A New Era in Magnetic Resonance Contrast Media.

ABSTRACT: Next-generation gadolinium-based contrast agents (GBCAs), including both high relaxivity agents and targeted agents, and manganese-based agents with a high probably of commercial success are discussed in some depth. It is highly likely that gadopiclenol and gadoquatrane, both next-generation high relaxivity gadolinium-based compounds, will come in time to replace the current macrocyclic gadolinium chelates, despite the wide acceptance, very high safety profile, and high stability of the latter group. Current research has also made possible the development of 2 new targeted gadolinium chelates, which look very promising, with the potential to improve cancer detection (for both MT218 and ProCA32.collagen) as well as diseases of collagen (for the latter agent). Further work with manganese-based compounds, a topic left fallow for more than 20 years, has also now produced 2 agents with high potential for clinical use, one (manganese chloride tetrahydrate, administered orally) developed primarily for imaging of the liver and the other (Mn-PyC3A, administered intravenously) as a gadolinium-free replacement for the GBCAs. New detail has recently emerged regarding specific circumscribed subregions of the brain with specialized cytoarchitecture and functions in which high gadolinium concentrations are seen following injection of the linear agent gadodiamide. These findings pave the way for tailored functional neurological testing, specifically in patients at potential risk due to the continued wide use in many countries across the world of the linear GBCAs. The impact of artificial intelligence is also critically discussed, with its most likely applications being dose reduction and new clinical indications.

Scientific Advances and Technical Innovations in Musculoskeletal Radiology.

ABSTRACT: Decades of technical innovations have propelled musculoskeletal radiology through an astonishing evolution. New artificial intelligence and deep learning methods capitalize on many past innovations in magnetic resonance imaging (MRI) to reach unprecedented speed, image quality, and new contrasts. Similarly exciting developments in computed tomography (CT) include clinically applicable molecular specificity and substantially improved spatial resolution of musculoskeletal structures and diseases. This special issue of Investigative Radiology comprises a collection of expert summaries and reviews on the most impactful innovations and cutting-edge topics in musculoskeletal radiology, including radiomics and deep learning methods for musculoskeletal disease detection, high-resolution MR neurography, deep learning-driven ultra-fast musculoskeletal MRI, MRI-based synthetic CT, quantitative MRI, modern low-field MRI, 7.0 T MRI, dual-energy CT, cone beam CT, kinematic CT, and synthetic contrast generation in musculoskeletal MRI.

High-fat diet affects measures of skeletal muscle contractile performance in a temperature-specific manner but does not influence regional thermal sensitivity.

The present study examined whether high-fat diet (HFD) consumption for 20 weeks had a temperature-specific effect on the contractile performance and regional thermal sensitivity of isolated mouse soleus and diaphragm muscle. Four-week-old female CD-1 mice were randomly selected to consume either a standard laboratory diet or a standard laboratory diet in conjunction with a HFD for 20 weeks. Peripheral soleus and core diaphragm were isolated from each animal and maximal isometric force and work loop power were assessed at 20, 28, 35 and 40°C. Increasing temperature to 35°C resulted in greater isometric stress, lower activation and relaxation time, and higher work loop power in both muscles. A further increase in temperature to 40°C did not affect isometric force but increased work loop power output of the soleus. Conversely, isometric force of the diaphragm was reduced and work loop power maintained when temperature was increased to 40°C. HFD consumption resulted in greater isometric force and absolute work loop power of the soleus and reduced isometric stress of the diaphragm, effects that were less apparent at lower temperatures. When the relationship between temperature and each measure of contractile function was examined by linear regression, there was no difference in slope between the control or HFD groups for either the soleus or diaphragm. These results indicate that whilst contractile function initially increases with temperature, the temperature to elicit maximal performance is muscle and contractile mode specific. Furthermore, HFD effects on contractile function are temperature specific, but HFD does not influence the relationship between temperature and performance.

The Clinical Utility of Magnetic Resonance Imaging According to Field Strength, Specifically Addressing the Breadth of Current State-of-the-Art Systems, Which Include 0.55 T, 1.5 T, 3 T, and 7 T.

ABSTRACT: This review provides a balanced perspective regarding the clinical utility of magnetic resonance systems across the range of field strengths for which current state-of-the-art units exist (0.55 T, 1.5 T, 3 T, and 7 T). Guidance regarding this issue is critical to appropriate purchasing, usage, and further dissemination of this important imaging modality, both in the industrial world and in developing nations. The review serves to provide an important update, although to a large extent this information has never previously been openly presented. In that sense, it serves also as a position paper, with statements and recommendations as appropriate.

Advocating the Development of Next-Generation, Advanced-Design Low-Field Magnetic Resonance Systems.

New next-generation low-field magnetic resonance imaging systems (operating in the range of 0.5 T) hold great potential for increasing access to clinical diagnosis and needed health care both in developed countries and worldwide. The relevant history concerning the choice of field strength, which resulted in 1.5 T still dominating today the number of installed systems, is considered, together with design advances possible because of interval developments, since low field was considered for clinical use in the 1980s, and current research. The potential impact of low-cost, advanced-generation low-field magnetic resonance imaging systems, properly designed, is high in terms of further dissemination of health care-across the gamut from industrial to developing countries-regardless of disease entity and anatomic region of involvement, with major niche applications likely as well.

Age-related changes in isolated mouse skeletal muscle function are dependent on sex, muscle, and contractility mode.

The present study aimed to simultaneously examine the age-related, muscle-specific, sex-specific, and contractile mode-specific changes in isolated mouse skeletal muscle function and morphology across multiple ages. Measurements of mammalian muscle morphology, isometric force and stress (force/cross-sectional area), absolute and normalized (power/muscle mass) work-loop power across a range of contractile velocities, fatigue resistance, and myosin heavy chain (MHC) isoform concentration were measured in 232 isolated mouse (CD-1) soleus, extensor digitorum longus (EDL), and diaphragm from male and female animals aged 3, 10, 30, 52, and 78 wk. Aging resulted in increased body mass and increased soleus and EDL muscle mass, with atrophy only present for female EDL by 78 wk despite no change in MHC isoform concentration. Absolute force and power output increased up to 52 wk and to a higher level for males. A 23-36% loss of isometric stress exceeded the 14-27% loss of power normalized to muscle mass between 10 wk and 52 wk, although the loss of normalized power between 52 and 78 wk continued without further changes in stress (P > 0.23). Males had lower power normalized to muscle mass than females by 78 wk, with the greatest decline observed for male soleus. Aging did not cause a shift toward slower contractile characteristics, with reduced fatigue resistance observed in male EDL and female diaphragm. Our findings show that the loss of muscle quality precedes the loss of absolute performance as CD-1 mice age, with the greatest effect seen in male soleus, and in most instances without muscle atrophy or an alteration in MHC isoforms.

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent.

OBJECTIVES: This preclinical study was devised to investigate potential cellular toxicity in human neurons induced by gadolinium-based contrast agents (GBCAs) used for contrast-enhanced magnetic resonance imaging (MRI). Neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is 1 of 2 brain regions that displays the greatest T1-dependent signal hyperintensity changes. METHODS: Eight GBCAs were tested. Dopaminergic neurons modeling a subset of those in the basal ganglia were differentiated from an established human neuroblastoma cell line and exposed to increasing concentrations of each agent for 7 days. The tested dosages ranged from clinically relevant concentrations measured in some autopsy patients who had received repeated injections of contrast for MRI, to higher concentrations to reveal dose-dependent toxicity trends. Cell death, mitochondrial membrane potential, mitochondrial oxidative capacity, and mitochondrial function measured by oxygen consumption were quantified in cells treated with each GBCA or the osmolality control mannitol and compared to untreated cells which served as a negative control. RESULTS: Mannitol caused no change from negative controls in any of the tests, at any concentration tested. For all GBCAs, cell death increased with exposure dose, with toxicity at clinically relevant doses for agents with lower kinetic stability. Reduction of mitochondrial membrane potential and oxidative respiratory function also generally mirrored the agents' structural kinetic stabilities, with greater impairment at lower concentration for the less stable agents. CONCLUSIONS: In human neurons modeling a subset of those in the basal ganglia, these results demonstrate a toxic effect of gadolinium-containing MRI contrast agents on mitochondrial respiratory function and cell viability. Toxicity increases as agent concentration increases and as the kinetic stability of the agent decreases.

Motion in Magnetic Resonance: New Paradigms for Improved Clinical Diagnosis.

Recent innovations in magnetic resonance, involving both hardware and software, that effectively deal with motion-whether inadvertent on the part of the patient or due to respiration and cardiac contraction-are reviewed, emphasizing major current advances. New technology involving motion sensing (kinetic, respiratory, and beat) is enabling simpler, faster, and more robust monitoring of the sources of motion. This information is being integrated, with new innovative imaging approaches, to effectively manage motion and its impact on image quality. Additional impact has been made by the use of compressed sensing and simultaneous multislice imaging, with these techniques maturing and being adopted to decrease scan time and thus the effect of motion. Guidance in terms of clinical use for techniques that effectively combat motion is provided, focusing on enabling faster and improved clinical scans. Magnetic resonance imaging is on the cusp of a major new leap forward in terms of image quality and clinical utility enabled by these technological advances.

Does Dietary-Induced Obesity in Old Age Impair the Contractile Performance of Isolated Mouse Soleus, Extensor Digitorum Longus and Diaphragm Skeletal Muscles?

Ageing and obesity independently have been shown to significantly impair isolated muscle contractile properties, though their synergistic effects are poorly understood. We uniquely examined the effects of 9 weeks of a high-fat diet (HFD) on isometric force, work loop power output (PO) across a range of contractile velocities, and fatigability of 79-week-old soleus, extensor digitorum longus (EDL) and diaphragm compared with age-matched lean controls. The dietary intervention resulted in a significant increase in body mass and gonadal fat pad mass compared to the control group. Despite increased muscle mass for HFD soleus and EDL, absolute isometric force, isometric stress (force/CSA), PO normalised to muscle mass and fatigability was unchanged, although absolute PO was significantly greater. Obesity did not cause an alteration in the contractile velocity that elicited maximal PO. In the obese group, normalised diaphragm PO was significantly reduced, with a tendency for reduced isometric stress and fatigability was unchanged. HFD soleus isolated from larger animals produced lower maximal PO which may relate to impaired balance in older, larger adults. The increase in absolute PO is smaller than the magnitude of weight gain, meaning in vivo locomotor function is likely to be impaired in old obese adults, with an association between greater body mass and poorer normalised power output for the soleus. An obesity-induced reduction in diaphragm contractility will likely impair in vivo respiratory function and consequently contribute further to the negative cycle of obesity.

Investigating a dose-response relationship between high-fat diet consumption and the contractile performance of isolated mouse soleus, EDL and diaphragm muscles.

PURPOSE: Recent evidence has demonstrated an obesity-induced, skeletal muscle-specific reduction in contractile performance. The extent and magnitude of these changes in relation to total dose of high-fat diet consumption remains unclear. This study aimed to examine the dose-response relationship between a high-fat diet and isolated skeletal muscle contractility. METHODS: 120 female CD1 mice were randomly assigned to either control group or groups receiving 2, 4, 8 or 12 weeks of a high-calorie diet (N = 24). At 20 weeks, soleus, EDL or diaphragm muscle was isolated (n = 8 in each case) and isometric force, work loop power output and fatigue resistance were measured. RESULTS: When analysed with respect to feeding duration, there was no effect of diet on the measured parameters prior to 8 weeks of feeding. Compared to controls, 8-week feeding caused a reduction in normalised power of the soleus, and 8- and 12-week feeding caused reduced normalised isometric force, power and fatigue resistance of the EDL. Diaphragm from the 12-week group produced lower normalised power, whereas 8- and 12-week groups produced significantly lower normalised isometric force. Correlation statistics indicated that body fat accumulation and decline in contractility will be specific to the individual and independent of the feeding duration. CONCLUSION: The data indicate that a high-fat diet causes a decline in muscle quality with specific contractile parameters being affected in each muscle. We also uniquely demonstrate that the amount of fat gain, irrespective of feeding duration, may be the main factor in reducing contractile performance.

In vitro T2 relaxivities of the Gd-based contrast agents (GBCAs) in human blood at 1.5 and 3 T.

BACKGROUND: The availability of data in the medical literature for the T2 relaxivities of the Gd-based contrast agents (GBCAs) is limited. A comprehensive comparison between the agents available commercially (other than in Europe) is lacking, with no data available that most closely reflect the clinic, which is in human whole blood at body temperature. PURPOSE: To complement the existing literature by determining T2 relaxivity data for eight GBCAs in vitro. MATERIAL AND METHODS: The relaxivities of eight GBCAs diluted in human whole blood at 1.5 and 3 T were determined at 37 ± 0.5 °C. Gd was in the range of 0-4 mM. Multi-echo sequences with variable echo times were acquired using a phantom containing a dilution series with each agent, and SigmaPlot 12.0 was used to calculate the R2 relaxation rate and finally r2. Statistical comparisons between agents and field strengths were conducted. RESULTS: The relationship between R2 vs. Gd was observed to be linear at 1.5 and 3 T, with a mild increase in r2 from 1.5 to 3 T for all GBCAs. T2 relaxivity data were compared with prior results. The GBCAs are closely clustered into two groups, with higher r2 noted for the two lipophilic (those with partial hepatobiliary excretion) compounds. CONCLUSION: The r2 values at 1.5 and 3 T, determined for the eight GBCAs still clinically available (other than in Europe), provide a definitive baseline for future evaluations, including theoretical calculations of signal intensity and their clinical impact on T2-weighted scans.

An exercise-induced improvement in isolated skeletal muscle contractility does not affect the performance-enhancing benefit of 70†µmol†l-1 caffeine treatment.

This study aimed to examine the effects of exercise-induced increases in skeletal muscle contractile performance on isolated skeletal muscle caffeine sensitivity in mice. CD1 mice (n=28; 30 weeks old) either served as controls or underwent 8 weeks of voluntary wheel running. Following the treatment intervention, whole soleus (SOL) or a section of the costal diaphragm (DIA) was isolated from each mouse and tested to determine the effect of 70 µmol l-1 caffeine on work loop power output. Although caffeine elicited a significant increase in power of both the SOL and the DIA relative to levels in a non-caffeine-treated control, the effect was not different between the experimental groups, despite the muscles of the trained group producing significantly greater muscle power. There was no significant relationship between training volume or baseline work loop power and the caffeine response. These results indicate that an exercise-induced increase in muscle performance did not influence the performance-enhancing effects of caffeine.

Dechelation (Transmetalation): Consequences and Safety Concerns With the Linear Gadolinium-Based Contrast Agents, In View of Recent Health Care Rulings by the EMA (Europe), FDA (United States), and PMDA (Japan).

The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis-like symptoms-including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).

Disease Progression After Lateral and Medial Unicondylar Knee Arthroplasty.

BACKGROUND: Medial unicompartmental knee arthroplasty (UKA) has been a successful option for treatment of arthritis in patients with a healthy lateral compartment. However, lateral UKA is less common and results are less consistent. The purpose of this study is to compare progression of radiographically evident osteoarthritis in unoperated compartments during 5 years after lateral and medial UKA. METHODS: We undertook serial radiographic evaluation of 20 lateral and 114 medial UKA performed by the senior author during calendar years 2007-2008. Anteroposterior, lateral, and skyline radiographs obtained preoperatively and 1 and 5+ (mean, 5.3; range, 5.1-6.4) years postoperatively were independently graded for osteoarthritis in the unoperated tibiofemoral (TF) and patellofemoral (PF) compartments using established scales of Kellgren (0-4 point global scale for osteoarthritis), Ahlbäck (0-5 point scale based on joint space narrowing), and Altman (0-12 point composite criteria score). Rates of disease progression were compared between lateral and medial UKA groups using bivariate methods and multilevel growth models that adjusted for baseline characteristics. RESULTS: All mean disease grades for the TF and PF compartments increased (worsened) over time. The adjusted rate of Kellgren grade change was statistically (P < .05) faster for lateral UKA in the TF and PF compartments, as was Ahlbäck change in the TF compartment. Kellgren grade for the TF compartment of lateral and medial UKA groups increased 1.1 vs 0.6 points on average over 5 years adjusted for age, sex, and body mass index (P < .001). CONCLUSION: Surgeons should consider the propensity for faster disease progression after UKA in evaluating patients with isolated lateral compartment disease. LEVEL OF EVIDENCE: Level III, therapeutic study.