4 months, respectively (p < 0.0001). Propensity-matched survival analysis demonstrated PAVMs treated with HVDNF coils recurred significantly less frequently than PAVMs treated with non-HVNDF coils (p = 0.023). The use of HVDNF coils was more expensive than standard coils, however not significantly different for the treatment of complex PAVMs. The use of high-volume detachable non-fibered coils was associated with higher persistent-occlusion rates when compared with non-HVDNF coils. HVDNF coils were more expensive on average; however, cost was similar between groups for the treatment of complex PAVMs.

Chemical strategies that augment genetic polymers with amino acid residues that are overrepresented on the paratope surface of an antibody offer a promising route for enhancing the binding properties of nucleic acid aptamers. Here, we describe the chemical synthesis of α-l-threofuranosyl cytidine nucleoside triphosphate (tCTP) carrying either a benzyl or phenylpropyl side chain at the pyrimidine C-5 position. Polymerase recognition studies indicate that both substrates are readily incorporated into a full-length α-l-threofuranosyl nucleic acid (TNA) product by extension of a DNA primer-template duplex with an engineered TNA polymerase. Similar primer extension reactions performed using nucleoside triphosphate mixtures containing both C-5 modified tCTP and C-5 modified tUTP substrates enable the production of doubly modified TNA strands for a panel of 20 chemotype combinations. Kinetic measurements reveal faster on-rates (kon) and tighter binding affinity constants (Kd) for engineered versions of TNA aptamers carrying chemotypes at both pyrimidine positions as compared to their singly modified counterparts. These findings expand the chemical space of evolvable non-natural genetic polymers by offering a path for improving the quality of biologically stable TNA aptamers for future clinical applications.

Stabilization of topological spin textures in layered magnets has the potential to drive the development of advanced low-dimensional spintronics devices. However, achieving reliable and flexible manipulation of the topological spin textures beyond skyrmion in a two-dimensional magnet system remains challenging. Here, we demonstrate the introduction of magnetic iron atoms between the van der Waals gap of a layered magnet, Fe3GaTe2, to modify local anisotropic magnetic interactions. Consequently, we present direct observations of the order-disorder skyrmion lattices transition. In addition, non-trivial topological solitons, such as skyrmioniums and skyrmion bags, are realized at room temperature. Our work highlights the influence of random spin control of non-trivial topological spin textures.

BACKGROUNDInformation about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments.METHODSCT lung scans from 57 patients with asthma were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow.RESULTSThe length distribution of 778 annotated mucus plugs was multimodal, and a 12 mm length defined short ("stubby", ≤12 mm) and long ("stringy", >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6-9, and 47% of plugs in baseline scans persisted in the same airway for 3 years and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted a greater effect for proximal generations and more numerous mucus plugs.CONCLUSIONPersistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy.TRIAL REGISTRATIONClinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915.FUNDINGAstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.

A 2D U-Net was trained to generate synthetic T1p maps from T2 maps for knee MRI to explore the feasibility of domain adaptation for enriching existing datasets and enabling rapid, reliable image reconstruction. The network was developed using 509 healthy contralateral and injured ipsilateral knee images from patients with ACL injuries and reconstruction surgeries acquired across three institutions. Network generalizability was evaluated on 343 knees acquired in a clinical setting and 46 knees from simultaneous bilateral acquisition in a research setting. The deep neural network synthesized high-fidelity reconstructions of T1p maps, preserving textures and local T1p elevation patterns in cartilage with a normalized mean square error of 2.4% and Pearsons correlation coefficient of 0.93. Analysis of reconstructed T1p maps within cartilage compartments revealed minimal bias (-0.10 ms), tight limits of agreement, and quantification error (5.7%) below the threshold for clinically significant change (6.42%) associated with osteoarthritis. In an out-of-distribution external test set, synthetic maps preserved T1p textures, but exhibited increased bias and wider limits of agreement. This study demonstrates the capability of image synthesis to reduce acquisition time, derive meaningful information from existing datasets, and suggest a pathway for standardizing T1p as a quantitative biomarker for osteoarthritis.

BACKGROUND: Rates of cartilage degeneration in asymptomatic elite basketball players are significantly higher compared with the general population due to excessive loads on the knee. Compositional quantitative magnetic resonance imaging (qMRI) techniques can identify local biochemical changes of macromolecules observed in cartilage degeneration. PURPOSE/HYPOTHESIS: The purpose of this study was to utilize multiparametric qMRI to (1) quantify how T1ρ and T2 relaxation times differ based on the presence of anatomic abnormalities and (2) correlate T1ρ and T2 with self-reported functional deficits. It was hypothesized that prolonged relaxation times will be associated with knees with MRI-graded abnormalities and knees belonging to basketball players with greater self-reported functional deficits. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 75 knees from National Collegiate Athletic Association Division I basketball players (40 female, 35 male) were included in this multicenter study. All players completed the Knee injury and Osteoarthritis Outcome Score (KOOS) and had bilateral knee MRI scans taken. T1ρ and T2 were calculated on a voxel-by-voxel basis. The cartilage surfaces were segmented into 6 compartments: lateral femoral condyle, lateral tibia, medial femoral condyle, medial tibia (MT), patella (PAT), and trochlea (TRO). Lesions from the MRI scans were graded for imaging abnormalities, and statistical parametric mapping was performed to study cross-sectional differences based on MRI scan grading of anatomic knee abnormalities. Pearson partial correlations between relaxation times and KOOS subscore values were computed, obtaining r value statistical parametric mappings and P value clusters. RESULTS: Knees without patellar tendinosis displayed significantly higher T1ρ in the PAT compared with those with patellar tendinosis (average percentage difference, 10.4%; P = .02). Significant prolongation of T1ρ was observed in the MT, TRO, and PAT of knees without compared with those with quadriceps tendinosis (average percentage difference, 12.7%, 13.3%, and 13.4%, respectively; P ≤ .05). A weak correlation was found between the KOOS-Symptoms subscale values and T1ρ/T2. CONCLUSION: Certain tissues that bear the brunt of impact developed tendinosis but spared cartilage degeneration. Whereas participants reported minimal functional deficits, their high-impact activities resulted in structural damage that may lead to osteoarthritis after their collegiate careers.

ObjectiveTo assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness.DesignIndividuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)).ResultsIndividuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p

TURBOMOLE is a highly optimized software suite for large-scale quantum-chemical and materials science simulations of molecules, clusters, extended systems, and periodic solids. TURBOMOLE uses Gaussian basis sets and has been designed with robust and fast quantum-chemical applications in mind, ranging from homogeneous and heterogeneous catalysis to inorganic and organic chemistry and various types of spectroscopy, light-matter interactions, and biochemistry. This Perspective briefly surveys TURBOMOLEs functionality and highlights recent developments that have taken place between 2020 and 2023, comprising new electronic structure methods for molecules and solids, previously unavailable molecular properties, embedding, and molecular dynamics approaches. Select features under development are reviewed to illustrate the continuous growth of the program suite, including nuclear electronic orbital methods, Hartree-Fock-based adiabatic connection models, simplified time-dependent density functional theory, relativistic effects and magnetic properties, and multiscale modeling of optical properties.

Large-language models (LLMs) such as GPT-4 caught the interest of many scientists. Recent studies suggested that these models could be useful in chemistry and materials science. To explore these possibilities, we organized a hackathon. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines.

ObjectiveTo determine the longitudinal changes of patellofemoral joint (PFJ) contact pressure following anterior cruciate ligament reconstruction (ACLR). To identify the associations between PFJ contact pressure and cartilage health.DesignForty-nine subjects with hamstring autograft ACLR (27 males; age 28.8 [standard deviation, 8.3] years) and 19 controls (12 males; 30.7 [4.6] years) participated. A sagittal plane musculoskeletal model was used to estimate PFJ contact pressure. A combined T1ρ/T2 magnetic resonance sequence was obtained. Assessments were performed preoperatively, at 6 months, 1, 2, and 3 years postoperatively in ACLR subjects and once for controls. Repeated Analysis of Variance (ANOVA) was used to compare peak PFJ contact pressure between ACLR and contralateral knees, and t-tests to compare with control knees. Statistical parametric mapping was used to evaluate the associations between PFJ contact pressure and cartilage relaxation concurrently and longitudinally.ResultsNo changes in peak PFJ contact pressure were found within ACLR knees over 3 years (preoperative to 3 years, 0.36 [CI, -0.08, 0.81] MPa), but decreased over time in the contralateral knees (0.75 [0.32, 1.18] MPa). When compared to the controls, ACLR knees exhibited lower PFJ contact pressure at all time points (at baseline, -0.64 [-1.25, -0.03] MPa). Within ACLR knees, lower PFJ contact pressure at 6 months was associated with elevated T2 times (r = -0.47 to -0.49, p = 0.021-0.025).ConclusionsUnderloading of the PFJ following ACLR persists for up to 3 years and has concurrent and future consequences in cartilage health. The non-surgical knees exhibited normal contact pressure initially but decreased over time achieving limb symmetry.

As the most abundant element in the universe, hydrogen is a promising energy carrier for decarbonizing various economic sectors. Green hydrogen production from water electrolysis is critical to the success of this path with polymer electrolyte membrane (PEM) water electrolyzer (WE) as a key technology due to its quick dynamic response and high energy efficiency. Nevertheless, vigorous control algorithms are necessary to maximize the performance, efficiency, and useable lifetime of PEM WEs. This review attempts to collate the modeling frameworks relevant to controller design and provides a survey of various control techniques used in literature to overcome the challenges associated with the transient operation of PEM WEs. To better understand the underlying physics and the coupling between different subsystems, we first review control-oriented electrochemical, thermal, mass transport, and equivalent circuit models. We identify manipulable system variables and control knobs that can be employed for a better system operation in the next step, and finally, we discuss different controllers used in literature, including traditional control approaches, optimal control methods, and other advanced techniques such as nonlinear and neural network controllers.

Management of patients suffering from low back pain (LBP) is challenging and requires development of diagnostic techniques to identify specific patient subgroups and phenotypes in order to customize treatment and predict clinical outcome. The Back Pain Consortium (BACPAC) Research Program Spine Imaging Working Group has developed standard operating procedures (SOPs) for spinal imaging protocols to be used in all BACPAC studies. These SOPs include procedures to conduct spinal imaging assessments with guidelines for standardizing the collection, reading/grading (using structured reporting with semi-quantitative evaluation using ordinal rating scales), and storage of images. This article presents the approach to image acquisition and evaluation recommended by the BACPAC Spine Imaging Working Group. While the approach is specific to BACPAC studies, it is general enough to be applied at other centers performing magnetic resonance imaging (MRI) acquisitions in patients with LBP. The herein presented SOPs are meant to improve understanding of pain mechanisms and facilitate patient phenotyping by codifying MRI-based methods that provide standardized, non-invasive assessments of spinal pathologies. Finally, these recommended procedures may facilitate the integration of better harmonized MRI data of the lumbar spine across studies and sites within and outside of BACPAC studies.

STUDY DESIGN: In vivo retrospective study of fully automatic quantitative imaging feature extraction from clinically acquired lumbar spine magnetic resonance imaging (MRI). OBJECTIVE: To demonstrate the feasibility of substituting automatic for human-demarcated segmentation of major anatomic structures in clinical lumbar spine MRI to generate quantitative image-based features and biomechanical models. SETTING: Previous studies have demonstrated the viability of automatic segmentation applied to medical images; however, the feasibility of these networks to segment clinically acquired images has not yet been demonstrated, as they largely rely on specialized sequences or strict quality of imaging data to achieve good performance. METHODS: Convolutional neural networks were trained to demarcate vertebral bodies, intervertebral disc, and paraspinous muscles from sagittal and axial T1-weighted MRIs. Intervertebral disc height, muscle cross-sectional area, and subject-specific musculoskeletal models of tissue loading in the lumbar spine were then computed from these segmentations and compared against those computed from human-demarcated masks. RESULTS: Segmentation masks, as well as the morphological metrics and biomechanical models computed from those masks, were highly similar between human- and computer-generated methods. Segmentations were similar, with Dice similarity coefficients of 0.77 or greater across networks, and morphological metrics and biomechanical models were similar, with Pearson R correlation coefficients of 0.69 or greater when significant. CONCLUSIONS: This study demonstrates the feasibility of substituting computer-generated for human-generated segmentations of major anatomic structures in lumbar spine MRI to compute quantitative image-based morphological metrics and subject-specific musculoskeletal models of tissue loading quickly, efficiently, and at scale without interrupting routine clinical care.

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

OBJECTIVES: To evaluate whether combining fast acquisitions with deep-learning reconstruction can provide diagnostically useful images and quantitative assessment comparable to standard-of-care acquisitions for lumbar spine magnetic resonance imaging (MRI). METHODS: Eighteen patients were imaged with both standard protocol and fast protocol using reduced signal averages, each protocol including sagittal fat-suppressed T2-weighted, sagittal T1-weighted, and axial T2-weighted 2D fast spin-echo sequences. Fast-acquisition data was additionally reconstructed using vendor-supplied deep-learning reconstruction with three different noise reduction factors. For qualitative analysis, standard images as well as fast images with and without deep-learning reconstruction were graded by three radiologists on five different categories. For quantitative analysis, convolutional neural networks were applied to sagittal T1-weighted images to segment intervertebral discs and vertebral bodies, and disc heights and vertebral body volumes were derived. RESULTS: Based on noninferiority testing on qualitative scores, fast images without deep-learning reconstruction were inferior to standard images for most categories. However, deep-learning reconstruction improved the average scores, and noninferiority was observed over 24 out of 45 comparisons (all with sagittal T2-weighted images while 4/5 comparisons with sagittal T1-weighted and axial T2-weighted images). Interobserver variability increased with 50 and 75% noise reduction factors. Deep-learning reconstructed fast images with 50% and 75% noise reduction factors had comparable disc heights and vertebral body volumes to standard images (r2≥ 0.86 for disc heights and r2≥ 0.98 for vertebral body volumes). CONCLUSIONS: This study demonstrated that deep-learning-reconstructed fast-acquisition images have the potential to provide noninferior image quality and comparable quantitative assessment to standard clinical images.

The medical imaging community has embraced Machine Learning (ML) as evidenced by the rapid increase in the number of ML models being developed, but validating and deploying these models in the clinic remains a challenge. The engineering involved in integrating and assessing the efficacy of ML models within the clinical workflow is complex. This paper presents a general-purpose, end-to-end, clinically integrated ML model deployment and validation system implemented at UCSF. Engineering and usability challenges and results from 3 use cases are presented. A generalized validation system based on free, open-source software (OSS) was implemented, connecting clinical imaging modalities, the Picture Archiving and Communication System (PACS), and an ML inference server. ML pipelines were implemented in NVIDIAs Clara Deploy framework with results and clinician feedback stored in a customized XNAT instance, separate from the clinical record but linked from within PACS. Prospective clinical validation studies of 3 ML models were conducted, with data routed from multiple clinical imaging modalities and PACS. Completed validation studies provided expert clinical feedback on model performance and usability, plus system reliability and performance metrics. Clinical validation of ML models entails assessing model performance, impact on clinical infrastructure, robustness, and usability. Study results must be easily accessible to participating clinicians but remain outside the clinical record. Building a system that generalizes and scales across multiple ML models takes the concerted effort of software engineers, clinicians, data scientists, and system administrators, and benefits from the use of modular OSS. The present work provides a template for institutions looking to translate and clinically validate ML models in the clinic, together with required resources and expected challenges.

The Escherichia coli (E. coli) ribosome can incorporate a variety of non-l-α-amino acid monomers into polypeptide chains in vitro but with poor efficiency. Although these monomers span a diverse set of compounds, there exists no high-resolution structural information regarding their positioning within the catalytic center of the ribosome, the peptidyl transferase center (PTC). Thus, details regarding the mechanism of amide bond formation and the structural basis for differences and defects in incorporation efficiency remain unknown. Within a set of three aminobenzoic acid derivatives-3-aminopyridine-4-carboxylic acid (Apy), ortho-aminobenzoic acid (oABZ), and meta-aminobenzoic acid (mABZ)-the ribosome incorporates Apy into polypeptide chains with the highest efficiency, followed by oABZ and then mABZ, a trend that does not track with the nucleophilicity of the reactive amines. Here, we report high-resolution cryo-EM structures of the ribosome with each of these three aminobenzoic acid derivatives charged on tRNA bound in the aminoacyl-tRNA site (A-site). The structures reveal how the aromatic ring of each monomer sterically blocks the positioning of nucleotide U2506, thereby preventing rearrangement of nucleotide U2585 and the resulting induced fit in the PTC required for efficient amide bond formation. They also reveal disruptions to the bound water network that is believed to facilitate formation and breakdown of the tetrahedral intermediate. Together, the cryo-EM structures reported here provide a mechanistic rationale for differences in reactivity of aminobenzoic acid derivatives relative to l-α-amino acids and each other and identify stereochemical constraints on the size and geometry of non-monomers that can be accepted efficiently by wild-type ribosomes.

BackgroundThe shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.MethodsWe collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.ResultsWe observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.ConclusionsOverall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

PurposeTo use T1ρ and T2 magnetic resonance imaging to evaluate the effect of leukocyte-poor platelet-rich plasma (LP-PRP) injections on knee cartilage health and to correlate structural changes with patient-reported outcome measurements.MethodsTen patients with symptomatic unilateral mild-to-moderate knee osteoarthritis (Kellgren-Lawrence Grade 1-2) underwent T1ρ and T2 magnetic resonance imaging of both the symptomatic and contralateral knee before injection and 6 months after injection with LP-PRP. Patient-reported outcome questionnaires (Knee Osteoarthritis Outcome Score and International Knee Documentation Committee) that evaluate the domains of pain, symptoms, activities of daily living, sports function, and quality of life were completed at baseline, 3 months, 6 months, and 12 months after injection. T1ρ and T2 relaxation times, which are correlated with the proteoglycan and collagen concentration of cartilage, were measured in compartments with and without chondral lesions.ResultsTen patients were prospectively enrolled (9 female, 1 male) with a mean age of 52.9 years (range, 42-68) years and mean body mass index of 23.2 ± 1.9. Significant increases in Knee Osteoarthritis Outcome Score for all subscales and International Knee Documentation Committee scores were observed 3 months after injection and the improvements were sustained at 12 months. T1ρ and T2 values of compartments with chondral lesions were observed to significantly decrease by 6.0% (P = .036) and 7.1% (P = .017) 6 months after LP-PRP injection, respectively. No significant associations between T1ρ and T2 relaxation times and improvement in patient-reported outcomes were observed.ConclusionsPatients undergoing LP-PRP injections for the treatment of mild-to-moderate knee osteoarthritis had increased proteoglycan and collagen deposition in the cartilage of affected compartments by 6 months after injection. Patient-reported outcomes scores improved 3 months after injection and were sustained through 1 year after injection, but these improvements were not associated with the changes in proteoglycan and collagen deposition in knee cartilage.Level of evidenceLevel II, prospective cohort study.

OBJECTIVES: To evaluate a deep learning model for automated and interpretable classification of central canal stenosis, neural foraminal stenosis, and facet arthropathy from lumbar spine MRI. METHODS: T2-weighted axial MRI studies of the lumbar spine acquired between 2008 and 2019 were retrospectively selected (n = 200) and graded for central canal stenosis, neural foraminal stenosis, and facet arthropathy. Studies were partitioned into patient-level train (n = 150), validation (n = 20), and test (n = 30) splits. V-Net models were first trained to segment the dural sac and the intervertebral disk, and localize facet and foramen using geometric rules. Subsequently, Big Transfer (BiT) models were trained for downstream classification tasks. An interpretable model for central canal stenosis was also trained using a decision tree classifier. Evaluation metrics included linearly weighted Cohens kappa score for multi-grade classification and area under the receiver operator characteristic curve (AUROC) for binarized classification. RESULTS: Segmentation of the dural sac and intervertebral disk achieved Dice scores of 0.93 and 0.94. Localization of foramen and facet achieved intersection over union of 0.72 and 0.83. Multi-class grading of central canal stenosis achieved a kappa score of 0.54. The interpretable decision tree classifier had a kappa score of 0.80. Pairwise agreement between readers (R1, R2), (R1, R3), and (R2, R3) was 0.86, 0.80, and 0.74. Binary classification of neural foraminal stenosis and facet arthropathy achieved AUROCs of 0.92 and 0.93. CONCLUSION: Deep learning systems can be performant as well as interpretable for automated evaluation of lumbar spine MRI including classification of central canal stenosis, neural foraminal stenosis, and facet arthropathy. KEY POINTS: • Interpretable deep-learning systems can be developed for the evaluation of clinical lumbar spine MRI. Multi-grade classification of central canal stenosis with a kappa of 0.80 was comparable to inter-reader agreement scores (0.74, 0.80, 0.86). Binary classification of neural foraminal stenosis and facet arthropathy achieved favorable and accurate AUROCs of 0.92 and 0.93, respectively. • While existing deep-learning systems are opaque, leading to clinical deployment challenges, the proposed system is accurate as well as interpretable, providing valuable information to a radiologist in clinical practice.

BACKGROUND: Although T1ρ and T2 have emerged as early indicators for hip osteoarthritis (OA), there is little information regarding longitudinal changes across the cartilage in the early stages of this disease. PURPOSE: To characterize the variability in 2-year hip cartilage T1ρ and T2 changes and investigate associations between these patterns of change and common indicators of hip OA. STUDY TYPE: Prospective. POPULATION: A total of 25 women (age: 51.9 ± 16.3 years old; BMI: 22.6 ± 2.0 kg/m2 ) and 17 men (age: 55.8 ± 14.9 years old; body mass index (BMI): 24.4 ± 3.8 kg/m2 ) who were healthy or with early-to-moderate hip OA. FIELD STRENGTH/SEQUENCE: A 3 T MRI (GE), 3D combined T1ρ /T2 magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots. ASSESSMENT: Principal component (PC) analysis of Z-score difference maps of 2-year changes in hip cartilage T1ρ and T2 relaxation times, participant hip disability and osteoarthritis outcome scores (HOOS) and functional tests at 2-year follow-up. STATISTICAL TESTS: Shapiro-Wilk test, unpaired t-tests, Kruskal Wallis tests, Pearson or Spearman (ρ) correlations. Significance was set at P

Radiologists today play a central role in making diagnostic decisions and labeling images for training and benchmarking artificial intelligence (AI) algorithms. A key concern is low inter-reader reliability (IRR) seen between experts when interpreting challenging cases. While team-based decisions are known to outperform individual decisions, inter-personal biases often creep up in group interactions which limit nondominant participants from expressing true opinions. To overcome the dual problems of low consensus and interpersonal bias, we explored a solution modeled on bee swarms. Two separate cohorts, three board-certified radiologists, (cohort 1), and five radiology residents (cohort 2) collaborated on a digital swarm platform in real time and in a blinded fashion, grading meniscal lesions on knee MR exams. These consensus votes were benchmarked against clinical (arthroscopy) and radiological (senior-most radiologist) standards of reference using Cohen's kappa. The IRR of the consensus votes was then compared to the IRR of the majority and most confident votes of the two cohorts. IRR was also calculated for predictions from a meniscal lesion detecting AI algorithm. The attending cohort saw an improvement of 23% in IRR of swarm votes (k = 0.34) over majority vote (k = 0.11). Similar improvement of 23% in IRR (k = 0.25) in 3-resident swarm votes over majority vote (k = 0.02) was observed. The 5-resident swarm had an even higher improvement of 30% in IRR (k = 0.37) over majority vote (k = 0.07). The swarm consensus votes outperformed individual and majority vote decision in both the radiologists and resident cohorts. The attending and resident swarms also outperformed predictions from a state-of-the-art AI algorithm.

Confined fluids and electrolyte solutions in nanopores exhibit rich and surprising physics and chemistry that impact the mass transport and energy efficiency in many important natural systems and industrial applications. Existing theories often fail to predict the exotic effects observed in the narrowest of such pores, called single-digit nanopores (SDNs), which have diameters or conduit widths of less than 10 nm, and have only recently become accessible for experimental measurements. What SDNs reveal has been surprising, including a rapidly increasing number of examples such as extraordinarily fast water transport, distorted fluid-phase boundaries, strong ion-correlation and quantum effects, and dielectric anomalies that are not observed in larger pores. Exploiting these effects presents myriad opportunities in both basic and applied research that stand to impact a host of new technologies at the water-energy nexus, from new membranes for precise separations and water purification to new gas permeable materials for water electrolyzers and energy-storage devices. SDNs also present unique opportunities to achieve ultrasensitive and selective chemical sensing at the single-ion and single-molecule limit. In this review article, we summarize the progress on nanofluidics of SDNs, with a focus on the confinement effects that arise in these extremely narrow nanopores. The recent development of precision model systems, transformative experimental tools, and multiscale theories that have played enabling roles in advancing this frontier are reviewed. We also identify new knowledge gaps in our understanding of nanofluidic transport and provide an outlook for the future challenges and opportunities at this rapidly advancing frontier.

OBJECTIVE: To evaluate whether the deep learning (DL) segmentation methods from the six teams that participated in the IWOAI 2019 Knee Cartilage Segmentation Challenge are appropriate for quantifying cartilage loss in longitudinal clinical trials. DESIGN: We included 556 subjects from the Osteoarthritis Initiative study with manually read cartilage volume scores for the baseline and 1-year visits. The teams used their methods originally trained for the IWOAI 2019 challenge to segment the 1130 knee MRIs. These scans were anonymized and the teams were blinded to any subject or visit identifiers. Two teams also submitted updated methods. The resulting 9,040 segmentations are available online.The segmentations included tibial, femoral, and patellar compartments. In post-processing, we extracted medial and lateral tibial compartments and geometrically defined central medial and lateral femoral sub-compartments. The primary study outcome was the sensitivity to measure cartilage loss as defined by the standardized response mean (SRM). RESULTS: For the tibial compartments, several of the DL segmentation methods had SRMs similar to the gold standard manual method. The highest DL SRM was for the lateral tibial compartment at 0.38 (the gold standard had 0.34). For the femoral compartments, the gold standard had higher SRMs than the automatic methods at 0.31/0.30 for medial/lateral compartments. CONCLUSION: The lower SRMs for the DL methods in the femoral compartments at 0.2 were possibly due to the simple sub-compartment extraction done during post-processing. The study demonstrated that state-of-the-art DL segmentation methods may be used in standardized longitudinal single-scanner clinical trials for well-defined cartilage compartments.

To determine the cross-sectional and longitudinal associations of patella alignment with cartilage relaxation and patients self-reported symptoms. Thirty participants with isolated patellofemoral joint (PFJ) degeneration (six males, 53.7 ± 9.3 years) and 24 controls (12 males, 47.6 ± 10.7 years) were included. Magnetic resonance assessment was performed to provide grading of structural abnormalities, cartilage relaxation times, and patella alignment. Self-reported symptoms were assessed using the self-administrated knee injury and osteoarthritis outcome score (KOOS). All participants were examined at baseline and 3 years. Statistical parametric mapping and Pearson partial correlation were used to evaluate the associations between patella alignment with cartilage relaxation times and self-reported symptoms, respectively. The analyses were performed between baseline (cross-sectional) as well as the baseline against 3 years (longitudinal). Results indicated that patella height and patella flexion were associated with T1ρ and T2 relaxation times at baseline (percentages of voxels showing significant correlation [PSV] = 10.1%-24.8%; mean correlations [R] = 0.34-0.36; mean p = 0.015-0.026). Furthermore, greater patella lateral alignment, lateral tilt, and lateral spin were associated with longer T2 times at 3 years (PSV = 11.0%-14.4%, R = 0.39-0.44, p = 0.017-0.028). Last, a higher patella was associated with a lower KOOS at baseline and at 3 years (R = -0.33 to -0.35). The study suggests that patella malalignment is a risk factor for worsening cartilage health, informing clinicians of a better rehabilitation program that targets PFJ degeneration.

Magnetic Resonance Imaging (MRI) offers strong soft tissue contrast but suffers from long acquisition times and requires tedious annotation from radiologists. Traditionally, these challenges have been addressed separately with reconstruction and image analysis algorithms. To see if performance could be improved by treating both as end-to-end, we hosted the K2S challenge, in which challenge participants segmented knee bones and cartilage from 8× undersampled k-space. We curated the 300-patient K2S dataset of multicoil raw k-space and radiologist quality-checked segmentations. 87 teams registered for the challenge and there were 12 submissions, varying in methodologies from serial reconstruction and segmentation to end-to-end networks to another that eschewed a reconstruction algorithm altogether. Four teams produced strong submissions, with the winner having a weighted Dice Similarity Coefficient of 0.910 ± 0.021 across knee bones and cartilage. Interestingly, there was no correlation between reconstruction and segmentation metrics. Further analysis showed the top four submissions were suitable for downstream biomarker analysis, largely preserving cartilage thicknesses and key bone shape features with respect to ground truth. K2S thus showed the value in considering reconstruction and image analysis as end-to-end tasks, as this leaves room for optimization while more realistically reflecting the long-term use case of tools being developed by the MR community.

Four-dimensional scanning transmission electron microscopy (4D-STEM) has recently gained widespread attention for its ability to image atomic electric fields with sub-Ångstrom spatial resolution. These electric field maps represent the integrated effect of the nucleus, core electrons and valence electrons, and separating their contributions is non-trivial. In this paper, we utilized simultaneously acquired 4D-STEM center of mass (CoM) images and annular dark field (ADF) images to determine the projected electron charge density in monolayer MoS2. We evaluate the contributions of both the core electrons and the valence electrons to the derived electron charge density; however, due to blurring by the probe shape, the valence electron contribution forms a nearly featureless background while most of the spatial modulation comes from the core electrons. Our findings highlight the importance of probe shape in interpreting charge densities derived from 4D-STEM and the need for smaller electron probes.

Background: Gadolinium (Gd)-enhanced Magnetic Resonance Imaging (MRI) is crucial in several applications, including oncology, cardiac imaging, and musculoskeletal inflammatory imaging. One use case is rheumatoid arthritis (RA), a widespread autoimmune condition for which Gd MRI is crucial in imaging synovial joint inflammation, but Gd administration has well-documented safety concerns. As such, algorithms that could synthetically generate post-contrast peripheral joint MR images from non-contrast MR sequences would have immense clinical utility. Moreover, while such algorithms have been investigated for other anatomies, they are largely unexplored for musculoskeletal applications such as RA, and efforts to understand trained models and improve trust in their predictions have been limited in medical imaging. Methods: A dataset of 27 RA patients was used to train algorithms that synthetically generated post-Gd IDEAL wrist coronal T1-weighted scans from pre-contrast scans. UNets and PatchGANs were trained, leveraging an anomaly-weighted L1 loss and global generative adversarial network (GAN) loss for the PatchGAN. Occlusion and uncertainty maps were also generated to understand model performance. Results: UNet synthetic post-contrast images exhibited stronger normalized root mean square error (nRMSE) than PatchGAN in full volumes and the wrist, but PatchGAN outperformed UNet in synovial joints (UNet nRMSEs: volume = 6.29 ± 0.88, wrist = 4.36 ± 0.60, synovial = 26.18 ± 7.45; PatchGAN nRMSEs: volume = 6.72 ± 0.81, wrist = 6.07 ± 1.22, synovial = 23.14 ± 7.37; n = 7). Occlusion maps showed that synovial joints made substantial contributions to PatchGAN and UNet predictions, while uncertainty maps showed that PatchGAN predictions were more confident within those joints. Conclusions: Both pipelines showed promising performance in synthesizing post-contrast images, but PatchGAN performance was stronger and more confident within synovial joints, where an algorithm like this would have maximal clinical utility. Image synthesis approaches are therefore promising for RA and synthetic inflammatory imaging.

The sandwich format immunoassay is generally more sensitive and specific than more common assay formats, including direct, indirect, or competitive. A sandwich assay, however, requires two receptors to bind non-competitively to the target analyte. Typically, pairs of antibodies (Abs) or antibody fragments (Fabs) that are capable of forming a sandwiching with the target are identified through a slow, guess-and-check method with panels of candidate binding partners. Additionally, sandwich assays that are reliant on commercial antibodies can suffer from changes to reagent quality outside the researchers' control. This report presents a reimagined and simplified phage display selection protocol that directly identifies sandwich binding peptides and Fabs. The approach yielded two sandwich pairs, one peptide-peptide and one Fab-peptide sandwich for the cancer and Parkinson's disease biomarker DJ-1. Requiring just a few weeks to identify, the sandwich pairs delivered apparent affinity that is comparable to other commercial peptide and antibody sandwiches. The results reported here could expand the availability of sandwich binding partners for a wide range of clinical biomarker assays.

BackgroundTo assess the compound effects of BMI and sustained depressive symptoms on changes in knee structure, cartilage composition, and knee pain over 4 years using statistical interaction analyses.MethodsOne thousand eight hundred forty-four individuals from the Osteoarthritis Initiative Database were analyzed at baseline and 4-year follow-up. Individuals were categorized according to their BMI and presence of depressive symptoms (based on the Center for Epidemiological Studies Depression Scale (threshold≥16)) at baseline and 4-year follow-up. 3 T MRI was used to quantify knee cartilage T2 over 4 years, while radiographs were used to assess joint space narrowing (JSN). Mixed effects models examined the effect of BMI-depressive symptoms interactions on outcomes of cartilage T2, JSN, and knee pain over 4-years.ResultsThe BMI-depressive symptoms interaction was significantly associated with knee pain (p

To preserve scientific data created by publicly and/or philanthropically funded research projects and to make it ready for exploitation using recent and ongoing advances in advanced and large-scale computational modeling methods, publicly available data must use in common, now-evolving standards for formatting, identifying and annotating should share data. The OpenNeuro.org archive, built first as a repository for magnetic resonance imaging data based on the Brain Imaging Data Structure formatting standards, aims to house and share all types of human neuroimaging data. Here, we present NEMAR.org, a web gateway to OpenNeuro data for human neuroelectromagnetic data. NEMAR allows users to search through, visually explore and assess the quality of shared electroencephalography (EEG), magnetoencephalography and intracranial EEG data and then to directly process selected data using high-performance computing resources of the San Diego Supercomputer Center via the Neuroscience Gateway (nsgportal.org, NSG), a freely available web portal to high-performance computing serving a variety of neuroscientific analysis environments and tools. Combined, OpenNeuro, NEMAR and NSG form an efficient, integrated data, tools and compute resource for human neuroimaging data analysis and meta-analysis. Database URL: https://nemar.org.

BackgroundIt is unknown if football players with femoroacetabular impingement (FAI) syndrome report worse burden than those with other causes of hip/groin pain, and to what extent this is mediated by cartilage defects and labral tears.HypothesisFootball players with FAI syndrome would report worse burden than other symptomatic players, with the effect partially mediated by cartilage defects and/or labral tears.Study designCross-sectional study.Level of evidenceLevel 4.MethodsFootball (soccer and Australian football) players (n = 165; 35 women) with hip/groin pain (≥6 months and positive flexion-adduction-internal rotation test) were recruited. Participants completed 2 patient-reported outcome measures (PROMs; the International Hip Outcome Tool-33 [iHOT-33] and Copenhagen Hip and Groin Outcome Score [HAGOS]) and underwent hip radiographs and magnetic resonance imaging (MRI). FAI syndrome was determined to be present when cam and/or pincer morphology were present. Cartilage defects and labral tears were graded as present or absent using MRI. Linear regression models investigated relationships between FAI syndrome (dichotomous independent variable) and PROM scores (dependent variables). Mediation analyses investigated the effect of cartilage defects and labral tears on these relationships.ResultsFAI syndrome was not related to PROM scores (unadjusted b values ranged from -4.693 (P = 0.23) to 0.337 (P = 0.93)) and cartilage defects and/or labral tears did not mediate its effect (P = 0.22-0.97).ConclusionFootball players with FAI syndrome did not report worse burden than those with other causes of hip/groin pain. Cartilage defects and/or labral tears did not explain the effect of FAI syndrome on reported burden.Clinical relevanceFAI syndrome, cartilage defects, and labral tears were prevalent but unrelated to reported burden in symptomatic football players.

Four-dimensional scanning transmission electron microscopy (4D-STEM) hasrecently gained widespread attention for its ability to image atomic electricfields with sub-{\AA}ngstrom spatial resolution. These electric field mapsrepresent the integrated effect of the nucleus, core electrons and valenceelectrons, and separating their contributions is non-trivial. In this paper, weutilized simultaneously acquired 4D-STEM center of mass (CoM) images andannular dark field (ADF) images to determine the electron charge density inmonolayer MoS2. We find that both the core electrons and the valence electronscontribute to the derived electron charge density. However, due to blurring bythe probe shape, the valence electron contribution forms a nearly featurelessbackground while most of the spatial modulation comes from the core electrons.Our findings highlight the importance of probe shape in interpreting chargedensities derived from 4D STEM.

BACKGROUND AND PURPOSE: Quantitative metrics of the dural sac such as the cross-sectional area are commonly used to evaluate central canal stenosis. The aim of this study was to analyze 2 new metrics to measure spinal stenosis on the basis of the ratio between the dural sac and disc cross-sectional areas (DDRCA) and the dural sac and disc anterior-posterior diameters (DDRDIA) and compare them with established quantitative metrics of the dural sac. MATERIALS AND METHODS: T2-weighted axial MR images (n = 260 patients) were retrospectively evaluated, graded for central canal stenosis as normal (no stenosis), mild, moderate, or severe from L1/L2 through L5/S1 with 1 grade per spinal level and annotated to measure the DDRCA and DDRDIA. Thresholds were obtained using a decision tree classifier on a subset of patients (n = 130) and evaluated on the remaining patients (n = 130) for accuracy and consistency across demographics, anatomic variation, and clinical outcomes. RESULTS: DDRCA and DDRDIA had areas under the receiver operating characteristic curve of 98.6 (97.4-99.3) and 98.0 (96.7-98.9) compared with dural sac cross-sectional area at 96.5 (95.0-97.7) for binary classification. DDRDIA and DDRCA had κ scores of 0.75 (0.71-0.79) and 0.80 (0.75-0.83) compared with dural sac cross-sectional area at 0.62 (0.57-0.66) for multigrade classification. No significant differences (P > .1) in the area under the receiver operating characteristic curve were observed for the DDRDIA across variations in the body mass index. The DDRDIA also had the highest area under the receiver operating characteristic curve among symptomatic patients (visual analog scale ≥ 7) or patients who underwent surgery. CONCLUSIONS: Ratio-based metrics (DDRDIA and DDRCA) are accurate and robust to anatomic and demographic variability compared with quantitative metrics of the dural sac and better correlated with symptomatology and surgical outcomes.

ObjectiveTo summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market.DesignSummary of the one-day workshop held virtually on June 22nd, 2021.ResultsSpeakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit.ConclusionsDemonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

The aims of this case-control study were to: (1) Identify cartilage locations and volumes at risk of osteoarthritis (OA) using subject-specific finite element (FE) models; (2) Quantify the relationships between the simulated biomechanical parameters and T2 and T1ρ relaxation times of magnetic resonance imaging (MRI). We created subject-specific FE models for seven patients with anterior cruciate ligament (ACL) reconstruction and six controls based on a previous proof-of-concept study. We identified locations and cartilage volumes susceptible to OA, based on maximum principal stresses and absolute maximum shear strains in cartilage exceeding thresholds of 7 MPa and 32%, respectively. The locations and volumes susceptible to OA were compared qualitatively and quantitatively against 2-year longitudinal changes in T2 and T1ρ relaxation times. The degeneration volumes predicted by the FE models, based on excessive maximum principal stresses, were significantly correlated (r = 0.711, p

Folded proteins are assumed to be built upon fixed scaffolds of secondary structure, α-helices and β-sheets. Experimentally determined structures of >58,000 non-redundant proteins support this assumption, though it has recently been challenged by ~100 fold-switching proteins. Though ostensibly rare, these proteins raise the question of how many uncharacterized proteins have shapeshifting-rather than fixed-secondary structures. Here, we use a comparative sequence-based approach to predict fold switching in the universally conserved NusG transcription factor family, one member of which has a 50-residue regulatory subunit experimentally shown to switch between α-helical and β-sheet folds. Our approach predicts that 24% of sequences in this family undergo similar α-helix ⇌ β-sheet transitions. While these predictions cannot be reproduced by other state-of-the-art computational methods, they are confirmed by circular dichroism and nuclear magnetic resonance spectroscopy for 10 out of 10 sequence-diverse variants. This work suggests that fold switching may be a pervasive mechanism of transcriptional regulation in all kingdoms of life.

BackgroundModic changes (MCs) are the most prevalent classification system for describing magnetic resonance imaging (MRI) signal intensity changes in the vertebrae. However, there is a growing need for novel quantitative and standardized methods of characterizing these anomalies, particularly for lesions of transitional or mixed nature, due to the lack of conclusive evidence of their associations with low back pain. This retrospective imaging study aims to develop an interpretable deep learning-based detection tool for voxel-wise mapping of MCs.MethodsSeventy-five lumbar spine MRI exams that presented with acute-to-chronic low back pain, radiculopathy, and other symptoms of the lumbar spine were enrolled. The pipeline consists of two deep convolutional neural networks to generate an interpretable voxel-wise Modic map. First, an autoencoder was trained to segment vertebral bodies from T1-weighted sagittal lumbar spine images. Next, two radiologists segmented and labeled MCs from a combined T1- and T2-weighted assessment to serve as ground truth for training a second autoencoder that performs segmentation of MCs. The voxels in the detected regions were then categorized to the appropriate Modic type using a rule-based signal intensity algorithm. Post hoc, three radiologists independently graded a second dataset with the aid of the model predictions in an artificial (AI)-assisted experiment.ResultsThe model successfully identified the presence of changes in 85.7% of samples in the unseen test set with a sensitivity of 0.71 (±0.072), specificity of 0.95 (±0.022), and Cohen's kappa score of 0.63. In the AI-assisted experiment, the agreement between the junior radiologist and the senior neuroradiologist significantly improved from Cohen's kappa score of 0.52 to 0.58 (p

In genetic studies of psychiatric disorders in the pre-genome-wide association study (GWAS) era, one of the most commonly studied loci is the serotonin transporter (SLC6A4) promoter polymorphism, a 43-base-pair insertion/deletion polymorphism in the promoter region (5-HTTLPR). The genetic association signals between 5-HTTLPR and psychiatric phenotypes, however, have been inconsistent across many studies. Since the polymorphism cannot be tested via available SNP arrays, we had previously proposed an efficient machine learning algorithm to predict the genotypes of 5-HTTLPR based on the genotypes of eight nearby SNPs, which requires access to individual-level genotype and phenotype data. To utilize the advantage of publicly available GWAS summary statistics obtained from studies with very large sample sizes, we develop a GWAS summary-statistics-based approach for testing the variable number of tandem repeat (VNTR) associations with various phenotypes. We first cross-verify the accuracy of the summary-statistics-based approach for 61 phenotypes in the UK Biobank. Since we observed a strong similarity between the predicted individual-level 5-HTTLPR genotype-based approach and the summary-statistics-based approach, we applied our method to the available neurobehavioral GWAS summary statistics data obtained from large-scale GWAS. We found no genome-wide significant evidence for association between 5-HTTLPR and any of the neurobehavioral traits. We did observe, however, genome-wide significant evidence for association between this locus and human adult height, BMI, and total cholesterol. Our summary-statistics-based approach provides a systematic way to examine the role of VNTRs and related types of genetic polymorphisms in disease risk and trait susceptibility of phenotypes for which large-scale GWAS summary statistics data are available.

Taq DNA polymerase functions at elevated temperatures with fast conformational dynamics-regimes previously inaccessible to mechanistic, single-molecule studies. Here, single-walled carbon nanotube transistors recorded the motions of Taq molecules processing matched or mismatched template-deoxynucleotide triphosphate pairs from 22° to 85°C. By using four enzyme orientations, the whole-enzyme closures of nucleotide incorporations were distinguished from more rapid, 20-μs closures of Taq's fingers domain testing complementarity and orientation. On average, one transient closure was observed for every nucleotide binding event; even complementary substrate pairs averaged five transient closures between each catalytic incorporation at 72°C. The rate and duration of the transient closures and the catalytic events had almost no temperature dependence, leaving all of Taq's temperature sensitivity to its rate-determining open state.

Sertoli cells (Sc) are the sole target of follicle-stimulating hormone (FSH) in the testis and attain functional maturation post-birth to significantly augment germ cell (Gc) division and differentiation at puberty. Despite having an operational microRNA (miRNA) machinery, limited information is available on miRNA-mediated regulation of Sc maturation and male fertility. We have shown before that miR-92a-3p levels decline in pubertal rat Sc. In response to FSH treatment, the expressions of FSH Receptor, Claudin11 and Klf4 were found to be elevated in pubertal rat Sc coinciding with our finding of FSH-induced decline in miR-92a-3p levels. To investigate the association of miR-92a-3p and spermatogenesis, we generated transgenic mice where such pubertal decline of miR-92a-3p was prevented by its overexpression in pubertal Sc under proximal Rhox5 promoter, which is known to be activated specifically at puberty, in Sc. Our in vivo observations provided substantial evidence that FSH-induced decline in miR-92a-3p expression during Sc maturation acts as an essential prerequisite for the pubertal onset of spermatogenesis. Elevated expression of miR-92a-3p in post-pubertal testes results into functionally compromised Sc, leading to impairment of the blood-testis barrier formation and apoptosis of pre-meiotic Gc, ultimately culminating into infertility. Collectively, our data suggest that regulation of miR-92a-3p expression is crucial for Sc-mediated induction of active spermatogenesis at puberty and regulation of male fertility.

PurposeTo assess the correlation between changes in hip capsule morphology with improvements in patient-reported outcome (PRO) scores after arthroscopic surgery for femoroacetabular impingement syndrome (FAIS) using the periportal capsulotomy technique.MethodsTwenty-eight patients with cam morphology FAIS (without arthritis, dysplasia, or hypermobility) were prospectively enrolled before arthroscopic labral repair and femoroplasty through periportal capsulotomy (anterolateral/midanterior portals) without closure. Patients completed the Hip Disability and Osteoarthritis Outcomes Score (HOOS) and had nonarthrographic 3T magnetic resonance imaging (MRI) scans of the affected hip before and 1 year after surgery. Anterior capsule thickness, posterior capsule thickness, anterior-posterior capsule thickness ratio, and proximal-distal anterior capsule thickness ratio were measured on axial-oblique MRI sequences. Pearson correlation coefficients were calculated to determine the association between hip capsule morphology and PRO scores.ResultsPostoperative imaging showed that for all 28 patients (12 female), labral repairs and capsulotomies had healed within 1 year of surgery. Analysis revealed postoperative decreases in anterior hip capsule thickness (1395.4 ± 508.4 mm3 vs 1758.4 ± 487.9 mm3; P = .003) and anterior-posterior capsule thickness ratio (0.92 ± 0.33 vs 1.12 ± 0.38; P = .02). Higher preoperative anterior-posterior capsule thickness ratio correlated with lower preoperative scores for HOOS pain (R = -0.43; P = .02), activities of daily living (ADL) (R = -0.43; P = .02), and sport (R = -0.38; P = .04). Greater decrease from preoperative to postoperative anterior-posterior capsule thickness ratio correlated with greater improvement for HOOS pain (R = -0.40; P = .04), ADL (R = -0.45; P = .02), and sport (R = -0.46; P = .02).ConclusionsPeriportal capsulotomy without closure demonstrates capsule healing by 1 year after arthroscopic FAIS treatment. Changes in hip capsule morphology including decreased anterior-posterior capsule thickness ratio after surgery may be correlated with improvements in patient pain, function, and ability to return to sports.Level of evidenceLevel II, prospective cohort study.