Determinants of thermal homeostasis in the preimplantation embryo: a role for the embryo's central heating system?

A number of factors may impinge on thermal homeostasis in the early embryo. The most obvious is the ambient temperature in which development occurs. Physiologically, the temperature in the lumen of the female tract is typically lower than the core body temperature, yet rises at ovulation in the human, while in an IVF setting, embryos are usually maintained at core body temperature. However, internal cellular developmental processes may modulate thermal control within the embryo itself, especially those occurring in the mitochondria which generate intracellular heat through proton leak and provide the embryo with its own 'central heating system'. Moreover, mitochondrial movements may serve to buffer high local intracellular temperatures. It is also notable that the preimplantation stages of development would generate proportionally little heat within their mitochondria until the blastocyst stage as mitochondrial metabolism is comparatively low during the cleavage stages. Despite these data, the specific notion of thermal control of preimplantation development has received remarkably scant consideration. This opinion paper illustrates the lack of reliable quantitative data on these markers and identifies a major research agenda which needs to be addressed with urgency in view of laboratory conditions in which embryos are maintained as well as climate change-derived heat stress which has a negative effect on numerous clinical markers of early human embryo development.

Immunogenic Treatment for Metastatic Breast Cancer Using Targeted Carbon Nanotube Mediated Photothermal Therapy in Combination with Anti-PD-1.

The high prevalence of breast cancer is a global health concern, but there are no safe or effective treatments for it at its advanced stages. These facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells and the tumor vasculature. Here, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of single walled carbon nanotubes (SWCNTs) to ANXA5-the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition, creating a systemic anti-cancer immune response. In vitro ablation of cells incubated with the conjugate promoted cell death in a dose-dependent and targeted manner. This treatment strategy was tested in vivo with the orthotopic EMT6 breast tumor model in female balb/cJ mice. Enhanced therapeutic effects were achieved by using intratumoral injection of the conjugate and treating tumors at a lower PTT temperature (45oC). Intratumoral injection prevented the accumulation of the SWCNTs in major clearance organs. When combined with checkpoint inhibition of anti-PD-1, SWCNT-ANXA5-mediated PTT increased survival and 80% of the mice survived for 100 days. Evidence of immune system activation by flow cytometry of splenic cells strengthens the hypothesis of an abscopal effect as a mechanism of prolonged survival. Significance Statement This study demonstrated a relatively high survival rate (80% at 100 days) of mice with aggressive breast cancer when treated with photothermal therapy using the SWCNT-ANXA5 conjugate injected intratumorally and combined with immune stimulation using the anti-PD-1 checkpoint inhibitor. Photothermal therapy was accomplished by maintaining the tumor temperature at a relatively low level of 45oC and avoiding accumulation of the nanotubes in the clearance organs by using intratumoral administration.

Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.

This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.

Synthesis and insecticidal activity of N-(5-phenylpyrazin-2-yl)-benzamide derivatives: Elucidation of mode of action on chitin biosynthesis through symptomology and genetic studies.

Among the six-membered heterocycles, the pyrazine ring is poorly explored in crop protection and does not feature in any product listed in the current IRAC MoA classification. In an effort to identify new leads for internal research, we synthesized a series of N-(5-phenylpyrazin-2-yl)-benzamide derivatives and evaluated them for their insecticidal activity. N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3 were prepared using an automated two-step synthesis protocol. These compounds were tested for their initial biological activity against a wide range of sucking and chewing insect pests and found to be active against lepidopterans only. More detailed experiments, including symptomology studies on the diamondback moth, Plutella xylostella (L.) and the Egyptian cotton leafworm, Spodoptera littoralis (Boisduval) showed that analog 3q causes severe abnormalities in the lepidopteran cuticle leading to larval mortality. Compound 3q shows strong potency against both P. xylostella and S. littoralis, whereas analog 3i shows better potency against S. littoralis causing also impaired cuticular structure and death of the larvae. Additionally, P. xylostella genetic studies showed that compound 3q resistance is linked to Chitin Synthase 1. Our studies show that N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3, and in particular analogs 3i and 3q, act as insect growth modulator insecticides. Conformational similarities with lufenuron are discussed.

Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

Differential responses of cerebral and renal oxygenation to altered perfusion conditions during experimental cardiopulmonary bypass in sheep.

We tested whether the brain and kidney respond differently to cardiopulmonary bypass (CPB) and to changes in perfusion conditions during CPB. Therefore, in ovine CPB, we assessed regional cerebral oxygen saturation (rSO2 ) by near-infrared spectroscopy and renal cortical and medullary tissue oxygen tension (PO2 ), and, in some protocols, brain tissue PO2 , by phosphorescence lifetime oximetry. During CPB, rSO2 correlated with mixed venous SO2 (r = 0.78) and brain tissue PO2 (r = 0.49) when arterial PO2 was varied. During the first 30 min of CPB, brain tissue PO2 , rSO2 and renal cortical tissue PO2 did not fall, but renal medullary tissue PO2 did. Nevertheless, compared with stable anaesthesia, during stable CPB, rSO2 (66.8 decreasing to 61.3%) and both renal cortical (90.8 decreasing to 43.5 mm Hg) and medullary (44.3 decreasing to 19.2 mm Hg) tissue PO2 were lower. Both rSO2 and renal PO2 increased when pump flow was increased from 60 to 100 mL kg-1 min-1 at a target arterial pressure of 70 mm Hg. They also both increased when pump flow and arterial pressure were increased simultaneously. Neither was significantly altered by partially pulsatile flow. The vasopressor, metaraminol, dose-dependently decreased rSO2 , but increased renal cortical and medullary PO2 . Increasing blood haemoglobin concentration increased rSO2 , but not renal PO2 . We conclude that both the brain and kidney are susceptible to hypoxia during CPB, which can be alleviated by increasing pump flow, even without increasing arterial pressure. However, increasing blood haemoglobin concentration increases brain, but not kidney oxygenation, whereas vasopressor support with metaraminol increases kidney, but not brain oxygenation.

Whole-body fasciculation detection in amyotrophic lateral sclerosis using motor unit MRI.

OBJECTIVE: Compare fasciculation rates between amyotrophic lateral sclerosis (ALS) patients and healthy controls in body regions relevant for diagnosing ALS using motor unit MRI (MUMRI) at baseline and 6 months follow-up, and relate this to single-channel surface EMG (SEMG). METHODS: Tongue, biceps brachii, paraspinals and lower legs were assessed with MUMRI and biceps brachii and soleus with SEMG in 10 healthy controls and 10 patients (9 typical ALS, 1 primary lateral sclerosis [PLS]). RESULTS: MUMRI-detected fasciculation rates in typical ALS patients were higher compared to healthy controls for biceps brachii (2.40 ± 1.90 cm-3min-1vs. 0.04 ± 0.10 cm-3min-1, p = 0.004), paraspinals (1.14 ± 1.61 cm-3min-1vs. 0.02 ± 0.02 cm-3min-1, p = 0.016) and lower legs (1.42 ± 1.27 cm-3min-1vs. 0.13 ± 0.10 cm-3min-1, p = 0.004), but not tongue (1.41 ± 1.94 cm-3min-1vs. 0.18 ± 0.18 cm-3min-1, p = 0.556). The PLS patient showed no fasciculation. At baseline, 6/9 ALS patients had increased fasciculation rates compared to healthy controls in at least 2 body regions. At follow-up every patient had increased fasciculation rates in at least 2 body regions. The MUMRI-detected fasciculation rate correlated with SEMG-detected fasciculation rates (τ = 0.475, p = 0.006). CONCLUSION: MUMRI can non-invasively image fasciculation in multiple body regions and appears sensitive to disease progression in individual patients. SIGNIFICANCE: MUMRI has potential as diagnostic tool for ALS.

Valorization of Agricultural Rice Straw as a Sustainable Feedstock for Rigid Polyurethane/Polyisocyanurate Foam Production.

Agricultural rice straw (RS), often discarded as waste in farmlands, represents a vast and underutilized resource. This study explores the valorization of RS as a potential feedstock for rigid polyurethane/polyisocyanurate foam (RPUF) production. The process begins with the liquefaction of RS to create an RS-based polyol, which is then used in a modified foam formulation to prepare RPUFs. The resulting RPUF samples were comprehensively characterized according to their physical, mechanical, and thermal properties. The results demonstrated that up to 50% by weight of petroleum-based polyol can be substituted with RS-based polyol to produce a highly functional RPUF. The obtained foams exhibited a notably low apparent density of 18-24 kg/m3, exceptional thermal conductivity ranging from 0.031-0.041 W/m-K, and a high compressive strength exceeding 250 kPa. This study underlines the potential of the undervalued agricultural RS as a green alternative to petroleum-based feedstocks to produce a high-value RPUF. Additionally, the findings contribute to the sustainable utilization of abundant agricultural waste while offering an eco-friendly option for various applications, including construction materials and insulation.

Development of High-Performance Coconut Oil-Based Rigid Polyurethane-Urea Foam: A Novel Sequential Amidation and Prepolymerization Process.

The utilization of coconut diethanolamide (p-CDEA) as a substitute polyol for petroleum-based polyol in fully biobased rigid polyurethane-urea foam (RPUAF) faces challenges due to its short chain and limited cross-linking capability. This leads to compromised cell wall resistance during foam expansion, resulting in significant ruptured cells and adverse effects on mechanical and thermal properties. To address this, a novel sequential amidation-prepolymerization route was employed on coconut oil, yielding a hydroxyl-terminated poly(urethane-urea) prepolymer polyol (COPUAP). Compared to p-CDEA, COPUAP exhibited a decreased hydroxyl value (496.3-473.2 mg KOH/g), an increase in amine value (13.464-24.561 mg KOH/g), and an increase in viscosity (472.4-755.8 mPa·s), indicating enhanced functionality of 34.3 mgKOH/g and chain lengthening. Further, COPUAP was utilized as the sole B-side polyol in the production of RPUAF (PU-COPUAP). The improved functionality of COPUAP and its improved cross-linking capability during foaming have significantly improved cell morphology, resulting in a remarkable 4.7-fold increase in compressive strength (132-628 kPa), a 3.5-fold increase in flexural strength (232-828 kPa), and improved insulation properties with a notable decrease in thermal conductivity (48.02-34.52 mW/m·K) compared to PU-CDEA in the literature. Additionally, PU-COPUAP exhibited a 16.5% increase in the water contact angle (114.93° to 133.87°), attributing to the formation of hydrophobic biuret segments and a tightly packed, highly cross-linked structure inhibiting water penetration. This innovative approach sets a new benchmark for fully biobased rigid foam production, delivering high load-bearing capacity, exceptional insulation, and significantly improved hydrophobicity.

Targeted sampling of natural product space to identify bioactive natural product-like polyketide macrolides.

Polyketide or polyketide-like macrolides (pMLs) continue to serve as a source of inspiration for drug discovery. However, their inherent structural and stereochemical complexity challenges efforts to explore related regions of chemical space more broadly. Here, we report a strategy termed the Targeted Sampling of Natural Product space (TSNaP) that is designed to identify and assess regions of chemical space bounded by this important class of molecules. Using TSNaP, a family of tetrahydrofuran-containing pMLs are computationally assembled from pML inspired building blocks to provide a large collection of natural product-like virtual pMLs. By scoring functional group and volumetric overlap against their natural counterparts, a collection of compounds are prioritized for targeted synthesis. Using a modular and stereoselective synthetic approach, a library of polyketide-like macrolides are prepared to sample these unpopulated regions of pML chemical space. Validation of this TSNaP approach by screening this library against a panel of whole-cell biological assays, reveals hit rates exceeding those typically encountered in small molecule libraries. This study suggests that the TSNaP approach may be more broadly useful for the design of improved chemical libraries for drug discovery.

Incorporating climate-readiness into fisheries management strategies.

Tropical oceans are among the first places to exhibit climate change signals, affecting the habitat distribution and abundance of marine fish. These changes to stocks, and subsequent impacts on fisheries production, may have considerable implications for coastal communities dependent on fisheries for food security and livelihoods. Understanding the impacts of climate change on tropical marine fisheries is therefore an important step towards developing sustainable, climate-ready fisheries management measures. We apply an established method of spatial meta-analysis to assess species distribution modelling datasets for key species targeted by the Philippines capture fisheries. We analysed datasets under two global emissions scenarios (RCP4.5 and RCP8.5) and varying degrees of fishing pressure to quantify potential climate vulnerability of the target community. We found widespread responses to climate change in pelagic species in particular, with abundances projected to decline across much of the case study area, highlighting the challenges of maintaining food security in the face of a rapidly changing climate. We argue that sustainable fisheries management in the Philippines in the face of climate change can only be achieved through management strategies that allow for the mitigation of, and adaptation to, pressures already locked into the climate system for the near term. Our analysis may support this, providing fisheries managers with the means to identify potential climate change hotspots, bright spots and refugia, thereby supporting the development of climate-ready management plans.

Risk factors for incident cardiovascular events and their population attributable fractions in rural India: The Rishi Valley Prospective Cohort Study.

OBJECTIVE: We prospectively determined incident cardiovascular events and their association with risk factors in rural India. METHODS: We followed up with 7935 adults from the Rishi Valley Prospective Cohort Study to identify incident cardiovascular events. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) with 95% confidence intervals (95% CI) for associations between potential risk factors and cardiovascular events. Population attributable fractions (PAFs) for risk factors were estimated using R ('averisk' package). RESULTS: Of the 4809 participants without prior cardiovascular disease, 57.7% were women and baseline mean age was 45.3 years. At follow-up (median of 4.9 years, 23,180 person-years [PYs]), 202 participants developed cardiovascular events, equating to an incidence of 8.7 cardiovascular events/1000 PYs. Incidence was greater in those with hypertension (hazard ratio [HR] [95% CI] 1.73 [1.21-2.49], adjusted PAF 18%), diabetes (1.96 [1.15-3.36], 4%) or central obesity (1.77 [1.23, 2.54], 9%) which together accounted for 31% of the PAF. Non-traditional risk factors such as night sleeping hours and number of children accounted for 16% of the PAF. CONCLUSIONS: Both traditional and non-traditional cardiovascular risk factors are important contributors to incident cardiovascular events in rural India. Interventions targeted to these factors could assist in reducing the incidence of cardiovascular events.

Antibacterial Marinopyrroles and Pseudilins Act as Protonophores.

Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles, pentachloropseudilin, and pentabromopseudilin are densely halogenated, hybrid pyrrole-phenol natural products with potent activity against Gram-positive bacterial pathogens like Staphylococcus aureus. However, the exact way they exert this antibacterial activity has not been established. In this study, we explore their structure-activity relationship, determine their spatial location in bacterial cells, and investigate their MoA. We show that the natural products share a common MoA based on membrane depolarization and dissipation of the proton motive force (PMF) that is essential for cell viability. The compounds show potent protonophore activity but do not appear to destroy the integrity of the cytoplasmic membrane via the formation of larger pores or interfere with the stability of the peptidoglycan sacculus. Thus, our current model for the antibacterial MoA of marinopyrrole, pentachloropseudilin, and pentabromopseudilin stipulates that the acidic compounds insert into the membrane and transport protons inside the cell. This MoA may explain many of the deleterious biological effects in mammalian cells, plants, phytoplankton, viruses, and protozoans that have been reported for these compounds.

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.

ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Evaluating Prognostic Bias of Critical Illness Severity Scores Based on Age, Sex, and Primary Language in the United States: A Retrospective Multicenter Study.

OBJECTIVES: Although illness severity scoring systems are widely used to support clinical decision-making and assess ICU performance, their potential bias across different age, sex, and primary language groups has not been well-studied. DESIGN SETTING AND PATIENTS: We aimed to identify potential bias of Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) IVa scores via large ICU databases. SETTING/PATIENTS: This multicenter, retrospective study was conducted using data from the Medical Information Mart for Intensive Care (MIMIC) and eICU Collaborative Research Database. SOFA and APACHE IVa scores were obtained from ICU admission. Hospital mortality was the primary outcome. Discrimination (area under receiver operating characteristic [AUROC] curve) and calibration (standardized mortality ratio [SMR]) were assessed for all subgroups. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: A total of 196,310 patient encounters were studied. Discrimination for both scores was worse in older patients compared with younger patients and female patients rather than male patients. In MIMIC, discrimination of SOFA in non-English primary language speakers patients was worse than that of English speakers (AUROC 0.726 vs. 0.783, p < 0.0001). Evaluating calibration via SMR showed statistically significant underestimations of mortality when compared with overall cohort in the oldest patients for both SOFA and APACHE IVa, female patients (1.09) for SOFA, and non-English primary language patients (1.38) for SOFA in MIMIC. CONCLUSIONS: Differences in discrimination and calibration of two scores across varying age, sex, and primary language groups suggest illness severity scores are prone to bias in mortality predictions. Caution must be taken when using them for quality benchmarking and decision-making among diverse real-world populations.

Motor Unit Magnetic Resonance Imaging (MUMRI) In Skeletal Muscle.

Magnetic resonance imaging (MRI) is routinely used in the musculoskeletal system to measure skeletal muscle structure and pathology in health and disease. Recently, it has been shown that MRI also has promise for detecting the functional changes, which occur in muscles, commonly associated with a range of neuromuscular disorders. This review focuses on novel adaptations of MRI, which can detect the activity of the functional sub-units of skeletal muscle, the motor units, referred to as "motor unit MRI (MUMRI)." MUMRI utilizes pulsed gradient spin echo, pulsed gradient stimulated echo and phase contrast MRI sequences and has, so far, been used to investigate spontaneous motor unit activity (fasciculation) and used in combination with electrical nerve stimulation to study motor unit morphology and muscle twitch dynamics. Through detection of disease driven changes in motor unit activity, MUMRI shows promise as a tool to aid in both earlier diagnosis of neuromuscular disorders and to help in furthering our understanding of the underlying mechanisms, which proceed gross structural and anatomical changes within diseased muscle. Here, we summarize evidence for the use of MUMRI in neuromuscular disorders and discuss what future research is required to translate MUMRI toward clinical practice. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.