Amide proton transfer weighted imaging in pediatric neuro-oncology: initial experience.

Amide proton transfer weighted (APTw) imaging enables in vivo assessment of tissue-bound mobile proteins and peptides through the detection of chemical exchange saturation transfer. Promising applications of APTw imaging have been shown in adult brain tumors. As pediatric brain tumors differ from their adult counterparts, we investigate the radiological appearance of pediatric brain tumors on APTw imaging. APTw imaging was conducted at 3 T. APTw maps were calculated using magnetization transfer ratio asymmetry at 3.5 ppm. First, the repeatability of APTw imaging was assessed in a phantom and in five healthy volunteers by calculating the within-subject coefficient of variation (wCV). APTw images of pediatric brain tumor patients were analyzed retrospectively. APTw levels were compared between solid tumor tissue and normal-appearing white matter (NAWM) and between pediatric high-grade glioma (pHGG) and pediatric low-grade glioma (pLGG) using t-tests. APTw maps were repeatable in supratentorial and infratentorial brain regions (wCV ranged from 11% to 39%), except those from the pontine region (wCV between 39% and 50%). APTw images of 23 children with brain tumor were analyzed (mean age 12 years ± 5, 12 male). Significantly higher APTw values are present in tumor compared with NAWM for both pHGG and pLGG (p < 0.05). APTw values were higher in pLGG subtype pilocytic astrocytoma compared with other pLGG subtypes (p < 0.05). Non-invasive characterization of pediatric brain tumor biology with APTw imaging could aid the radiologist in clinical decision-making.

Renal function in patients with chronic hepatitis B during antiviral therapy.

Aim To analyse the impact of the length of antiviral therapy with tenofovir disoproxil fumarate (TDF) on the renal function in patients with chronic hepatitis B (CHB). Methods A cross-sectional study included 75 patients with CHB treated with tenofovir, who had a normal renal function at the beginning of the treatment. Renal function was determined based on glomerular filtration rate (eGFR) value using the Modification of Diet in Renal Disease formula (MDRD). Measurement of serum creatinine concentration and urinary protein excretion were performed using standard laboratory analyses. Viral load quantification (HBV-DNA) was determined by polymerase chain reaction (PCR). The degree of liver fibrosis was determined using fibrosis4 (FIB-4) and aspartate transaminase to platelet ratio index (APRI) fibrosis score. Results Out of 75 CHB patients, 37 were on antiviral treatment for up to 2 years (group 1) and 38 patients on antiviral treatment longer than two years (group 2). Mean age of patients was not significantly different between the groups (p=0.076), nor was the gender distribution. There was no statistically significant difference between the mean values of the eGFR in the two groups (91.89±9.24 vs. 88.42±7.84 mL/min/1.73m2; p=0.42), as well as between the mean values of serum creatinine (p=0.360) and 24-hour urine protein excretion (p=0.380). There was no statistically significant correlation between renal parameters and viral load, APRI and FIB-4 fibrosis score. Conclusion Results of our study did not show significant changes in the measured parameters of renal function in group 1 and group 2 of patients, regardless of the length of antiviral treatment, indicating a good renal safety profile of TDF.

Performance of a Nonlinear Magnetic Handheld Probe for Intraoperative Sentinel Lymph Node Detection: A Phantom Study.

OBJECTIVE: This study investigates the performance of the DiffMag handheld probe (nonlinear magnetometry), to be used for sentinel lymph node detection. Furthermore, the performance of DiffMag is compared with a gamma probe and a first-order magnetometer (Sentimag®, linear magnetometry). METHODS: The performance of all three probes was evaluated based on longitudinal distance, transverse distance, and resolving power for two tracer volumes. A phantom was developed to investigate the performance of the probes for a clinically relevant situation in the floor of the mouth (FOM). RESULTS: Considering the longitudinal distance, both DiffMag handheld and Sentimag® probe had comparable performance, while the gamma probe was able to detect at least a factor of 10 deeper. Transverse distances of 13, 11, and 51 mm were measured for the small tracer volume by the DiffMag handheld, Sentimag®, and the gamma probe, respectively. For the large tracer volume this was 21, 18, and 55 mm, respectively. The full width at half maximum, at 7 mm probe height from the phantom surface, was 14, 12, and 18 mm for the small tracer volume and 15, 18, and 25 mm for the large tracer volume with the DiffMag handheld, Sentimag®, and gamma probe, respectively. CONCLUSIONS: With a high resolving power but limited longitudinal distance, the DiffMag handheld probe seems suitable for detecting SLNs which are in close proximity to the primary tumor. In this study, comparable results were shown using linear magnetometry. The gamma probe reached 10 times deeper, but has a lower resolving power compared with the DiffMag handheld probe.

Radiofrequency localization of nonpalpable breast cancer in a multicentre prospective cohort study: feasibility, clinical acceptability, and safety.

PURPOSE: In breast conserving surgery, accurate lesion localization is essential for obtaining adequate surgical margins. Preoperative wire localization (WL) and radioactive seed localization (RSL) are widely accepted methods to guide surgical excision of nonpalpable breast lesions but are limited by logistical challenges, migration issues, and legislative complexities. Radiofrequency identification (RFID) technology may offer a viable alternative. The purpose of this study was to evaluate the feasibility, clinical acceptability, and safety of RFID surgical guidance for localization of nonpalpable breast cancer. METHODS: In a prospective multicentre cohort study, the first 100 RFID localization procedures were included. The primary outcome was the percentage of clear resection margins and re-excision rate. Secondary outcomes included procedure details, user experience, learningcurve, and adverse events. RESULTS: Between April 2019 and May 2021, 100 women underwent RFID guided breast conserving surgery. Clear resection margins were obtained in 89 out of 96 included patients (92.7%), re-excision was indicated in three patients (3.1%). Radiologists reported difficulties with the placement of the RFID tag, partially related to the relatively large needle-applicator (12-gauge). This led to the premature termination of the study in the hospital using RSL as regular care. The radiologist experience was improved after a manufacturer modification of the needle-applicator. Surgical localization involved a low learning curve. Adverse events (n = 33) included dislocation of the marker during insertion (8%) and hematomas (9%). The majority of adverse events (85%) occurred using the first-generation needle-applicator. CONCLUSION: RFID technology is a potential alternative for non-radioactive and non-wire localization of nonpalpable breast lesions.

Near-Infrared Spectral Similarity between Ex Vivo Porcine and In Vivo Human Tissue.

BACKGROUND: In vivo diffuse reflectance spectroscopy provides additional contrast in discriminating nerves embedded in adipose tissue during surgery. However, large datasets are required to achieve clinically acceptable classification levels. This study assesses the spectral similarity between ex vivo porcine and in vivo human spectral data of nerve and adipose tissue, as porcine tissue could contribute to generate large datasets. METHODS: Porcine diffuse reflectance spectra were measured at 124 nerve and 151 adipose locations. A previously recorded dataset of 32 in vivo human nerve and 23 adipose tissue locations was used for comparison. In total, 36 features were extracted from the raw porcine to generate binary logistic regression models for all combinations of two, three, four and five features. Feature selection was performed by assessing similar means between normalized features of nerve and of adipose tissue (Kruskal-Wallis test, p < 0.05) and for models performing best on the porcine cross validation set. The human test set was used to assess classification performance. RESULTS: The binary logistic regression models with selected features showed an accuracy of 60% on the test set. CONCLUSIONS: Spectral similarity between ex vivo porcine and in vivo human adipose and nerve tissue was present, but further research is required.

Intracerebral Hemorrhage Segmentation on Noncontrast Computed Tomography Using a Masked Loss Function U-Net Approach.

OBJECTIVE: Intracerebral hemorrhage (ICH) volume is a strong predictor of outcome in patients presenting with acute hemorrhagic stroke. It is necessary to segment the hematoma for ICH volume estimation and for computerized extraction of features, such as spot sign, texture parameters, or extravasated iodine content at dual-energy computed tomography. Manual and semiautomatic segmentation methods to delineate the hematoma are tedious, user dependent, and require trained personnel. This article presents a convolutional neural network to automatically delineate ICH from noncontrast computed tomography scans of the head. METHODS: A model combining a U-Net architecture with a masked loss function was trained on standard noncontrast computed tomography images that were down sampled to 256 × 256 size. Data augmentation was applied to prevent overfitting, and the loss score was calculated using the soft Dice loss function. The Dice coefficient and the Hausdorff distance were computed to quantitatively evaluate the segmentation performance of the model, together with the sensitivity and specificity to determine the ICH detection accuracy. RESULTS: The results demonstrate a median Dice coefficient of 75.9% and Hausdorff distance of 2.65 pixels in segmentation performance, with a detection sensitivity of 77.0% and specificity of 96.2%. CONCLUSIONS: The proposed masked loss U-Net is accurate in the automatic segmentation of ICH. Future research should focus on increasing the detection sensitivity of the model and comparing its performance with other model architectures.

The OSE complotype and its clinical potential.

Cellular death, aging, and tissue damage trigger inflammation that leads to enzymatic and non-enzymatic lipid peroxidation of polyunsaturated fatty acids present on cellular membranes and lipoproteins. This results in the generation of highly reactive degradation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), that covalently modify free amino groups of proteins and lipids in their vicinity. These newly generated neoepitopes represent a unique set of damage-associated molecular patterns (DAMPs) associated with oxidative stress termed oxidation-specific epitopes (OSEs). OSEs are enriched on oxidized lipoproteins, microvesicles, and dying cells, and can trigger sterile inflammation. Therefore, prompt recognition and removal of OSEs is required to maintain the homeostatic balance. This is partially achieved by various humoral components of the innate immune system, such as natural IgM antibodies, pentraxins and complement components that not only bind OSEs but in some cases modulate their pro-inflammatory potential. Natural IgM antibodies are potent complement activators, and 30% of them recognize OSEs such as oxidized phosphocholine (OxPC-), 4-HNE-, and MDA-epitopes. Furthermore, OxPC-epitopes can bind the complement-activating pentraxin C-reactive protein, while MDA-epitopes are bound by C1q, C3a, complement factor H (CFH), and complement factor H-related proteins 1, 3, 5 (FHR-1, FHR-3, FHR-5). In addition, CFH and FHR-3 are recruited to 2-(ω-carboxyethyl)pyrrole (CEP), and full-length CFH also possesses the ability to attenuate 4-HNE-induced oxidative stress. Consequently, alterations in the innate humoral defense against OSEs predispose to the development of diseases associated with oxidative stress, as shown for the prototypical OSE, MDA-epitopes. In this mini-review, we focus on the mechanisms of the accumulation of OSEs, the pathophysiological consequences, and the interactions between different OSEs and complement components. Additionally, we will discuss the clinical potential of genetic variants in OSE-recognizing complement proteins - the OSE complotype - in the risk estimation of diseases associated with oxidative stress.

A Comprehensive Grading System for a Magnetic Sentinel Lymph Node Biopsy Procedure in Head and Neck Cancer Patients.

A magnetic sentinel lymph node biopsy ((SLN)B) procedure has recently been shown feasible in oral cancer patients. However, a grading system is absent for proper identification and classification, and thus for clinical reporting. Based on data from eight complete magnetic SLNB procedures, we propose a provisional grading system. This grading system includes: (1) a qualitative five-point grading scale for MRI evaluation to describe iron uptake by LNs; (2) an ex vivo count of resected SLN with a magnetic probe to quantify iron amount; and (3) a qualitative five-point grading scale for histopathologic examination of excised magnetic SLNs. Most SLNs with iron uptake were identified and detected in level II. In this level, most variance in grading was seen for MRI and histopathology; MRI and medullar sinus were especially highly graded, and cortical sinus was mainly low graded. On average 82 ± 58 µg iron accumulated in harvested SLNs, and there were no significant differences in injected tracer dose (22.4 mg or 11.2 mg iron). In conclusion, a first step was taken in defining a comprehensive grading system to gain more insight into the lymphatic draining system during a magnetic SLNB procedure.

Breast MRI in patients after breast conserving surgery with sentinel node procedure using a superparamagnetic tracer.

BACKGROUND: A procedure for sentinel lymph node biopsy (SLNB) using superparamagnetic iron-oxide (SPIO) nanoparticles and intraoperative sentinel lymph node (SLN) detection was developed to overcome drawbacks associated with the current standard-of-care SLNB. However, residual SPIO nanoparticles can result in void artefacts at follow-up magnetic resonance imaging (MRI) scans. We present a grading protocol to quantitatively assess the severity of these artefacts and offer an option to minimise the impact of SPIO nanoparticles on diagnostic imaging. METHODS: Follow-up mammography and MRI of two patient groups after a magnetic SLNB were included in the study. They received a 2-mL subareolar dose of SPIO (high-dose, HD) or a 0.1-mL intratumoural dose of SPIO (low-dose, LD). Follow-up mammography and MRI after magnetic SLNB were acquired within 4 years after breast conserving surgery (BCS). Two radiologists with over 10-year experience in breast imaging assessed the images and analysed the void artefacts and their impact on diagnostic follow-up. RESULTS: A total of 19 patients were included (HD, n = 13; LD, n = 6). In the HD group, 9/13 patients displayed an artefact on T1-weighted images up to 3.6 years after the procedure, while no impact of the SPIO remnants was observed in the LD group. CONCLUSIONS: SLNB using a 2-mL subareolar dose of magnetic tracer in patients undergoing BCS resulted in residual artefacts in the breast in the majority of patients, which may hamper follow-up MRI. This can be avoided by using a 0.1-mL intratumoural dose.

Advancing intraoperative magnetic tracing using 3D freehand magnetic particle imaging.

PURPOSE: Sentinel lymph node biopsy is a routine procedure for nodal staging in penile cancer. Most commonly, this procedure is guided by radioactive tracers, providing various forms of preoperative and intraoperative guidance. This is further extended with fluorescence imaging using hybrid radioactive-fluorescence tracers. Alternatively, a magnetic-based approach has become available using superparamagnetic iron-oxide nanoparticles (SPIONs). This study investigates a novel freehand magnetic particle imaging and navigation modality (fhMPI) for intraoperative localization, along with a hybrid approach, combining magnetic and fluorescence guidance. MATERIALS AND METHODS: The fhMPI set-up was built with a surgical navigation device, optical tracking system and magnetometer probe. A dedicated reconstruction software based on a look-up-table method was used to reconstruct a superficial 3D volume of the SPION distribution in tissue. For fluorescence guidance, indocyanine green (ICG) was added to the SPIONs. The fhMPI modality was characterized in phantoms, ex vivo human skin and in vivo porcine surgery. RESULTS: Phantom and human skin explants illustrated that the current fhMPI modality had a sensitivity of 2.2 × 10-2 mg/mL SPIONs, a resolving power of at least 7 mm and a depth penetration up to 1.5 cm. Evaluation during porcine surgery showed that fhMPI allowed for an augmented reality image overlay of the tracer distribution in tissue, as well as 3D virtual navigation. Besides, using the hybrid approach, fluorescence imaging provided a visual confirmation of localized nodes. CONCLUSION: fhMPI is feasible in vivo, providing 3D imaging and navigation for magnetic nanoparticles in the operating room, expanding the guidance possibilities during magnetic sentinel lymph node procedures. Furthermore, the integration of ICG provides the ability to visually refine and confirm correct localization. Further clinical evaluation should verify these findings in human patients as well.

Laparoscopic Probe for Sentinel Lymph Node Harvesting Using Magnetic Nanoparticles.

OBJECTIVE: Sentinel lymph node harvesting is an essential step in the surgical treatment of a growing number of malignancies. Various techniques are available to facilitate this purpose. The present study reports a new laparoscopic technique for lymph node harvesting using magnetic nanoparticles containing a superparamagnetic iron-oxide core and dextran coating. This study assesses the clinical relevance of the prototype and provides input for further technological development on the way to clinical implementation. METHODS: A laparoscopic differential magnetometer prototype was built, utilizing a nonlinear detection principle (differential magnetometry) for magnetic identification of lymph nodes. The iron content sensitivity, depth & spatial sensitivity, and angular sensitivity were analyzed to investigate clinical options. RESULTS: The minimum detectable amount of iron was 9.8 µg at a distance of 1 mm. The detection depth was 5, 8, and 10 mm for samples containing 126, 252, and 504 µg iron, respectively. The maximum lateral detection distance was 5, 7, and 8 mm for samples containing 126, 252, and 504 µg iron, respectively. A sample containing 504 µg iron was detectable at all angulations assessed (0°, 30°, 60° and 90°). CONCLUSION: The laparoscopic differential magnetometer demonstrates promising results for further investigation and development towards laparoscopic lymph node harvesting using magnetic nanoparticles. SIGNIFICANCE: The laparoscopic differential magnetometer facilitates a novel method for sentinel lymph node harvesting, which helps to determine prognosis and treatment of cancer patients.

Modelling of Dynamic Behaviour in Magnetic Nanoparticles.

The efficient development and utilisation of magnetic nanoparticles (MNPs) for applications in enhanced biosensing relies on the use of magnetisation dynamics, which are primarily governed by the time-dependent motion of the magnetisation due to externally applied magnetic fields. An accurate description of the physics involved is complex and not yet fully understood, especially in the frequency range where Néel and Brownian relaxation processes compete. However, even though it is well known that non-zero, non-static local fields significantly influence these magnetisation dynamics, the modelling of magnetic dynamics for MNPs often uses zero-field dynamics or a static Langevin approach. In this paper, we developed an approximation to model and evaluate its performance for MNPs exposed to a magnetic field with varying amplitude and frequency. This model was initially developed to predict superparamagnetic nanoparticle behaviour in differential magnetometry applications but it can also be applied to similar techniques such as magnetic particle imaging and frequency mixing. Our model was based upon the Fokker-Planck equations for the two relaxation mechanisms. The equations were solved through numerical approximation and they were then combined, while taking into account the particle size distribution and the respective anisotropy distribution. Our model was evaluated for Synomag®-D70, Synomag®-D50 and SHP-15, which resulted in an overall good agreement between measurement and simulation.

A complete magnetic sentinel lymph node biopsy procedure in oral cancer patients: A pilot study.

OBJECTIVES: To assess the feasibility and merits of a complete magnetic approach for a sentinel lymph node biopsy (SLNB) procedure in oral cancer patients. MATERIALS AND METHODS: This study included ten oral cancer patients (stage cT1-T2N0M0) scheduled for elective neck dissection (END). Superparamagnetic iron oxide nanoparticles (SPIO) were administered peritumorally prior to surgery. A preoperative MRI was acquired to identify lymph nodes (LNs) with iron uptake. A magnetic detector was used to identify magnetic hotspots prior, during, and after the SLNB procedure. The resected sentinel LNs (SLNs) were evaluated using step-serial sectioning, and the neck dissection specimen was assessed by routine histopathological examination. A postoperative MRI was acquired to observe any residual iron. RESULTS: Of ten primary tumors, eight were located in the tongue, one floor-of-mouth (FOM), and one tongue-FOM transition. SPIO injections were experienced as painful by nine patients, two of whom developed a tongue swelling. In eight patients, magnetic SLNs were successfully detected and excised during the magnetic SLNB procedure. During the END procedure, additional magnetic SLNs were identified in three patients. Histopathology confirmed iron deposits in sinuses of excised SLNs. Three SLNs were harboring metastases, of which one was identified only during the END procedure. The END specimens revealed no further metastases. CONCLUSION: A complete magnetic SLNB procedure was successfully performed in eight of ten patients (80% success rate), therefore the procedure seems feasible. Recommendations for further investigation are made including: use of anesthetics, magnetic tracer volume, planning preoperative MRI, comparison to conventional technique and follow-up.

Using MRI to quantify skeletal muscle pathology in Duchenne muscular dystrophy: A systematic mapping review.

There is a great demand for accurate non-invasive measures to better define the natural history of disease progression or treatment outcome in Duchenne muscular dystrophy (DMD) and to facilitate the inclusion of a large range of participants in DMD clinical trials. This review aims to investigate which MRI sequences and analysis methods have been used and to identify future needs. Medline, Embase, Scopus, Web of Science, Inspec, and Compendex databases were searched up to 2 November 2019, using keywords "magnetic resonance imaging" and "Duchenne muscular dystrophy." The review showed the trend of using T1w and T2w MRI images for semi-qualitative inspection of structural alterations of DMD muscle using a diversity of grading scales, with increasing use of T2map, Dixon, and MR spectroscopy (MRS). High-field (>3T) MRI dominated the studies with animal models. The quantitative MRI techniques have allowed a more precise estimation of local or generalized disease severity. Longitudinal studies assessing the effect of an intervention have also become more prominent, in both clinical and animal model subjects. Quality assessment of the included longitudinal studies was performed using the Newcastle-Ottawa Quality Assessment Scale adapted to comprise bias in selection, comparability, exposure, and outcome. Additional large clinical trials are needed to consolidate research using MRI as a biomarker in DMD and to validate findings against established gold standards. This future work should use a multiparametric and quantitative MRI acquisition protocol, assess the repeatability of measurements, and correlate findings to histologic parameters.

New Developments in Imaging for Sentinel Lymph Node Biopsy in Early-Stage Oral Cavity Squamous Cell Carcinoma.

Sentinel lymph node biopsy (SLNB) is a diagnostic staging procedure that aims to identify the first draining lymph node(s) from the primary tumor, the sentinel lymph nodes (SLN), as their histopathological status reflects the histopathological status of the rest of the nodal basin. The routine SLNB procedure consists of peritumoral injections with a technetium-99m [99mTc]-labelled radiotracer followed by lymphoscintigraphy and SPECT-CT imaging. Based on these imaging results, the identified SLNs are marked for surgical extirpation and are subjected to histopathological assessment. The routine SLNB procedure has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). However, an infamous limitation arises in situations where SLNs are located in close vicinity of the tracer injection site. In these cases, the hotspot of the injection site can hide adjacent SLNs and hamper the discrimination between tracer injection site and SLNs (shine-through phenomenon). Therefore, technical developments are needed to bring the diagnostic accuracy of SLNB for early-stage OSCC to a higher level. This review evaluates novel SLNB imaging techniques for early-stage OSCC: MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Furthermore, their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined.

MR Image-Based Attenuation Correction of Brain PET Imaging: Review of Literature on Machine Learning Approaches for Segmentation.

Recent emerging hybrid technology of positron emission tomography/magnetic resonance (PET/MR) imaging has generated a great need for an accurate MR image-based PET attenuation correction. MR image segmentation, as a robust and simple method for PET attenuation correction, has been clinically adopted in commercial PET/MR scanners. The general approach in this method is to segment the MR image into different tissue types, each assigned an attenuation constant as in an X-ray CT image. Machine learning techniques such as clustering, classification and deep networks are extensively used for brain MR image segmentation. However, only limited work has been reported on using deep learning in brain PET attenuation correction. In addition, there is a lack of clinical evaluation of machine learning methods in this application. The aim of this review is to study the use of machine learning methods for MR image segmentation and its application in attenuation correction for PET brain imaging. Furthermore, challenges and future opportunities in MR image-based PET attenuation correction are discussed.

Thoughts and expectations of young professionals about the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).

Objectives: Young laboratory medicine professionals (YLMPs) are the future of clinical laboratories. Although everyday practice shows significant differences among countries, especially during residency training, most of them face the same challenges. Besides promoting scientific, professional and clinical aspects of laboratory medicine in Europe, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) should take into consideration YLMPs' concerns and interests to help them achieve excellence. The aim of this survey was to assess the opinion and expectations of YLMPs about their involvement in the activities of EFLM. Methods: An online survey was distributed to YLMPs in Europe through different channels. The questionnaire consisted of 21 items grouped into five sections: demographic questions, opinion about the current status of YLMPs within EFLM, YLMPs network, suggestions and opportunities, and scientific training and exchange. Where appropriate, responses from residents and specialists were compared. Results: A total of 329 valid responses were obtained from 53 different countries. Countries with the highest number of participants were Spain, Turkey, Croatia and Romania. A significant percentage would like to know more about EFLM and their activities (86%) and wish EFLM promoted networking and scientific exchanges (95%), for instance by means of a European YLMPs network (93%). EFLMLabX project was widely unknown (75%). Conclusions: YLMPs demand better connection to share concerns about daily healthcare duties, to keep updated and to advance professionally. EFLM needs to improve their advertising through national societies to increase YLMPs' participation. In addition to international meetings and congresses, respondents have emphasized that workshops and other small group activities would significantly help promote laboratory medicine practice in Europe.

A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes.

Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.

Predicting long-term type 2 diabetes with support vector machine using oral glucose tolerance test.

Diabetes is a large healthcare burden worldwide. There is substantial evidence that lifestyle modifications and drug intervention can prevent diabetes, therefore, an early identification of high risk individuals is important to design targeted prevention strategies. In this paper, we present an automatic tool that uses machine learning techniques to predict the development of type 2 diabetes mellitus (T2DM). Data generated from an oral glucose tolerance test (OGTT) was used to develop a predictive model based on the support vector machine (SVM). We trained and validated the models using the OGTT and demographic data of 1,492 healthy individuals collected during the San Antonio Heart Study. This study collected plasma glucose and insulin concentrations before glucose intake and at three time-points thereafter (30, 60 and 120 min). Furthermore, personal information such as age, ethnicity and body-mass index was also a part of the data-set. Using 11 OGTT measurements, we have deduced 61 features, which are then assigned a rank and the top ten features are shortlisted using minimum redundancy maximum relevance feature selection algorithm. All possible combinations of the 10 best ranked features were used to generate SVM based prediction models. This research shows that an individual's plasma glucose levels, and the information derived therefrom have the strongest predictive performance for the future development of T2DM. Significantly, insulin and demographic features do not provide additional performance improvement for diabetes prediction. The results of this work identify the parsimonious clinical data needed to be collected for an efficient prediction of T2DM. Our approach shows an average accuracy of 96.80% and a sensitivity of 80.09% obtained on a holdout set.

Muscle percentage index as a marker of disease severity in golden retriever muscular dystrophy.

INTRODUCTION: Golden retriever muscular dystrophy (GRMD) is a spontaneous X-linked canine model of Duchenne muscular dystrophy that resembles the human condition. Muscle percentage index (MPI) is proposed as an imaging biomarker of disease severity in GRMD. METHODS: To assess MPI, we used MRI data acquired from nine GRMD samples using a 4.7 T small-bore scanner. A machine learning approach was used with eight raw quantitative mapping of MRI data images (T1m, T2m, two Dixon maps, and four diffusion tensor imaging maps), three types of texture descriptors (local binary pattern, gray-level co-occurrence matrix, gray-level run-length matrix), and a gradient descriptor (histogram of oriented gradients). RESULTS: The confusion matrix, averaged over all samples, showed 93.5% of muscle pixels classified correctly. The classification, optimized in a leave-one-out cross-validation, provided an average accuracy of 80% with a discrepancy in overestimation for young (8%) and old (20%) dogs. DISCUSSION: MPI could be useful for quantifying GRMD severity, but careful interpretation is needed for severe cases.