Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

A registration strategy to characterize DTI-observed changes in skeletal muscle architecture due to passive shortening.

Skeletal muscle architecture is a key determinant of muscle function. Architectural properties such as fascicle length, pennation angle, and curvature can be characterized using Diffusion Tensor Imaging (DTI), but acquiring these data during a contraction is not currently feasible. However, an image registration-based strategy may be able to convert muscle architectural properties observed at rest to their contracted state. As an initial step toward this long-term objective, the aim of this study was to determine if an image registration strategy could be used to convert the whole-muscle average architectural properties observed in the extended joint position to those of a flexed position, following passive rotation. DTI and high-resolution fat/water scans were acquired in the lower leg of seven healthy participants on a 3T MR system in +20° (plantarflexion) and -10° (dorsiflexion) foot positions. The diffusion and anatomical images from the two positions were used to propagate DTI fiber-tracts from seed points along a mesh representation of the aponeurosis of fiber insertion. The -10° and +20° anatomical images were registered and the displacement fields were used to transform the mesh and fiber-tracts from the +20° to the -10° position. Student's paired t-tests were used to compare the mean architectural parameters between the original and transformed fiber-tracts. The whole-muscle average fiber-tract length, pennation angle, curvature, and physiological cross-sectional areas estimates did not differ significantly. DTI fiber-tracts in plantarflexion can be transformed to dorsiflexion position without significantly affecting the average architectural characteristics of the fiber-tracts. In the future, a similar approach could be used to evaluate muscle architecture in a contracted state.

Quantitative Muscle Fascicle Tractography Using Brightness-Mode Ultrasound.

A muscle's architecture, defined as the geometric arrangement of its fibers with respect to its mechanical line of action, impacts its abilities to produce force and shorten or lengthen under load. Ultrasound and other noninvasive imaging methods have contributed significantly to our understanding of these structure-function relationships. The goal of this work was to develop a MATLAB toolbox for tracking and mathematically representing muscle architecture at the fascicle scale, based on brightness-mode ultrasound imaging data. The MuscleUS_Toolbox allows user-performed segmentation of a region of interest and automated modeling of local fascicle orientation; calculation of streamlines between aponeuroses of origin and insertion; and quantification of fascicle length, pennation angle, and curvature. A method is described for optimizing the fascicle orientation modeling process, and the capabilities of the toolbox for quantifying and visualizing fascicle architecture are illustrated in the human tibialis anterior muscle. The toolbox is freely available.

A MATLAB toolbox for muscle diffusion-tensor MRI tractography.

Diffusion-tensor MRI fiber tractography has been used to reconstruct skeletal muscle architecture, but remains a specialized technique using custom-written data processing routines. In this work, we describe the public release of a software toolbox having the following design objectives: accomplish the pre-processing tasks of file input, image registration, denoising, and diffusion-tensor calculation; allow muscle-specific methods for defining seed points; make fiber-tract architectural measurements referenced to tendinous structures; visualize fiber tracts and other muscle structures of interest; analyze the goodness of outcomes; and provide a programming structure that allows the addition of new capabilities in future versions. The proper function of the code was verified using simulated datasets. The toolbox capabilities for characterizing human muscle structure in vivo were demonstrated in a case study. These capabilities included measurements of muscle morphology; contractile and non-contractile tissue volumes; fiber-tract length, pennation angle, curvature; and the physiological cross-sectional area,. The free public release of this software is a first step in creating of a community of users who use these tools in studies of muscle physiology and biomechanics. Users may further contribute to code development. Along with simulated and actual datasets for benchmarking, these tools will further create mechanisms for enhancing scientific rigor and developing and validating new code features. Planned future developments include additional options for image pre-processing, development of a graphical user interface, analysis of architectural patterns during muscle contraction, and integration of functional imaging data.

Cold exposure induces dynamic, heterogeneous alterations in human brown adipose tissue lipid content.

Brown adipose tissue undergoes a dynamic, heterogeneous response to cold exposure that can include the simultaneous synthesis, uptake, and oxidation of fatty acids. The purpose of this work was to quantify these changes in brown adipose tissue lipid content (fat-signal fraction (FSF)) using fat-water magnetic resonance imaging during individualized cooling to 3 °C above a participant's shiver threshold. Eight healthy men completed familiarization, perception-based cooling, and MRI-cooling visits. FSF maps of the supraclavicular region were acquired in thermoneutrality and during cooling (59.5 ± 6.5 min). Brown adipose tissue regions of interest were defined, and voxels were grouped into FSF decades (0-10%, 10-20%…90-100%) according to their initial value. Brown adipose tissue contained a heterogeneous morphology of lipid content. Voxels with initial FSF values of 60-100% (P < 0.05) exhibited a significant decrease in FSF while a simultaneous increase in FSF occurred in voxels with initial FSF values of 0-30% (P < 0.05). These data suggest that in healthy young men, cold exposure elicits a dynamic and heterogeneous response in brown adipose tissue, with areas initially rich with lipid undergoing net lipid loss and areas of low initial lipid undergoing a net lipid accumulation.

Fat-Water Phantoms for Magnetic Resonance Imaging Validation: A Flexible and Scalable Protocol.

As new techniques are developed to image adipose tissue, methods to validate such protocols are becoming increasingly important. Phantoms, experimental replicas of a tissue or organ of interest, provide a low cost, flexible solution. However, without access to expensive and specialized equipment, constructing stable phantoms with high fat fractions (e.g., >50% fat fraction levels such as those seen in brown adipose tissue) can be difficult due to the hydrophobic nature of lipids. This work presents a detailed, low cost protocol for creating 5x 100 mL phantoms with fat fractions of 0%, 25%, 50%, 75%, and 100% using basic lab supplies (hotplate, beakers, etc.) and easily accessible components (distilled water, agar, water-soluble surfactant, sodium benzoate, gadolinium-diethylenetriaminepentacetate (DTPA) contrast agent, peanut oil, and oil-soluble surfactant). The protocol was designed to be flexible; it can be used to create phantoms with different fat fractions and a wide range of volumes. Phantoms created with this technique were evaluated in the feasibility study that compared the fat fraction values from fat-water magnetic resonance imaging to the target values in the constructed phantoms. This study yielded a concordance correlation coefficient of 0.998 (95% confidence interval: 0.972-1.00). In summary, these studies demonstrate the utility of fat phantoms for validating adipose tissue imaging techniques across a range of clinically relevant tissues and organs.

Accelerometer-based prediction of running injury in National Collegiate Athletic Association track athletes.

Running-related injuries (RRI) may result from accumulated microtrauma caused by combinations of high load magnitudes (vertical ground reaction forces; vGRFs) and numbers (strides). Yet relationships between vGRF and RRI remain unclear - potentially because previous research has largely been constrained to collecting vGRFs in laboratory settings and ignoring relationships between RRI and stride number. In this preliminary proof-of-concept study, we addressed these constraints: Over a 60-day period, each time collegiate athletes (n = 9) ran they wore a hip-mounted activity monitor that collected accelerations throughout the entire run. Accelerations were used to estimate peak vGRF, number of strides, and weighted cumulative loading (sum of peak vGRFs weighted to the 9th power) across the entirety of each run. Runners also reported their post-training pain/fatigue and any RRI that prevented training. Across 419 runs and >2.1 million strides, injured (n = 3) and uninjured (n = 6) participants did not report significantly different pain/fatigue (p = 0.56) or mean number of strides per run (p = 0.91). Injured participants did, however, have significantly greater peak vGRFs (p = 0.01) and weighted cumulative loading per run (p < 0.01). Results from this small but extensively studied sample of elite runners demonstrate that loading profiles (load magnitude-number combinations) quantified with activity monitors can provide valuable information that may prove essential for: (1) testing hypotheses regarding overuse injury mechanisms, (2) developing injury-prediction models, and (3) designing and adjusting athlete- and loading-specific training programs and feedback.

An Individualized, Perception-Based Protocol to Investigate Human Physiological Responses to Cooling.

Cold exposure, a known stimulant of the thermogenic effects of brown adipose tissue (BAT), is the most widely used method to study BAT physiology in adult humans. Recently, individualized cooling has been recommended to standardize the physiological cold stress applied across participants, but critical experimental details remain unclear. The purpose of this work was to develop a detailed methodology for an individualized, perception-based protocol to investigate human physiological responses to cooling. Participants were wrapped in two water-circulating blankets and fitted with skin temperature probes to estimate BAT activity and peripheral vasoconstriction. We created a thermoesthesia graphical user interface (tGUI) to continuously record the subject's perception of cooling and shivering status during the cooling protocol. The protocol began with a 15 min thermoneutral phase followed by a series of 10 min cooling phases and concluded when sustained shivering (>1 min duration) occurred. Researchers used perception of cooling feedback (tGUI ratings) to manually adjust and personalize the water temperature at each cooling phase. Blanket water temperatures were recorded continuously during the protocol. Twelve volunteers (ages: 26.2 ± 1.4 years; 25% female) completed a feasibility study to evaluate the proposed protocol. Water temperature, perception of cooling, and shivering varied considerably across participants in response to cooling. Mean clavicle skin temperature, a surrogate measure of BAT activity, decreased (-0.99°C, 95% CI: -1.7 to -0.25°C, P = 0.16) after the cooling protocol, but an increase in supraclavicular skin temperature was observed in 4 participants. A strong positive correlation was also found between thermoesthesia and peripheral vasoconstriction (ρ = 0.84, P < 0.001). The proposed individualized, perception-based protocol therefore has potential to investigate the physiological responses to cold stress applied across populations with varying age, sex, body composition, and cold sensitivity characteristics.

Adaptive Clutter Demodulation for Non-Contrast Ultrasound Perfusion Imaging.

Conventional Doppler ultrasound is useful for visualizing fast blood flow in large resolvable vessels. However, frame rate and tissue clutter caused by movement of the patient or sonographer make visualizing slow flow with ultrasound difficult. Patient and sonographer motion causes spectral broadening of the clutter signal, which limits ultrasound's sensitivity to velocities greater than 5-10 mm/s for typical clinical imaging frequencies. To address this, we propose a clutter filtering technique that may increase the sensitivity of Doppler measurements to at least as low as 0.52 mm/s. The proposed technique uses plane wave imaging and an adaptive frequency and amplitude demodulation scheme to decrease the bandwidth of tissue clutter. To test the performance of the adaptive demodulation method at suppressing tissue clutter bandwidths due to sonographer hand motion alone, six volunteer subjects acquired data from a stationary phantom. Additionally, to test in vivo feasibility, arterial occlusion and muscle contraction studies were performed to assess the efficiency of the proposed filter at preserving signals from blood velocities 2 mm/s or greater at a 7.8 MHz center frequency. The hand motion study resulted in initial average bandwidths of 175 Hz (8.60mm/s), which were decreased to 10.5 Hz (0.52 mm/s) at -60 dB using our approach. The in vivo power Doppler studies resulted in 4.73 dB and 4.80 dB dynamic ranges of the blood flow with the proposed filter and 0.15 dB and 0.16 dB dynamic ranges of the blood flow with a conventional 50 Hz high-pass filter for the occlusion and contraction studies, respectively.

FloWave.US: validated, open-source, and flexible software for ultrasound blood flow analysis.

Automated software improves the accuracy and reliability of blood velocity, vessel diameter, blood flow, and shear rate ultrasound measurements, but existing software offers limited flexibility to customize and validate analyses. We developed FloWave.US-open-source software to automate ultrasound blood flow analysis-and demonstrated the validity of its blood velocity (aggregate relative error, 4.32%) and vessel diameter (0.31%) measures with a skeletal muscle ultrasound flow phantom. Compared with a commercial, manual analysis software program, FloWave.US produced equivalent in vivo cardiac cycle time-averaged mean (TAMean) velocities at rest and following a 10-s muscle contraction (mean bias <1 pixel for both conditions). Automated analysis of ultrasound blood flow data was 9.8 times faster than the manual method. Finally, a case study of a lower extremity muscle contraction experiment highlighted the ability of FloWave.US to measure small fluctuations in TAMean velocity, vessel diameter, and mean blood flow at specific time points in the cardiac cycle. In summary, the collective features of our newly designed software-accuracy, reliability, reduced processing time, cost-effectiveness, and flexibility-offer advantages over existing proprietary options. Further, public distribution of FloWave.US allows researchers to easily access and customize code to adapt ultrasound blood flow analysis to a variety of vascular physiology applications.

Feasibility of a dynamic web guidance approach for personalized physical activity prescription based on daily information from wearable technology.

BACKGROUND: Computer tailored, Web-based interventions have emerged as an effective approach to promote physical activity. Existing programs, however, do not adjust activities according to the participant's compliance or physiologic adaptations, which may increase risk of injury and program attrition in sedentary adults. To address this limitation, objective activity monitor (AM) and heart rate data could be used to guide personalization of physical activity, but improved Web-based frameworks are needed to test such interventions. OBJECTIVE: The objective of this study is to (1) develop a personalized physical activity prescription (PPAP) app that combines dynamic Web-based guidance with multi-sensor AM data to promote physical activity and (2) to assess the feasibility of using this system in the field. METHODS: The PPAP app was constructed using an open-source software platform and a custom, multi-sensor AM capable of accurately measuring heart rate and physical activity. A novel algorithm was written to use a participant's compliance and physiologic response to aerobic training (ie, changes in daily resting heart rate) recorded by the AM to create daily, personalized physical activity prescriptions. In addition, the PPAP app was designed to (1) manage the transfer of files from the AM to data processing software and a relational database, (2) provide interactive visualization features such as calendars and training tables to encourage physical activity, and (3) enable remote administrative monitoring of data quality and participant compliance. A 12-week feasibility study was performed to assess the utility and limitations of the PPAP app used by sedentary adults in the field. Changes in physical activity level and resting heart rate were monitored throughout the intervention. RESULTS: The PPAP app successfully created daily, personalized physical activity prescriptions and an interactive Web environment to guide and promote physical activity by the participants. The varied compliance of the participants enabled evaluation of administrative features of the app including the generation of automated email reminders, participation surveys, and daily AM file upload logs. CONCLUSIONS: This study describes the development of the PPAP app, a closed-loop technology framework that enables personalized physical activity prescription and remote monitoring of an individual's compliance and health response to the intervention. Data obtained during a 12-week feasibility study demonstrated the ability of the PPAP app to use objective AM data to create daily, personalized physical activity guidance, provide interactive feedback to users, and enable remote administrative monitoring of data quality and subject compliance. Using this approach, public health professionals, clinicians, and researchers can adapt the PPAP app to facilitate a range of personalized physical activity interventions to improve health outcomes, assess injury risk, and achieve fitness performance goals in diverse populations.

Standardizing accelerometer-based activity monitor calibration and output reporting.

Wearable accelerometer-based activity monitors (AMs) are used to estimate energy expenditure and ground reaction forces in free-living environments, but a lack of standardized calibration and data reporting methods limits their utility. The objectives of this study were to (1) design an inexpensive and easily reproducible AM testing system, (2) develop a standardized calibration method for accelerometer-based AMs, and (3) evaluate the utility of the system and accuracy of the calibration method. A centrifuge-type device was constructed to apply known accelerations (0-8g) to each sensitive axis of 30 custom and two commercial AMs. Accelerometer data were recorded and matrix algebra and a least squares solution were then used to determine a calibration matrix for the custom AMs to convert raw accelerometer output to units of g's. Accuracy was tested by comparing applied and calculated accelerations for custom and commercial AMs. AMs were accurate to within 4% of applied accelerations. The relatively inexpensive AM testing system (< $100) and calibration method has the potential to improve the sharing of AM data, the ability to compare data from different studies, and the accuracy of AM-based models to estimate various physiological and biomechanical quantities of interest in field-based assessments of physical activity.

Evaluation of an exercise field test using heart rate monitors to assess cardiorespiratory fitness and heart rate recovery in an asymptomatic population.

PURPOSE: Measures of cardiorespiratory fitness (CRF) and heart rate recovery (HRR) can improve risk stratification for cardiovascular disease, but these measurements are rarely made in asymptomatic individuals due to cost. An exercise field test (EFT) to assess CRF and HRR would be an inexpensive method for cardiovascular disease risk assessment in large populations. This study assessed 1) the predictive accuracy of a 12-minute run/walk EFT for estimating CRF ([Formula: see text]) and 2) the accuracy of HRR measured after an EFT using a heart rate monitor (HRM) in an asymptomatic population. METHODS: Fifty subjects (48% women) ages 18-45 years completed a symptom-limited exercise tolerance test (ETT) (Bruce protocol) and an EFT on separate days. During the ETT, [Formula: see text] was measured by a metabolic cart, and heart rate was measured continuously by a HRM and a metabolic cart. RESULTS: EFT distance and sex independently predicted[Formula: see text]. The average absolute difference between observed and predicted [Formula: see text] was 0.26 ± 3.27 ml·kg-1·min-1 for our model compared to 7.55 ± 3.64 ml·kg-1·min-1 for the Cooper model. HRM HRR data were equivalent to respective metabolic cart values during the ETT. HRR at 1 minute post-exercise during ETT compared to the EFT had a moderate correlation (r=0.75, p<0.001). CONCLUSION: A more accurate model to estimate CRF from a 12-minute run/walk EFT was developed, and HRR can be measured using a HRM in an asymptomatic population outside of clinical settings.