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BACKGROUND: Clinical trials for upcoming disease-modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes. OBJECTIVES: READISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations. METHODS: A total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3-T MR scanning at baseline and a median [interquartile range] follow-up of 6.2 [5.9-6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6-month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate. RESULTS: Rate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls (P < 0.005), with high effect sizes (Cohen's d = 1-2) and moderate-to-high responsiveness (|standardized response mean| = 0.6-0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups. CONCLUSIONS: Diffusion MRI is sensitive to disease progression at very early-stage SCA1 and SCA3 and may provide a >5-fold reduction in sample sizes relative to SARA as endpoint for 6-month-long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Self-powered neutron detectors (SPNDs) have been utilized within in-core instrumentation to measure neutron flux for control and core flux mapping in nuclear reactors. To estimate neutron flux with SPNDs, a mathematical dynamic model correlating neutron flux and SPND material has been established. Estimation and signal compensation for neutron flux have primarily been developed using transfer-function-based methods or state-space-based methods. Particularly for the rhodium SPND, to compensate for its delayed response to incident neutron flux input, both groups of compensation methods have been widely applied. This Review details the signal compensation methods of neutron flux using transfer-function-based methods, such as those employing analog circuits, dynamic modeling of neutron flux, compensation of neutron flux, and direct inversion. In addition, signal compensation and estimation of neutron flux using state-space-based methods, such as the Kalman filter and H-infinity filter, are reviewed, along with basic calculations based on certain assumptions. Since there are differences in the characteristics of the two groups of methods for the same type of SPND, review comments are also included regarding the stability of compensation methods, based on results obtained from calculations using certain assumptions.
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PURPOSE: Localized shimming in single-voxel MRS often results in large B0 inhomogeneity outside the volume-of-interest. This causes unacceptable degradation in motion navigator images. Switching back and forth between whole-brain shim and localized shim is possible for linear shims, but not for higher-order shims. Here we propose motion navigators largely insensitive to B0 inhomogeneity for prospective motion-corrected MRS with localized higher-order shimming. METHODS: A recent fast high-resolution motion navigator based on spiral-in/out k-space trajectories and multislice-to-volume registration was modified by splitting the readout into multiple shot interleaves which shortened the echo time and reduced the effect of B0 inhomogeneity. The performance of motion correction was assessed in healthy subjects in the prefrontal cortex using a sLASER sequence at 3T (N = 5) and 7T (N = 5). RESULTS: With multiple spatial interleaves, excellent quality navigator images were acquired in the whole brain in spite of large B0 inhomogeneity outside the MRS voxel. The total duration of the navigator in sLASER remained relatively short even with multiple shots (3T: 10 spatial interleaves 94 ms per slice; 7T: 15 spatial interleaves 103 ms per slice). Prospective motion correction using the multi-shot navigators yielded comparable spectral quality (water linewidth and metabolite SNR) with and without subject motion. CONCLUSION: B0-insensitive motion navigators enable prospective motion correction for MRS with all first- and second-order shims adjusted in the MRS voxel, providing optimal spectral linewidth.
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Algoritmos , Movimiento (Física) , Humanos , Espectroscopía de Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Artefactos , Masculino , Adulto , Femenino , Reproducibilidad de los Resultados , Corteza Prefrontal/diagnóstico por imagen , Sensibilidad y EspecificidadRESUMEN
RATIONALE: Guide wire aspiration during central venous catheter (CVC) insertion in a patient on extracorporeal membrane oxygenation (ECMO) is a very rare but dangerous complication. A guide wire aspirated inside the ECMO can cause thrombosis, the ECMO to break down or shut off, and unnecessary ECMO replacement. PATIENT CONCERNS: A 58-year-old man was scheduled for venovenous ECMO for acute respiratory distress syndrome. After his vital signs stabilized, we inserted a CVC. During CVC insertion, the guide wire was aspirated into the ECMO venous line. INTERVENTION: After confirming the guide wire inside the ECMO venous line, we replaced the entire ECMO circuit. OUTCOMES: ECMO was maintained for 57 days, and weaning was successful but the patient died 5 days afterward. LESSONS: Care must be taken when inserting a CVC using a guide wire in ECMO patients: the guide wire should not be inserted deeply, it should be secured during insertion, the ECMO venous cannula tip requires proper positioning, and ECMO flow should be temporarily reduced.
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Catéteres Venosos Centrales , Oxigenación por Membrana Extracorpórea , Síndrome de Dificultad Respiratoria , Masculino , Humanos , Persona de Mediana Edad , Cateterismo , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/terapia , Aspiración RespiratoriaRESUMEN
Objective: Several lines of evidence indicate verbal abuse (VA) critically impacts the developing brain; however, whether VA results in changes in brain neurochemistry has not been established. Here, we hypothesized that exposure to recurrent parental VA elicits heightened glutamate (Glu) responses during the presentation of swear words, which can be measured with functional magnetic resonance spectroscopy (fMRS). Methods: During an emotional Stroop task consisting of blocks of color and swear words, metabolite concentration changes were measured in the ventromedial prefrontal cortex (vmPFC) and the left amygdalohippocampal region (AMHC) of healthy adults (14 F/27 M, 23 ± 4 years old) using fMRS. The dynamic changes in Glu and their associations with the emotional state of the participants were finally evaluated based on 36 datasets from the vmPFC and 30 from the AMHC. Results: A repeated-measures analysis of covariance revealed a modest effect of parental VA severity on Glu changes in the vmPFC. The total score on the Verbal Abuse Questionnaire by parents (pVAQ) was associated with the Glu response to swear words (ΔGluSwe). The interaction term of ΔGluSwe and baseline N-acetyl aspartate (NAA) level in the vmPFC could be used to predict state-trait anxiety level and depressive mood. We could not find any significant associations between ΔGluSwe in the AMHC and either pVAQ or emotional states. Conclusion: Parental VA exposure in individuals is associated with a greater Glu response towards VA-related stimuli in the vmPFC and that the accompanying low NAA level may be associated with anxiety level or depressive mood.
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As online news increasingly include data journalism, there is a corresponding increase in the incorporation of visualization in article thumbnail images. However, little research exists on the design rationale for visualization thumbnails, such as resizing, cropping, simplifying, and embellishing charts that appear within the body of the associated article. Therefore, in this paper we aim to understand these design choices and determine what makes a visualization thumbnail inviting and interpretable. To this end, we first survey visualization thumbnails collected online and discuss visualization thumbnail practices with data journalists and news graphics designers. Based on the survey and discussion results, we then define a design space for visualization thumbnails and conduct a user study with four types of visualization thumbnails derived from the design space. The study results indicate that different chart components play different roles in attracting reader attention and enhancing reader understandability of the visualization thumbnails. We also find various thumbnail design strategies for effectively combining the charts' components, such as a data summary with highlights and data labels, and a visual legend with text labels and Human Recognizable Objects (HROs), into thumbnails. Ultimately, we distill our findings into design implications that allow effective visualization thumbnail designs for data-rich news articles. Our work can thus be seen as a first step toward providing structured guidance on how to design compelling thumbnails for data stories.
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Fístula Arteriovenosa , Procedimientos Endovasculares , Insuficiencia Cardíaca , Humanos , Fístula Arteriovenosa/diagnóstico , Fístula Arteriovenosa/etiología , Fístula Arteriovenosa/cirugía , Stents , Procedimientos Endovasculares/efectos adversos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiologíaRESUMEN
OBJECTIVE: To predict the recurrence of non-small cell lung cancer (NSCLC) within 2 years after curative-intent treatment using a machine-learning approach with PET/CT-based radiomics. PATIENTS AND METHODS: A total of 77 NSCLC patients who underwent pretreatment 18 F-fluorodeoxyglucose PET/CT were retrospectively analyzed. Five clinical features (age, sex, tumor stage, tumor histology, and smoking status) and 48 radiomic features extracted from primary tumors on PET were used for binary classifications. These were ranked, and a subset of useful features was selected based on Gini coefficient scores in terms of associations with relapsed status. Areas under the receiver operating characteristics curves (AUC) were yielded by six machine-learning algorithms (support vector machine, random forest, neural network, naive Bayes, logistic regression, and gradient boosting). Model performances were compared and validated via random sampling. RESULTS: A PET/CT-based radiomic model was developed and validated for predicting the recurrence of NSCLC during the first 2 years after curation. The most important features were SD and variance of standardized uptake value, followed by low-intensity short-zone emphasis and high-intensity zone emphasis. The naive Bayes model with the 15 best-ranked features displayed the best performance (AUC: 0.816). Prediction models using the five best PET-derived features outperformed those using five clinical variables. CONCLUSION: The machine learning model using PET-derived radiomic features showed good performance for predicting the recurrence of NSCLC during the first 2 years after a curative intent therapy. PET/CT-based radiomic features may help clinicians improve the risk stratification of relapsed NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Teorema de Bayes , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Fluorodesoxiglucosa F18 , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Aprendizaje Automático , Recurrencia Local de Neoplasia/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Estudios RetrospectivosRESUMEN
OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.
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[This corrects the article DOI: 10.3389/fneur.2020.00411.].
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The innominate artery is an uncommon site for an aneurysm, and tracheal compression caused by an innominate artery aneurysm is a very rare occurrence. An innominate artery aneurysm can cause catastrophic complications, such as rupture or thromboembolism. The most common surgical approach for open repair is median sternotomy with cardiopulmonary bypass, but cerebral ischemic injury and thromboembolism can occur during surgery. We present the case of a male patient who had an isolated giant innominate artery aneurysm causing tracheal compression, which was successfully managed by surgical repair.
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Eddy-current sensors are widely used for precise displacement sensing and non-destructive testing. Application of printed-circuit board (PCB) technology for manufacturing sensor coils may reduce the cost of the sensor and enhance the performance by ensuring consistency. However, these prospects depend on the uniformness of the sensor coil. Inductance measurements of sample coils reveal rather considerable variations. In this paper, we investigate the sources of these variations. Through image analysis of cut-away cross-sections of sensor coils, four factors that contribute to the inductance variations are identified: the distance between layers, the distance between tracings, cross-sectional areas, and misalignment among layers. By using and extending existing method of calculating inductance of spiral coils, the inductance distributions are obtained when these factors are randomly varied. A sensitivity analysis shows that the inductance uncertainty is most affected by the uniformness of the spacings between coil traces and the distances between layers. Improvements in PCB manufacturing process can help to reduce the uncertainty in inductance.
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The transcriptional repressor Rex plays important roles in regulating the expression of respiratory genes by sensing the reduction-oxidation (redox) state according to the intracellular NAD+/NADH balance. Previously, we reported on crystal structures of apo, NAD+-bound, and NADH-bound forms of Rex from Thermotoga maritima to analyze the structural basis of transcriptional regulation depending on either NAD+ or NADH binding. In this study, the crystal structure of Rex in ternary complex with NAD+ and operator DNA revealed that the N-terminal domain of Rex, including the helix-turn-helix motif, forms extensive contacts with DNA in addition to DNA sequence specificity. Structural comparison of the Rex in apo, NAD+-bound, NADH-bound, and ternary complex forms provides a comprehensive picture of transcriptional regulation in the Rex. These data demonstrate that the conformational change in Rex when binding with the reduced NADH or oxidized NAD+ determines operator DNA binding. The movement of the N-terminal domains toward the operator DNA was blocked upon binding of NADH ligand molecules. The structural results provide insights into the molecular mechanism of Rex binding with operator DNA and cofactor NAD+/NADH, which is conserved among Rex family repressors. Structural analysis of Rex from T. maritima also supports the previous hypothesis about the NAD+/NADH-specific transcriptional regulation mechanism of Rex homologues.
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ADN Bacteriano/metabolismo , NAD/metabolismo , Proteínas Represoras/metabolismo , Thermotoga maritima/metabolismo , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Modelos Moleculares , Oxidación-Reducción , Unión Proteica , Conformación Proteica , Dominios Proteicos , Thermotoga maritima/química , Thermotoga maritima/genéticaRESUMEN
Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aß) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aß, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones/métodos , Proteínas tau/metabolismoRESUMEN
PURPOSE: Advanced MRS protocols improve data quality and reproducibility relative to vendor-provided protocols; however, they are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high-quality spectroscopic data without local MRS expertise. METHODS: First, a B0 shimming protocol was selected for automation by comparing 3 widely used B0 algorithms (2 vendor protocols and FAST(EST)MAP). Next, voxel-based B0 and B1 calibrations were incorporated into the consensus-recommended semi-LASER sequence and combined with an automated VOI prescription tool, a recently developed method for automated voxel prescription. The efficiency of collecting single-voxel data from a clinical cohort (N = 40) with the automated protocol (calibration time and fraction of usable datasets) was compared with the nonautomated semi-LASER protocol (N = 35) whereby all prescan calibrations were executed manually in the academic hospital setting with rotating MR technologists in the neuroradiology unit. RESULTS: A multi-iteration FAST(EST)MAP protocol resulted in narrower water linewidths than vendor's B0 shim protocols for data acquired from 6 brain locations (p < 1e-5) and was selected for automation. The automated B0 and B1 calibrations resulted in a time saving of ~4.5 minutes per voxel relative to the same advanced protocol executed manually. All spectra acquired with the automated protocol were usable, whereas only 86% of those collected with the manual protocol were usable and spectral quality was more variable. CONCLUSION: The plug-and-play advanced MRS protocol allows automated acquisition of high-quality MRS data with high success rate and consistency on a clinical 3T platform.
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Encéfalo , Imagen por Resonancia Magnética , Algoritmos , Encéfalo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Reproducibilidad de los ResultadosRESUMEN
RATIONALE: Necrotizing sarcoid granulomatosis (NSG) has recently been termed "sarcoidosis with NSG pattern" for the disease entity representing nodular sarcoidosis with granulomatous pulmonary angiitis. It is characterized by sarcoid-like granulomas, vasculitis, and a variable degree of necrosis. Its rarity and nonspecific clinical symptoms can easily lead to misdiagnosis or delayed diagnosis. PATIENT CONCERNS: We report a 67-year-old female with a biopsy-confirmed sarcoidosis with NSG pattern mimicking pulmonary malignancy on initial chest computed tomography scan. DIAGNOSES: Sarcoidosis with NSG pattern. INTERVENTIONS: The patient underwent video-assisted thoracoscopic surgery with a lung biopsy. No further treatment was performed after the lung biopsy. OUTCOMES: Follow-up imaging studies revealed spontaneous regression of the disease after 2 months. LESSONS: Awareness of this rare benign disease entity and overlapping radiologic manifestations with pulmonary malignancy or other granulomatous diseases can be helpful for making a precise diagnosis with a better differential diagnosis.
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Pulmón/diagnóstico por imagen , Sarcoidosis Pulmonar/diagnóstico , Vasculitis del Sistema Nervioso Central/diagnóstico , Anciano , Femenino , Granuloma/diagnóstico , Humanos , Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Necrosis , Tomografía Computarizada por Tomografía de Emisión de Positrones , Enfermedades Raras , Sarcoidosis Pulmonar/cirugía , Cirugía Torácica Asistida por Video , Vasculitis del Sistema Nervioso Central/cirugíaRESUMEN
BACKGROUND: It is difficult to find a reliable outflow vein for vascular access in hemodialysis patients with bilateral central venous obstruction. The lower extremity veins are currently used as the most common alternative veins to make a new vascular access. However, in patients not amenable to make lower extremity access, intrathoracic vein should be considered as an outflow vein, but there are limitations in its use due to postoperative complications. METHODS: We introduce a series of cases that underwent arteriovenous graft operation using an intrathoracic vein, the azygos arch, as an outflow vein. Brachio-azygos transthoracic arteriovenous graft is a surgical procedure that anastomoses the azygos arch and the brachial artery with 7 mm ringed polytetrafluoroethylene graft via lateral thoracotomy without median sternotomy. RESULTS: The chest tubes of the patients were removed on the third postoperative day and they discharged within a week. About 1 month later, hemodialysis was initiated through the BATAVG, and it has been used without access dysfunction. CONCLUSION: Brachio-azygos transthoracic arteriovenous grafts were performed using the azygos arches without major complications. The azygos arch can be a good alternative outflow vein to make a new vascular access for hemodialysis patients with bilateral central venous obstruction.
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For human head magnetic resonance imaging at 10.5 tesla (T), we built an 8-channel transceiver dipole antenna array and evaluated the influence of coaxial feed cables. The influence of coaxial feed cables was evaluated in simulation and compared against a physically constructed array in terms of transmit magnetic field (B1+) and specific absorption rate (SAR) efficiency. A substantial drop (23.1% in simulation and 20.7% in experiment) in B1+ efficiency was observed with a tight coaxial feed cable setup. For the investigation of the feed location, the center-fed dipole antenna array was compared to two 8-channel end-fed arrays: monopole and sleeve antenna arrays. The simulation results with a phantom indicate that these arrays achieved ~24% higher SAR efficiency compared to the dipole antenna array. For a human head model, we observed 30.8% lower SAR efficiency with the 8-channel monopole antenna array compared to the phantom. Importantly, our simulation with the human model indicates that the sleeve antenna arrays can achieve 23.8% and 21% higher SAR efficiency compared to the dipole and monopole antenna arrays, respectively. Finally, we obtained high-resolution human cadaver images at 10.5 T with the 8-channel sleeve antenna array.
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Cabeza , Imagen por Resonancia Magnética , Simulación por Computador , Diseño de Equipo , Cabeza/diagnóstico por imagen , Humanos , Fantasmas de ImagenRESUMEN
The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) are thought to be involved in the response of the brain to changes in glycemia. Therefore, their reliable measurement is critical for understanding the dynamics of these responses. The concentrations of Glu and GABA, as well as glucose (Glc) in brain tissue, can be measured in vivo using proton (1H) magnetic resonance spectroscopy (MRS). Advanced MRS methodology at ultrahigh field allows reliable monitoring of these metabolites under changing metabolic states. However, the long acquisition times needed for these experiments while maintaining blood Glc levels at predetermined targets present many challenges. We present an advanced MRS acquisition protocol that combines commercial 7T hardware (Siemens Scanner and Nova Medical head coil), BaTiO3 dielectric padding, optical motion tracking, and dynamic frequency and B0 shim updates to ensure the acquisition of reproducibly high-quality data. Data were acquired with a semi-LASER sequence [repetition time/echo time (TR/TE) = 5,000/26 ms] from volumes of interest (VOIs) in the prefrontal cortex (PFC) and hypothalamus (HTL). Five healthy volunteers were scanned to evaluate the effect of the BaTiO3 pads on B 1 + distribution. Use of BaTiO3 padding resulted in a 60% gain in signal-to-noise ratio in the PFC VOI over the acquisition without the pad. The protocol was tested in six patients with type 1 diabetes during a clamp study where euglycemic (~100 mg/dL) and hypoglycemic (~50 mg/dL) blood Glc levels were maintained in the scanner. The new protocol allowed retention of all HTL data compared with our prior experience of having to exclude approximately half of the HTL data in similar clamp experiments in the 7T scanner due to subject motion. The advanced MRS protocol showed excellent data quality (reliable quantification of 11-12 metabolites) and stability (p > 0.05 for both signal-to-noise ratio and water linewidths) between euglycemia and hypoglycemia. Decreased brain Glc levels under hypoglycemia were reliably detected in both VOIs. In addition, mean Glu level trended lower at hypoglycemia than euglycemia for both VOIs, consistent with prior observations in the occipital cortex. This protocol will allow robust mechanistic investigations of the primary neurotransmitters, Glu and GABA, under changing glycemic conditions.
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The prevalence of non-suicidal self-injury (NSSI) is high in adolescents and young adults. However, there is a paucity of evidence-based treatments to address this clinical problem. An open-label, pilot study in the target population showed that treatment with oral N-acetylcysteine (NAC), a widely available dietary supplement, was associated with reduction in NSSI frequency. In preparation for a biologically informed design of an efficacy trial, a critical preliminary step is to clarify NAC's biological signatures, or measures of the mechanisms underlying its clinical effects. Toward that end, we propose a 2-stage project to investigate NAC's biological signatures (changes in glutathione (GSH) and/or glutamate (Glu)) in women with NSSI. The first stage; a double-blind randomized placebo-controlled study will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term (4 weeks) NAC treatment in 36 women aged 16-24 years with NSSI. Go/No-go criteria to determine if the study will progress to the second stage include pre-specified changes in brain and blood measures of GSH. Changes in the brain GSH are measured through magnetic resonance spectroscopy (MRS). The dose for the stage 2 will be selected based on the biological changes and the tolerability observed in the stage 1. The stage 2 will seek to replicate the biological signature findings in an 8-week trial in a new patient cohort, and examine the relationships among biological signatures, NAC pharmacokinetics and clinical response. This 2-stage project is unique as it unifies clinical psychiatric measurements, quantitative MRS and pharmacological approaches in the first placebo-controlled clinical trial of NAC in young women with NSSI. TRIAL REGISTRATION: The stage 1 trial protocol has been registered on https://clinicaltrials.gov/ with ClinicalTrials.gov ID "NCT04005053" (Registered on 02 July 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04005053).