Reproducibility Made Easy: A Tool for Methodological Transparency and Efficient Standardized Reporting based on the proposed MRSinMRS Consensus.

Purpose: Recent expert consensus publications have highlighted the issue of poor reproducibility in magnetic resonance spectroscopy (MRS) studies, mainly due to the lack of standardized reporting criteria, which affects their clinical applicability. To combat this, guidelines for minimum reporting standards (MRSinMRS) were introduced to aid journal editors and reviewers in ensuring the comprehensive documentation of essential MRS study parameters. Despite these efforts, the implementation of MRSinMRS standards has been slow, attributed to the diverse nomenclature used by different vendors, the variety of raw MRS data formats, and the absence of appropriate software tools for identifying and reporting necessary parameters. To overcome this obstacle, we have developed the REproducibility Made Easy (REMY) standalone toolbox. Methods: REMY software supports a range of MRS data formats from major vendors like GE (p. file), Siemens (.twix, .rda, .dcm), Philips (.spar/.sdat), and Bruker (.method), facilitating easy data import and export through a user-friendly interface. REMY employs external libraries such as spec2nii and pymapVBVD to accurately read and process these diverse data formats, ensuring compatibility and ease of use for researchers in generating reproducible MRS research outputs. Users can select and import datasets, choose the appropriate vendor and data format, and then generate an MRSinMRS table, log file, and methodological documents in both Latex and PDF formats. Results: REMY effectively populated key sections of the MRSinMRS table with data from all supported file types. In the hardware section, it successfully read and filled in fields for Field Strength [T], Manufacturer Name, and Software Version, covering three of the five required hardware fields. However, it could not input data for RF coil and additional hardware information due to their absence in the files. For the acquisition section, REMY accurately read and populated fields for the pulse sequence name, nominal voxel size, repetition time, echo time, number of acquisitions/excitations/shots, spectral width [Hz], and number of spectral points, significantly contributing to the completion of the Acquisition fields of the table. Furthermore, REMY generates a boilerplate methods text section for manuscripts. Conclusion: This approach reduces effort and obstacles associated with writing and reporting acquisition parameters and should lead to the widespread adoption of MRSinMRS within the MRS community.

Test-Retest Reproducibility of Reduced-Field-of-View Density-Weighted CRT MRSI at 3T.

Quantifying an imaging modality's ability to reproduce results is important for establishing its utility. In magnetic resonance spectroscopic imaging (MRSI), new acquisition protocols are regularly introduced which improve upon their precursors with respect to signal-to-noise ratio (SNR), total acquisition duration, and nominal voxel resolution. This study has quantified the within-subject and between-subject reproducibility of one such new protocol (reduced-field-of-view density-weighted concentric ring trajectory (rFOV-DW-CRT) MRSI) by calculating the coefficient of variance of data acquired from a test-retest experiment. The posterior cingulate cortex (PCC) and the right superior corona radiata (SCR) were selected as the regions of interest (ROIs) for grey matter (GM) and white matter (WM), respectively. CVs for between-subject and within-subject were consistently around or below 15% for Glx, tCho, and Myo-Ins, and below 5% for tNAA and tCr.

Stretchable receive coil for 7T small animal MRI.

Receive coils used in small animal MRI are rigid, inflexible surface loops that do not conform to the anatomy being imaged. The recent trend toward design of stretchable coils that are tailored to fit any anatomical curvature has been focused on human imaging. This work demonstrates the application of stretchable coils for small animal imaging at 7T. A stretchable coil measuring 3.5 × 3.5 cm was developed for acquisition of rat brain and spine images. The SNR maps of the stretchable coil were compared with those of a traditional flexible PCB coil and a commercial surface coil. Stretch and conformance testing of the coil was performed. Ex vivo images of rat brain and spine from the stretchable a coil was acquired using T1 FLASH and T2 Turbo RARE sequences. The axial phantom SNR maps showed that the stretchable coil provided 48.5% and 42.8% higher SNR than the commercial coil for T1-w and T2-w images within the defined ROI. A 33% increase in average penetration depth was observed within the ROI using the stretchable coil when compared to the commercial coil. The ex-vivo rat brain and spine images showed distinguishable anatomical details. Stretching the coil reduced the resonant frequency with reduction in SNR, while the conformance to varying sample volumes increased the resonant frequency with decreased SNR. This study also features an open-source plug-and-play system with preamplifiers that can be used to interface surface coils with the 7T Bruker scanner.

High-resolution 3D ultra-short echo time MRI with Rosette k-space pattern for brain iron content mapping.

BACKGROUND: The iron concentration increases during normal brain development and is identified as a risk factor for many neurodegenerative diseases, it is vital to monitor iron content in the brain non-invasively. PURPOSE: This study aimed to quantify in vivo brain iron concentration with a 3D rosette-based ultra-short echo time (UTE) magnetic resonance imaging (MRI) sequence. METHODS: A cylindrical phantom containing nine vials of different iron concentrations (iron (II) chloride) from 0.5 millimoles to 50 millimoles and six healthy subjects were scanned using 3D high-resolution (0.94 ×0.94 ×0.94 mm3) rosette UTE sequence at an echo time (TE) of 20 µs. RESULTS: Iron-related hyperintense signals (i.e., positive contrast) were detected based on the phantom scan, and were used to establish an association between iron concentration and signal intensity. The signal intensities from in vivo scans were then converted to iron concentrations based on the association. The deep brain structures, such as the substantia nigra, putamen, and globus pallidus, were highlighted after the conversion, which indicated potential iron accumulations. CONCLUSION: This study suggested that T1-weighted signal intensity could be used for brain iron mapping.

American Football Position-Specific Neurometabolic Changes in High School Athletes: A Magnetic Resonance Spectroscopic Study.

Reports estimate between 1.6-3.8 million sports-related concussions occur annually, with 30% occurring in youth male American football athletes. Many studies report neurophysiological changes in these athletes, but the exact reasons for these changes remain elusive. Investigation of injury mechanics highlights a need to address how player position might impact these changes. Here, 55 high school American football athletes (20 linemen; 35 non-linemen) underwent magnetic resonance spectroscopy four times over the course of a football season-once prior to the season (Pre), twice during (In1, In2), and once following (Post) to quantify metabolites (N-acetyl aspartate, choline, creatine, myo-inositol, and glutamate/glutamine) in the dorsolateral prefrontal cortex (DLPFC) and primary motor cortex (M1). Head acceleration events (HAEs) were monitored at each practice and game. Spectroscopic and HAE data were analyzed by imaging session and player position. Linear regression analyses were conducted between metabolite levels and HAEs, and metabolite levels in football athletes were compared with age-and gender-matched non-contact athletes. Across-season (i.e., between Pre and In1, In2, Post), different DLPFC and M1 metabolites decreased (p < 0.05) according to player position (i.e., linemen vs. non-linemen). The majority of regression results involved DLPFC metabolites in linemen, where metabolite levels were higher from Pre to Post, with increasing HAE load. Comparisons with control athletes revealed higher metabolite levels in football athletes both before and after the season. This study highlights the importance of player position when conducting analyses on American football athletes and demonstrates elevated DLPFC and M1 brain metabolites in football athletes compared with control athletes at both Pre and Post, suggesting potential HAE-related neurocompensatory mechanisms.

Carbon fiber reinforced polymers for implantable medical devices.

Carbon fibers reinforced polymers (CFRPs) are prolifically finding applications in the medical field, moving beyond the aerospace and automotive industries. Owing to its high strength-to-weight ratio, lightness and radiolucency, CFRP-based materials are emerging to replace traditional metal-based medical implants. Numerous types of polymers matrices can be incorporated with carbon fiber using various manufacturing methods, creating composites with distinct properties. Thus, prior to biomedical application, comprehensive evaluation of material properties, biocompatibility and safety are of paramount importance. In this study, we systematically evaluated a series of novel CFRPs, aiming at analyzing biocompatibility for future development into medical implants or implantable drug delivery systems. These CFRPs were produced either via Carbon Fiber-Sheet Molding Compound or Fused Deposition Modelling-based additive manufacturing. Unlike conventional methods, both fabrication processes afford high production rates in a time-and cost-effective manner. Importantly, they offer rapid prototyping and customization in view of personalized medical devices. Here, we investigate the physicochemical and surface properties, material mutagenicity or cytotoxicity of 20 CFRPs, inclusive of 2 surface finishes, as well as acute and sub-chronic toxicity in mice and rabbits, respectively. We demonstrate that despite moderate in vitro physicochemical and surface changes over time, most of the CFRPs were non-mutagenic and non-cytotoxic, as well as biocompatible in small animal models. Future work will entail extensive material assessment in the context of orthopedic applications such as evaluating potential for osseointegration, and a chronic toxicity study in a larger animal model, pigs.

Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1.

PURPOSE: Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. METHODS AND MATERIALS: We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. RESULTS: The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden. CONCLUSIONS: Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.

Nanofluidic microsystem for sustained intraocular delivery of therapeutics.

Globally, 145.2 million people suffer from moderate to severe vision impairment or blindness due to preventable or treatable causes. However, patient adherence to topical or intravitreal treatment is a leading cause of poor outcomes. To address this issue, we designed an intraocularly implantable device called the nanofluidic Vitreal System for Therapeutic Administration (nViSTA) for continuous and controlled drug release based on a nanochannel membrane that obviates the need for pumps or actuation. In vitro release analysis demonstrated that our device achieves sustained release of bimatoprost (BIM) and dexamethasone (DEX) at concentrations within clinically relevant therapeutic window. In this proof of concept study, we constructed an anatomically similar in silico human eye model to simulate DEX release from our implant and gain insight into intraocular pharmacokinetics profile. Overall, our drug-agnostic intraocular implant represents a potentially viable platform for long-term treatment of various chronic ophthalmologic diseases, including diabetic macular edema and uveitis.

Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.

Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer.

Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit efficient anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for injections or clinician intervention. In this study, the NDES was used to deliver immunotherapeutics intratumorally in the 4 T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors.