Quantification of early biofilm growth in microtiter plates through a novel image analysis software.

Given the significant impact of biofilms on human health and material corrosion, research in this field urgently needs more accessible techniques to facilitate the testing of new control agents and general understanding of biofilm biology. Microtiter plates offer a convenient format for standardized evaluations, including high-throughput assays of alternative treatments and molecular modulators. This study introduces a novel Biofilm Analysis Software (BAS) for quantifying biofilms from microtiter plate images. We focused on early biofilm growth stages and compared BAS quantification to common techniques: direct turbidity measurement, intrinsic fluorescence detection linked to pyoverdine production, and standard crystal violet staining which enables image analysis and optical density measurement. We also assessed their sensitivity for detecting subtle growth effects caused by cyclic AMP and gentamicin. Our results show that BAS image analysis is at least as sensitive as the standard method of spectrophotometrically quantifying the crystal violet retained by biofilms. Furthermore, we demonstrated that bacteria adhered after short incubations (from 10 min to 4 h), isolated from planktonic populations by a simple rinse, can be monitored until their growth is detectable by intrinsic fluorescence, BAS analysis, or resolubilized crystal violet. These procedures are widely accessible for many laboratories, including those with limited resources, as they do not require a spectrophotometer or other specialized equipment.

Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy.

BACKGROUND: Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1-year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo-controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles. METHODS: Quantitative MRI and 31P MRS data were collected at 3 T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year-1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross-sectional area (cCSA), and water T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadriceps or triceps surae. Analyses covered patient-control comparisons, annual change assessments via standard t-tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters. RESULTS: The quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1-year FF increase in the quadriceps was 3.2% (P < 0.001), whereas in the sirolimus group, it was 0.7% (P = 0.033). Both groups experienced a significant decrease in cCSA in the quadriceps after 1 year (P < 0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P < 0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T2 values were highest in the quadriceps muscles of both groups, significantly exceeding control values in both groups (P < 0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T2 increased significantly only in the sirolimus group's quadriceps (P < 0.01). Multiple 31P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T2 and FF at baseline and the change in FF (P < 0.001). Additionally, significant correlations were observed between FF, cCSA, water T2, and functional and strength outcome measures. CONCLUSIONS: This study has demonstrated that quantitative MRI/31P MRS can discern measurable differences between placebo and sirolimus-treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM.

A Late Pleistocene coastal ecosystem in French Guiana was hyperdiverse relative to today.

Warmer temperatures and higher sea level than today characterized the Last Interglacial interval [Pleistocene, 128 to 116 thousand years ago (ka)]. This period is a remarkable deep-time analog for temperature and sea-level conditions as projected for 2100 AD, yet there has been no evidence of fossil assemblages in the equatorial Atlantic. Here, we report foraminifer, metazoan (mollusks, bony fish, bryozoans, decapods, and sharks among others), and plant communities of coastal tropical marine and mangrove affinities, dating precisely from a ca. 130 to 115 ka time interval near the Equator, at Kourou, in French Guiana. These communities include ca. 230 recent species, some being endangered today and/or first recorded as fossils. The hyperdiverse Kourou mollusk assemblage suggests stronger affinities between Guianese and Caribbean coastal waters by the Last Interglacial than today, questioning the structuring role of the Amazon Plume on tropical Western Atlantic communities at the time. Grassland-dominated pollen, phytoliths, and charcoals from younger deposits in the same sections attest to a marine retreat and dryer conditions during the onset of the last glacial (ca. 110 to 50 ka), with a savanna-dominated landscape and episodes of fire. Charcoals from the last millennia suggest human presence in a mosaic of modern-like continental habitats. Our results provide key information about the ecology and biogeography of pristine Pleistocene tropical coastal ecosystems, especially relevant regarding the-widely anthropogenic-ongoing global warming.

Miyoshi myopathy associated with spine rigidity and multiple contractures: a case report.

BACKGROUND: Dysferlinopathy is a phenotypically heterogeneous group of hereditary diseases caused by mutations in the DYSF gene. Early contractures are considered rare, and rigid spine syndrome in dysferlinopathy has been previously reported only once. CASE PRESENTATION: We describe a 23-year-old patient with Miyoshi myopathy with a rigid spine and multiple contractures, a rare phenotypic variant. The disease first manifested when the patient was 13 years old, with fatigue of the gastrocnemius muscles and the development of pronounced contractures of the Achilles tendons, flexors of the fingers, and extensors of the toes, followed by the involvement of large joints and the spine. Magnetic resonance imaging revealed signs of connective tissue and fatty replacement of the posterior muscles of the thighs and lower legs. Edema was noted in the anterior and medial muscle groups of the thighs, lower legs, and the multifidus muscle of the back. Whole genome sequencing revealed previously described mutations in the DYSF gene in exon 39 (c.4282 C > T) and intron 51 (c.5785-824 C > T). An immunohistochemical analysis and Western blot showed the complete absence of dysferlin protein expression in the muscle fibers. CONCLUSIONS: This case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity.

Periodic tapping mechanisms of skill learning in a fast-paced video game.

Timing plays a critical role when building up motor skill. In this study, we investigated and simulated human skill learning in a simplified variant of the Space Fortress video game named Auto Orbit with a strong timing component. Our principal aim was to test whether a computational model designed to simulate keypress actions repeated at rates slower than 500 ms (>500 ms) could also simulate human learning with repeated keypress actions taking place at very fast rates (≤500 ms). The main finding was that increasing speed stress forced human participants to qualitatively switch their behavior from a cognitively controlled strategy to an inherently rhythmic motor strategy. We show how the adaptive control of thought rational architecture's periodic tapping motor extension can replicate such rhythmic patterns of keypresses in two different computational models of human learning. The first model implements streamed motor actions across hands that are temporally decoupled, while the second model implements a coupled motor strategy in which actions from both hands are executed relative to the same periodic motor clock. Different subsets of subjects correspond to these two models. Our modeling simulations integrate previous psychological and motor control findings within a single cognitive architecture, and successfully replicate human behavioral patterns across a range of experimental measures at fast speed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Hill-placement of manure and fertilizer for improving maize nutrient- and water-use efficiencies in the northern Benin.

Optimizing the use of organic and mineral fertilizer in rain-fed maize production is crucial for sustainable food production in sub-Saharan Africa. This study investigates the effect of hill-placement of two nutrient sources (farmyard manure and synthetic fertilizer) on nutrient- and water-use efficiencies of maize crops i.e. recovery efficiency (NUEre), internal utilization efficiency (NUEie) and water use efficiency (WUE). A four-year trial was conducted in the tropical sub-humid zone of the northern Benin with a factorial combination of farmyard manure at three levels (0, 3 and 6 t ha-1, hereafter NM, 3M and 6M, respectively) and three levels of fertilizer [0% (NF), 50% (50F) and 100% (100F) of the recommended rate (76 kg N + 13.1 kg P + 24.9 kg K ha-1) by the national center for agricultural research. The NUEre decreased with increasing rate of manure and/or fertilizer, but the decreasing rate was lower under combined manure and fertilizer application. However, the NUEie increased with the increasing manure and fertilizer amounts. The WUE was significantly higher in 3M and 6M treatments than in NM treatment, and higher in 50F and in 100F than in NF treatments. The combination of 3000 kg ha-1 farmyard manure with half recommended fertilizer rate (100 kg ha-1) could be suggested as an optimal nutrient management practice for maize production in the Northern Benin. Future studies should target the other agro-ecological zones in Benin, and also consider other widely cultivated crops in the study area for reducing yield gaps and promote food security.

Medieval demise of a Himalayan giant summit induced by mega-landslide.

Despite numerous studies on Himalayan erosion, it is not known how the very high Himalayan peaks erode. Although valley floors are efficiently eroded by glaciers, the intensity of periglacial processes, which erode the headwalls extending from glacial cirques to crest lines, seems to decrease sharply with altitude1,2. This contrast suggests that erosion is muted and much lower than regional rock uplift rates for the highest Himalayan peaks, raising questions about their long-term evolution3,4. Here we report geological evidence for a giant rockslide that occurred around 1190 AD in the Annapurna massif (central Nepal), involving a total rock volume of about 23 km3. This event collapsed a palaeo-summit, probably culminating above 8,000 m in altitude. Our data suggest that a mode of high-altitude erosion could be mega-rockslides, leading to the sudden reduction of ridge-crest elevation by several hundred metres and ultimately preventing the disproportionate growth of the Himalayan peaks. This erosion mode, associated with steep slopes and high relief, arises from a greater mechanical strength of the peak substratum, probably because of the presence of permafrost at high altitude. Giant rockslides also have implications for landscape evolution and natural hazards: the massive supply of finely crushed sediments can fill valleys more than 150 km farther downstream and overwhelm the sediment load in Himalayan rivers for a century or more.

Pulse contour techniques for perioperative hemodynamic monitoring: A nationwide carbon footprint and cost estimation.

BACKGROUND: The question of environmentally sustainable perioperative medicine represents a new challenge in an era of cost constraints and climate crisis. The French Society of Anaesthesia and Intensive Care (SFAR) recommends stroke volume optimization in high-risk surgical patients. Pulse contour techniques have become increasingly popular for stroke volume monitoring during surgery. Some require the use of specific disposable pressure transducers (DPTs), whereas others can be used with standard DPTs. OBJECTIVE: Quantify and compare the carbon footprint and cost of pulse contour techniques using specific and standard DPTs on a yearly basis and at a national level. METHODS: We estimated the number of high-risk surgical patients monitored every year in France with a pulse contour technique, and the plastic waste, carbon footprint and cost associated with the use of specific and standard DPTs. MAIN FINDINGS: When compared to pulse contour techniques working with a standard DPT, techniques requiring a specific DPT are responsible for an increase in carbon dioxide emission estimated at 65-83 tons/yr and for additional hospital cost estimated at €67 million/yr. If, as recommended by the SFAR, all high-risk surgical patients were monitored, the difference would reach 179-227 tons/yr for the environmental impact and €187 million/yr for the economic impact. CONCLUSION: From an environmental and economic standpoint, pulse contour techniques working with standard DPTs should be recommended for the perioperative hemodynamic monitoring of high-risk surgical patients.

New Insights into the Spread of MRS-Based Water T2 Values Observed in Highly Fatty Replaced Muscles.

BACKGROUND: The reference standard for assessing water T2 (T2,H2O ) at high fat fraction (FF) is 1 H MRS. T2,H2O (T2,H2O,MRS ) dependence on FF (FFMRS ) has recently been demonstrated in muscle at high FF (i.e. ≥60%). PURPOSE: To investigate the relationship between T2,H2O,MRS and FFMRS in the thigh/leg muscles of patients with neuromuscular diseases and to compare with quantitative MRI. STUDY TYPE: Retrospective case-control study. POPULATION: A total of 151 patients with neuromuscular disorders (mean age ± standard deviation = 52.5 ± 22.6 years, 54% male), 44 healthy volunteers (26.5 ± 13.0 years, 57% male). FIELD STRENGTH/SEQUENCE: A 3-T; single-voxel stimulated echo acquisition mode (STEAM) MRS, multispin echo (MSE) imaging (for T2 mapping, T2,H2O,MRI ), three-point Dixon imaging (for FFMRI and R 2 * mapping). ASSESSMENT: Mono-exponential and bi-exponential models were fitted to water T2 decay curves to extract T2,H2O,MRS and FFMRS . Water resonance full-width-at-half-maximum (FWHM) and B0 spread (∆B0 ) values were calculated. T2,H2O,MRI (mean), FFMRI (mean, kurtosis, and skewness), and R 2 * (mean) values were estimated in the MRS voxel. STATISTICAL TESTS: Mann-Whitney U tests, Kruskal-Wallis tests. A P-value <0.05 was considered statistically significant. RESULTS: Normal T2,H2O,MRS threshold was defined as the 90th percentile in healthy controls: 30.3 msec. T2,H2O,MRS was significantly higher in all patients with FFMRS < 60% compared to healthy controls. We discovered two subgroups in patients with FFMRS ≥ 60%: one with T2,H2O,MRS ≥ 30.3 msec and one with T2,H2O,MRS < 30.3 msec including abnormally low T2,H2O,MRS . The latter subgroup had significantly higher water resonance FWHM, ∆B0 , FFMRI kurtosis, and skewness values but nonsignificantly different R 2 * (P = 1.00) and long T2,H2O,MRS component and its fraction (P > 0.11) based on the bi-exponential analysis. DATA CONCLUSION: The findings suggest that the cause for (abnormally) T2,H2O,MRS at high FFMRS is biophysical, due to differences in susceptibility between muscle and fat (increased FWHM and ∆B0 ), rather than pathophysiological such as compartmentation changes, which would be reflected by the bi-exponential analysis. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Expanding the muscle imaging spectrum in dysferlinopathy: description of an outlier population from the classical MRI pattern.

Dysferlinopathy is a muscle disease characterized by a variable clinical presentation and is caused by mutations in the DYSF gene. The Jain Clinical Outcome Study for Dysferlinopathy (COS) followed the largest cohort of patients (n=187) with genetically confirmed dysferlinopathy throughout a three-year natural history study, in which the patients underwent muscle function tests and muscle magnetic resonance imaging (MRI). We previously described the pattern of muscle pathology in this population and established a series of imaging criteria for diagnosis. In this paper, we describe the muscle imaging and clinical features of a subgroup of COS participants whose muscle imaging results did not completely meet the diagnostic criteria. We reviewed 184 T1-weighted (T1w) muscle MRI scans obtained at the baseline visit of the COS study, of which 106 were pelvic and lower limb only and 78 were whole-body scans. We identified 116 of the 184 patients (63%) who did not meet at least one of the established imaging criteria. The highest number found of unmet criteria was four per patient. We identified 24 patients (13%) who did not meet three or more of the nine established criteria and considered them as "outliers". The most common unmet criterion (27.3% of cases) was the adductor magnus being equally or more affected than the adductor longus. We compared the genetic, demographic, clinical and muscle function data of the outlier patients with those who met the established criteria and observed that the outlier patients had an age of disease onset that was significantly older than the whole group (29.3 vs 20.5 years, p=0.0001). This study expands the phenotypic muscle imaging spectrum of patients with dysferlinopathy and can help to guide the diagnostic process in patients with limb girdle weakness of unknown origin.

Fabrication of Activated Carbon Decorated with ZnO Nanorod-Based Electrodes for Desalination of Brackish Water Using Capacitive Deionization Technology.

Capacitive deionization (CDI) is a promising and cost-effective technology that is currently being widely explored for removing dissolved ions from saline water. This research developed materials based on activated carbon (AC) materials modified with zinc oxide (ZnO) nanorods and used them as high-performance CDI electrodes for water desalination. The as-prepared electrodes were characterized by cyclic voltammetry, and their physical properties were studied through SEM and XRD. ZnO-coated AC electrodes revealed a better specific absorption capacity (SAC) and an average salt adsorption rate (ASAR) compared to pristine AC, specifically with values of 123.66 mg/g and 5.06 mg/g/min, respectively. The desalination process was conducted using a 0.4 M sodium chloride (NaCl) solution with flow rates from 45 mL/min to 105 mL/min under an applied potential of 1.2 V. Furthermore, the energy efficiency of the desalination process, the specific energy consumption (SEC), and the maximum and minimum of the effluent solution concentration were quantified using thermodynamic energy efficiency (TEE). Finally, this work suggested that AC/ZnO material has the potential to be utilized as a CDI electrode for the desalination of saline water.

Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy.

Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy.

Facts and Hopes in Cancer Antigens Recognized by T Cells.

T cells are key effectors of our immune response against tumors and exert their antitumor effects upon recognizing a variety of tumor-specific peptides presented by HLA molecules on the surface of tumor cells. The identification of the tumor-specific antigens of a given tumor is not required for immune checkpoint therapy (ICT), which mainly reactivates existing tumor-specific T cells together with T cells of unknown specificities. To decrease the activation of non-tumor-specific T cells, active or passive immunizations against tumor-specific antigens are considered. These immunizations require the identification of at least some of the tumor-specific antigens displayed on the tumor cells of a patient. While this has become an easy task for tumors with a large number of mutations generating neoantigens, it remains difficult for the remainder. Here, we review some facts about human tumor-specific or tumor-associated antigens, as well as some hopes for their future use in cancer immunotherapy.

Efficacy and toxicity of primary re-irradiation for malignant spinal cord compression based on radiobiological modelling: a phase II clinical trial.

BACKGROUND: The efficacy and safety of primary re-irradiation for MSCC are not known. Our aim was to establish the efficacy and safety of biologically effective dose-based re-irradiation. METHODS: Patients presenting with MSCC at a previously irradiated spine segment, and not proceeding with surgical decompression, were eligible. A 3 Gray per fraction experimental schedule (minimum 18 Gy/6 fractions, maximum 30 Gy/10 fractions) was used, delivering a maximum cumulative spinal dose of 100 Gy2 if the interval since the last radiotherapy was within 6 months, or 130 Gy2 if longer. The primary outcome was a change in mobility from week 1 to week 5 post-treatment, as assessed by the Tomita score. The RTOG SOMA score was used to screen for spinal toxicity, and an MRI performed to assess for radiation-induced myelopathy (RIM). RESULTS: Twenty-two patients were enroled, of whom eleven were evaluable for the primary outcome. Nine of eleven (81.8%) had stable or improved Tomita scores at 5 weeks. One of eight (12.5%) evaluable for late toxicity developed RIM. CONCLUSIONS: Re-irradiation is an efficacious treatment for MSCC. There is a risk of RIM with a cumulative dose of 120 Gy2. CLINICAL TRIAL REGISTRATION: Cancer Trials Ireland (ICORG 07-11); NCT00974168.

Therapeutic activity of GARP:TGF-ß1 blockade in murine primary myelofibrosis.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-ß1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-ß1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-ß1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-ß1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found an increased expression of GARP in the BM and spleen of mice with PMF and tested the therapeutic potential of a monoclonal antibody (mAb) that blocks TGF-ß1 activation by GARP-expressing cells. GARP:TGF-ß1 blockade reduced not only fibrosis but also the clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-ß1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-γ signals in the spleen, were lost upon CD8 T-cell depletion. Our results suggest that the selective blockade of TGF-ß1 activation by GARP-expressing Tregs increases a CD8 T-cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.

Challenges of design, implementation, acceptability, and potential for, biomedical technologies in the Peruvian Amazon.

BACKGROUND: Biomedical technologies have the potential to be advantageous in remote communities. However, information about barriers faced by users of technology in general and in remote Indigenous communities is scarce. The purpose of this study was to characterize the leading challenges faced by researchers who have used biomedical technologies in the Peruvian Amazon. METHODS: This exploratory, qualitative study with a phenomenological approach depicts the lived experience of participants who were researchers with experience working with biomedical technologies in the Peruvian Amazon in the past five years. Analysis was based on three core themes: design, implementation, and acceptability. Sub-themes included environment, community, and culture. Of the 24 potential participants identified and contacted, 14 agreed to participate, and 13 met inclusion criteria and completed semi-structured interviews. Results were sent to each participant with the opportunity to provide feedback and partake in a 30-minute validation meeting. Five participants consented to a follow-up meeting to validate the results and provide further understanding. RESULTS: Participants recognized significant challenges, including technologies designed out-of-context, difficulty transporting the technologies through the Amazon, the impact of the physical environment (e.g., humidity, flooding), and limited existing infrastructure, such as electricity and appropriately trained health personnel. Participants also identified cultural factors, including the need to address past experiences with technology and health interventions, understand and appropriately communicate community benefits, and understand the effect of demographics (e.g., age, education) on the acceptance and uptake of technology. Complementary challenges, such as corruption in authority and waste disposal, and recommendations for technological and health interventions such as co-design were also identified. CONCLUSIONS: This study proposes that technological and health interventions without efforts to respect local cultures and health priorities, or understand and anticipate contextual challenges, will not meet its goal of improving access to healthcare in remote Amazon communities. Furthermore, the implications of corruption on health services, and improper waste disposal on the environment may lead to more detrimental health inequities.

Climatic control on the location of continental volcanic arcs.

Orogens and volcanic arcs at continental plate margins are primary surface expressions of convergent plate tectonics. Although it is established that climate affects the shape, size, and architecture of orogens via orographic erosion gradients, the ascent of magma through the crust and location of volcanoes along magmatic arcs have been considered insensitive to erosion. However, available data reveal westward migration of late-Cenozoic volcanic activity in the Southern Andes and Cascade Range where orography drives an eastward migration of the topographic water divide by increased precipitation and erosion along west-facing slopes. Thermomechanical numerical modeling shows that orographic erosion and the associated leeward topographic migration may entail asymmetric crustal structures that drive the magma ascent toward the region of enhanced erosion. Despite the different tectonic histories of the Southern Andes and the Cascade Range, orographic erosion is a shared causal mechanism that can explain the late-Cenozoic westward migration of the volcanic front along both magmatic arcs.

Water T2 could predict functional decline in patients with dysferlinopathy.

BACKGROUND: Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. RESULTS: A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Muscle imaging in myositis: MRI, US, and PET.

Imaging is an important tool in the evaluation of idiopathic inflammatory myopathies. It plays a role in diagnosis, assessment of disease activity and follow-up, and as a non-invasive biomarker. Among the different modalities, nuclear magnetic resonance imaging (MRI), ultrasound (US), and positron emission tomography (PET) may have the most clinical utility in myositis. MRI is currently the best modality to evaluate skeletal muscle and provides excellent characterization of muscle edema and fat replacement through the use of T1-weighted and T2-weighted fat suppressed/STIR sequences. Although MRI can be read qualitatively for the presence of abnormalities, a more quantitative approach using Dixon sequences and the generation of water T2 parametric maps would be preferable for follow-up. Newer protocols such as diffusion-weighted imaging, functional imaging measures, and spectroscopy may be of interest to provide further insights into myositis. Despite the advantages of MRI, image acquisition is relatively time-consuming, expensive, and not accessible to all patients. The use of US to evaluate skeletal muscle in myositis is gaining interest, especially in chronic disease, where fat replacement and fibrosis are detected readily by this modality. Although easily deployed at the bedside, it is heavily dependent on operator experience to recognize disease states. Further, systematic characterization of muscle edema by US is still needed. PET provides valuable information on muscle function at a cellular level. Fluorodeoxyglucose (FDG-PET) has been the most common application in myositis to detect pathologic uptake indicative of inflammation. The use of neurodegenerative markers is now also being utilized for inclusion body myositis. These different modalities may prove to be complementary methods for myositis evaluation.

Three-year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy.

BACKGROUND: Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31 P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. METHODS: Quantitative MRI/31 P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T2 in both global leg and thigh segments and individual muscles and 31 P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31 P MRS markers and functional markers. RESULTS: Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T2 values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T2 values were found in the anterior part of thigh and leg. Almost all 31 P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pHw , and remained, similar as to water T2 , abnormal for the whole study duration. Global thigh water T2 at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010). CONCLUSIONS: This multi-centre study has shown that quantitative MRI/31 P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes.