Comparison between R2'-based and R2*-based χ-separation methods: A clinical evaluation in individuals with multiple sclerosis.

Susceptibility source separation, or χ-separation, estimates diamagnetic (χdia) and paramagnetic susceptibility (χpara) signals in the brain using local field and R2' (= R2* - R2) maps. Recently proposed R2*-based χ-separation methods allow for χ-separation using only multi-echo gradient echo (ME-GRE) data, eliminating the need for additional data acquisition for R2 mapping. Although this approach reduces scan time and enhances clinical utility, the impact of missing R2 information remains a subject of exploration. In this study, we evaluate the viability of two previously proposed R2*-based χ-separation methods as alternatives to their R2'-based counterparts: model-based R2*-χ-separation versus χ-separation and deep learning-based χ-sepnet-R2* versus χ-sepnet-R2'. Their performances are assessed in individuals with multiple sclerosis (MS), comparing them with their corresponding R2'-based counterparts (i.e., R2*-χ-separation vs. χ-separation and χ-sepnet-R2* vs. χ-sepnet-R2'). The evaluations encompass qualitative visual assessments by experienced neuroradiologists and quantitative analyses, including region of interest analyses and linear regression analyses. Qualitatively, R2*-χ-separation tends to report higher χpara and χdia values compared with χ-separation, leading to less distinct lesion contrasts, while χ-sepnet-R2* closely aligns with χ-sepnet-R2'. Quantitative analysis reveals a robust correlation between both R2*-based methods and their R2'-based counterparts (r ≥ 0.88). Specifically, in the whole-brain voxels, χ-sepnet-R2* exhibits higher correlation and better linearity than R2*-χ-separation (χdia/χpara from R2*-χ-separation: r = 0.88/0.90, slope = 0.79/0.86; χdia/χpara from χ-sepnet-R2*: r = 0.90/0.92, slope = 0.99/0.97). In MS lesions, both R2*-based methods display comparable correlation and linearity (χdia/χpara from R2*-χ-separation: r = 0.90/0.91, slope = 0.98/0.91; χdia/χpara from χ-sepnet-R2*: r = 0.88/0.88, slope = 0.91/0.95). Notably, χ-sepnet-R2* demonstrates negligible offsets, whereas R2*-χ-separation exhibits relatively large offsets (0.02 ppm in the whole brain and 0.01 ppm in the MS lesions), potentially indicating the false presence of myelin or iron in MS lesions. Overall, both R2*-based χ-separation methods demonstrated their viability as alternatives to their R2'-based counterparts. χ-sepnet-R2* showed better alignment with its R2'-based counterpart with minimal susceptibility offsets, compared with R2*-χ-separation that reported higher χpara and χdia values compared with R2'-based χ-separation.

The incidence and predictors of antibiotic-associated encephalopathy: a multicenter hospital-based study.

This study aimed to evaluate the incidence and likelihood of antibiotic-associated encephalopathy (AAE), comparing rates among the classes of antibiotics in monotherapy or in combination therapy. We also investigated the associations between the incidence of AAE and the glomerular filtration rate (GFR) and electroencephalogram features. Consecutive admissions that used any kind of antibiotics to treat infectious diseases were identified from six hospitals. We classified antibiotics according to three distinct pathophysiologic mechanisms and clinical subtypes. We searched for the incidence of AAE as the primary outcome. A total of 97,433 admission cases among 56,038 patients was identified. Cases that received type 1 antibiotics had significantly more frequent AAE compared to those that received type 2 antibiotics (adjusted odds ratio [OR], 2.62; 95% confidence interval [CI] 1.15-5.95; P = 0.021). Combined use of type 1 + 2 antibiotics was associated with a significantly higher incidence of AAE compared to the use of type 2 antibiotics alone (adjusted OR, 3.44; 95% CI 1.49-7.93; P = 0.004). Groups with GFR < 60 mL/min/1.73 m2 had significantly higher incidence rates of AAE compared to those with GFRs ≥ 90 mL/min/1.73 m2 among cases that received type 1 + 2 antibiotics. Detection of spike-and-wave or sharp-and-wave patterns on electroencephalogram was significantly more common in the combination therapy group. Combination use of antibiotics was associated with a higher incidence of AAE compared to monotherapy. The incidence of AAE significantly increased as renal function decreased, and epileptiform discharges were more likely to be detected in cases receiving combined antibiotics.

Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films.

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance.

RNA helicase DDX5 modulates sorafenib sensitivity in hepatocellular carcinoma via the Wnt/ß-catenin-ferroptosis axis.

Reduced expression of the RNA helicase DDX5 associated with increased hepatocellular carcinoma (HCC) tumor grade and poor patient survival following treatment with sorafenib. While immunotherapy is the first-line treatment for HCC, sorafenib and other multi-tyrosine kinase inhibitors (mTKIs) are widely used when immunotherapy is contra-indicated or fails. Herein, we elucidate the role of DDX5 in sensitizing HCC to sorafenib, offering new therapeutic strategies. Treatment of various human HCC cell lines with sorafenib/mTKIs downregulated DDX5 in vitro and in preclinical HCC models. Conversely, DDX5 overexpression reduced the viability of sorafenib-treated cells via ferroptosis, suggesting a role for DDX5 in sorafenib sensitivity. RNAseq of wild-type vs. DDX5-knockdown cells treated with or without sorafenib identified a set of common genes repressed by DDX5 and upregulated by sorafenib. This set significantly overlaps with Wnt signaling genes, including Disheveled-1 (DVL1), an indispensable Wnt activator and prognostic indicator of poor survival for sorafenib-treated patients. DDX5-knockout (DDX5KO) HCC cells exhibited DVL1 induction, Wnt/ß-catenin pathway activation, and ferroptosis upon inhibition of canonical Wnt signaling. Consistently, xenograft HCC tumors exhibited reduced growth by inhibition of Wnt/ß-catenin signaling via induction of ferroptosis. Significantly, overexpression of DDX5 in HCC xenografts repressed DVL1 expression and increased ferroptosis, resulting in reduced tumor growth by sorafenib. We conclude that DDX5 downregulation by sorafenib mediates adaptive resistance by activating Wnt/ß-catenin signaling, leading to ferroptosis escape. Conversely, overexpression of DDX5 in vivo enhances the anti-tumor efficacy of sorafenib by suppressing Wnt/ß-catenin activation and induction of ferroptosis. Thus, DDX5 overexpression in combination with mTKIs is a promising therapeutic strategy for HCC.

The Association of Nocturnal Seizures and Interictal Cardiac/Central Autonomic Function in Frontal Lobe Epilepsy: Heart Rate Variability and Central Autonomic Network Analysis.

Purpose: Patients with epilepsy frequently experience autonomic dysfunction, closely related to sudden unexplained death in epilepsy (SUDEP). SUDEP occurs most often at night or during sleep, and frequent nocturnal seizures are an established risk factor. This study investigated the influence of nocturnal seizures on autonomic dysfunction in epilepsy. Patients and Methods: This retrospective study enrolled frontal lobe epilepsy (FLE) patients who performed 24-hour EEG monitoring. All participants were divided into nocturnal FLE (NFLE, > 90% of seizures occurring during sleep) or diurnal FLE (DFLE) groups. EEG and ECG signals were simultaneously obtained during waking and sleep stages. EEG current density source and connectivity analysis of the autonomic network were performed. ECG was analyzed across time and frequency domains heart rate variability (HRV) analysis method was used. The obtained parameters were compared between the NFLE and DFLE groups. Results: Fifteen NFLE and 16 DFLE patients were enrolled with no significant difference in age, sex, disease duration, seizure frequency, or the number of anti-seizure medications between the two groups. During sleep, a decrease in HRV parameters and an increase of the beta-1 (13-22 Hz) current source density power in the bilateral paracentral lobule (BA4,5,6), precuneus (BA7), and cingulate (BA31) were observed in the NFLE group compared to DFLE group. The NFLE group also showed hyperconnectivity in the central autonomic (12 edges distributed over 10 nodes), sympathetic (2 edges distributed over 3 nodes), and parasympathetic (4 edges distributed over 6 nodes) beta-1 frequency band networks during sleep. During wakefulness, central and cardiac autonomic variables were not significantly different between the NFLE and DFLE groups. Conclusion: Interictal cardiac and central autonomic dysfunction occurred simultaneously and can be attributed to the brain-heart autonomic axis. Our findings suggest that nocturnal seizures may contribute to interictal autonomic dysfunction during sleep in people with epilepsy.

Low serum complement level is associated with higher mortality in tuberculous meningitis: a retrospective cohort study.

Purpose: We evaluated the associations between serum complement levels and tuberculous meningitis (TBM), bacterial meningitis (BM), and viral meningitis (VM), as well as the association between serum complement levels and mortality in TBM. Methods: Background information and blood/cerebrospinal fluid analysis results were collected from 2009 to 2019. Patients who had serum complement level data collected at admission and who were diagnosed with TBM (n = 97), BM (n = 31), or VM (n = 557) were enrolled. Results: Initial serum complement levels were significantly lower in the TBM group than the VM group in both the total population and the propensity score-matched population. In the TBM and VM groups, compared to patients with initial highest-quartile C4 level, patients in the lowest quartile (C4 < 24.3 mg/dL) had significantly greater odds of TBM diagnosis (odds ratio, 2.2; 95% confidence interval, 1.0-4.5; p = 0.038). In the TBM group, patients with the lowest-quartile C3 level (<96.9 mg/dL) experienced a significantly higher 90-day mortality rate compared to other TBM patients (hazard ratio, 19.0; 95% confidence interval, 2.1-167.4.5; p = 0.008). Conclusion: Both serum C3 and C4 levels were significantly lower in the TBM group than in the VM group. TBM patients with lower serum C3 level had a significantly higher mortality rate than those with higher C3 level.

Protein corona: Friend or foe? Co-opting serum proteins for nanoparticle delivery.

For systemically delivered nanoparticles to reach target tissues, they must first circulate long enough to reach the target and extravasate there. A challenge is that the particles end up engaging with serum proteins and undergo immune cell recognition and premature clearance. The serum protein binding, also known as protein corona formation, is difficult to prevent, even with artificial protection via "stealth" coating. Protein corona may be problematic as it can interfere with the interaction of targeting ligands with tissue-specific receptors and abrogate the so-called active targeting process, hence, the efficiency of drug delivery. However, recent studies show that serum protein binding to circulating nanoparticles may be actively exploited to enhance their downstream delivery. This review summarizes known issues of protein corona and traditional strategies to control the corona, such as avoiding or overriding its formation, as well as emerging efforts to enhance drug delivery to target organs via nanoparticles. It concludes with a discussion of prevailing challenges in exploiting protein corona for nanoparticle development.

An update on biologic treatments for neuromyelitis optica spectrum disorder.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system mediated by antibodies targeting the aquaporin-4 (AQP4) water channel expressed on astrocytes. The binding of specific antibodies to AQP4 causes complement-dependent cytotoxicity, leading to inflammation and demyelination. Several recent phase 2 and 3 randomized placebo-controlled trials showed the efficacy and safety of monoclonal antibody therapies targeting B-cells, interleukin-6 receptor, and complement. AREAS COVERED: Current biologic treatments for NMOSD and developments therein, and unresolved issues in NMOSD treatment. EXPERT OPINION: New biologic treatments demonstrate high efficacy and good safety for patients with AQP4-IgG-positive NMOSD. The optimal therapeutics for seronegative NMOSD, pediatric patients, and female patients who are pregnant or wish to be are unclear, and further research is needed. Also, real-world studies of new biological agents and the data on the durability of their beneficial effects and their long-term safety are required. Effective rescue therapy for an acute attack is critical given permanent disability in NMOSD is attack-related, and biologic agents that treat acute attack are emerging. If such treatments are to become widely applied, studies on the most cost-effective treatment strategies are needed.

χ-Separation Imaging for Diagnosis of Multiple Sclerosis versus Neuromyelitis Optica Spectrum Disorder.

Background Use of χ-separation imaging can provide surrogates for iron and myelin that relate closely to abnormal changes in multiple sclerosis (MS) lesions. Purpose To evaluate the appearances of MS and neuromyelitis optica spectrum disorder (NMOSD) brain lesions on χ-separation maps and explore their diagnostic value in differentiating the two diseases in comparison with previously reported diagnostic criteria. Materials and Methods This prospective study included individuals with MS or NMOSD who underwent χ-separation imaging from October 2017 to October 2020. Positive (χpos) and negative (χneg) susceptibility were estimated separately by using local frequency shifts and calculating R2' (R2' = R2* - R2). R2 mapping was performed with a machine learning approach. For each lesion, presence of the central vein sign (CVS) and paramagnetic rim sign (PRS) and signal characteristics on χneg and χpos maps were assessed and compared. For each participant, the proportion of lesions with CVS, PRS, and hypodiamagnetism was calculated. Diagnostic performances were assessed using receiver operating characteristic (ROC) curve analysis. Results A total of 32 participants with MS (mean age, 34 years ± 10 [SD]; 25 women, seven men) and 15 with NMOSD (mean age, 52 years ± 17; 14 women, one man) were evaluated, with a total of 611 MS and 225 NMOSD brain lesions. On the χneg maps, 80.2% (490 of 611) of MS lesions were categorized as hypodiamagnetic versus 13.8% (31 of 225) of NMOSD lesions (P < .001). Lesion appearances on the χpos maps showed no evidence of a difference between the two diseases. In per-participant analysis, participants with MS showed a higher proportion of hypodiamagnetic lesions (83%; IQR, 72-93) than those with NMOSD (6%; IQR, 0-14; P < .001). The proportion of hypodiamagnetic lesions achieved excellent diagnostic performance (area under the ROC curve, 0.96; 95% CI: 0.91, 1.00). Conclusion On χ-separation maps, multiple sclerosis (MS) lesions tend to be hypodiamagnetic, which can serve as an important hallmark to differentiate MS from neuromyelitis optica spectrum disorder. © RSNA, 2022 Supplemental material is available for this article.

Brighter spotty lesions on spinal MRI help differentiate AQP4 antibody-positive NMOSD from MOGAD.

In a large acute myelitis cohort, we aimed to determine whether brighter spotty lesions (BSLs)-using the refined terminology-on spinal magnetic resonance imaging (MRI) help distinguish aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) from myelin oligodendrocyte glycoprotein antibody disease (MOGAD). An experienced neuro-radiologist and two neurologists independently analyzed 133 spinal MRI scans (65 from MOGAD and 68 from AQP4-NMOSD) acquired within 1 month of attacks. BSLs were observed in 18 of 61 (30%) participants with AQP4-NMOSD, while none of 49 participants with MOGAD showed BSL (p < 0.001). BSL during the acute phase would be useful to differentiate AQP4-NMOSD from MOGAD.

Posterior Interosseous Fascicular Constriction Within the Radial Nerve in a Diabetic Patient With Bilateral Neuralgic Amyotrophy: A Case Report.

Background: Neuralgic amyotrophy (NA) is an acute, monophasic, painful inflammatory dysimmune focal, or multifocal mononeuropathy. The lesion in NA is not always restricted to the brachial plexus but also involves individual nerves or branches. The prognosis of NA is less favorable than previously assumed, but the reasons for poor recovery remain unknown. Nerve constriction may be one of the causes of poor prognosis in NA. Case Presentation: Herein, we described a 54-year-old male with a history of type 2 diabetes in whom bilateral neuralgic amyotrophy developed with constriction of the posterior interosseous fascicle within the radial nerve. The patient experienced sudden-onset severe pain in both shoulders followed, 2 days later, by weakness in bilateral shoulders and the left forearm extensors over the subsequent month. The left forearm extensors were more severely affected than both shoulder girdle muscles. He noted a 7-kg weight loss for 1 month before pain onset. After diagnosing diabetic NA based on the clinical symptoms, imaging, and electrophysiological studies, treatment with systemic steroids improved pain and weakness in both shoulder muscles. Weakness in the left forearm extensors persisted after 1 month of steroid treatment. Follow-up ultrasound revealed constriction of the posterior interosseous fascicle within the main trunk of the left radial nerve at the elbow. Surgical exploration at 6 months after onset identified fascicle constriction, for which neurolysis was performed. Weakness in the extensors of the wrist and fingers did not improve during the 16-month follow-up. Conclusion: A single constriction of the fascicle within a peripheral nerve may often be under-recognized if NA presents with variable degrees of weakness in bilateral upper limbs. Furthermore, fascicular constriction without edema of the parent nerve may be easily missed on the initial ultrasound. A lack of early recognition of nerve constriction and delay in surgical intervention can result in unfavorable outcomes. The physician should consider the possibility of the fascicular constriction when evaluating patients suspected of brachial NA with significant weakness in the distal upper limb compared to the proximal weakness or weakness of the distal upper limb that does not improve over time.

Survey on Antiepileptic Drug Therapy in Patients with Drug Resistant Epilepsy.

BACKGROUND AND PURPOSE: Individualized anti-epileptic drug (AED) selection in patient with epilepsy is crucial. However, there is no unified opinion in treating patients with drug resistant epilepsy (DRE). This survey aimed to make a consolidate consensus with epileptologists' perspectives of the treatment for Korean DRE patients by survey responses. METHODS: The survey was conducted with Korean epilepsy experts who have experience prescribing AEDs via e-mail. Survey questionnaires consisted of six items regarding prescription patterns and practical questions in treating patients with DRE in Korea. The research period was from February 2021 to March 2021. RESULTS: The survey response rate was 83.3% (90/108). Most (77.8%) of the responders are neurologists. The proportion of patients whose seizures were not controlled by the second AED was 26.9%. The proportion of patients who had taken five or more AEDs is 13.9%, and those who are currently taking five or more AEDs are 7.3%, of which 54.5% and 37.9% reported positive effects on additional AED, respectively. The majority (91.1%) of respondents answered that the mechanism of action was the top priority factor when adding AED. Regarding data priority, responders considered that expert opinion should have the top priority, followed by clinical experiences, reimbursement guidelines and clinical evidence. Responders gave 64.9 points (range from 0 to 100) about overall satisfaction on reimbursement system of Health Insurance Review and Assessment Service for AED. CONCLUSIONS: This study on AED therapy for DRE patients is the first nationwide trial in Korean epilepsy experts. In five drug failure, the top priorities on AED selection are mechanism of action and expert opinion. These findings might help to achieve consensus and recognize the insight on optimal therapy of AED in DRE.

Recurrent Transient Neurological Deficit Due to Intracerebral Steal Phenomenon in Association with a Developmental Venous Anomaly.

We report a symptomatic developmental venous anomaly (DVA) not causing parenchymal abnormality to provide a pathophysiologic clue in patients with recurrent transient neurologic deficit. A 32-year-old male presented with recurrent transient motor aphasia and headache in the left fronto-temporal region for three years. The symptoms usually lasted for one hour. Brain computed tomography (CT) angiography and magnetic resonance imaging using gradient recalled echo showed a prominent penetrating vein at the left frontal periventricular region. Brain CT perfusion imaging performed during the symptoms revealed increased perfusion in the corresponding area with relatively decreased perfusion in the left fronto-temporal cortices. Digital subtraction angiography revealed collecting venous blood from the left septal and thalamostriate veins draining into the left cavernous sinus without early arteriovenous shunting. In this patient, an inciting incident might have led to imbalance of the venous flow surrounding the DVA, causing venous hypertension and the intracerebral steal phenomenon in the surrounding area. The relatively hypoperfused cortical area adjacent to the DVA could be considered the cause of the transient motor aphasia, while venous hypertension could be the cause of the headache.

χ-separation: Magnetic susceptibility source separation toward iron and myelin mapping in the brain.

Obtaining a histological fingerprint from the in-vivo brain has been a long-standing target of magnetic resonance imaging (MRI). In particular, non-invasive imaging of iron and myelin, which are involved in normal brain functions and are histopathological hallmarks in neurodegenerative diseases, has practical utilities in neuroscience and medicine. Here, we propose a biophysical model that describes the individual contribution of paramagnetic (e.g., iron) and diamagnetic (e.g., myelin) susceptibility sources to the frequency shift and transverse relaxation of MRI signals. Using this model, we develop a method, χ-separation, that generates the voxel-wise distributions of the two sources. The method is validated using computer simulation and phantom experiments, and applied to ex-vivo and in-vivo brains. The results delineate the well-known histological features of iron and myelin in the specimen, healthy volunteers, and multiple sclerosis patients. This new technology may serve as a practical tool for exploring the microstructural information of the brain.

The association between serum sodium level and tuberculous meningitis compared with viral and bacterial meningitis.

We evaluated the association between hyponatremia and tuberculous meningitis (TBM) with the aim of providing additional information for differential diagnosis from other types of infectious meningitis, especially viral meningitis (VM). Cross-sectional and longitudinal data involving 5026 participants older than 18 years were analyzed in the total population and a propensity-matched population. The initial and lowest sodium levels and longitudinal changes in TBM, bacterial meningitis (BM), and VM patients were compared. Participants in the TBM group were enrolled when they were diagnosed as possible, probable, or definite TBM according to the Marais' criteria. The initial serum sodium level was significantly lower in TBM patients than in BM and VM patients (136.9 ± 5.9 vs. 138.3 ± 4.7 mmol/L, p < 0.001 for TBM vs. BM, and 139.0 ± 3.1, p < 0.001 for TBM vs. VM), and it decreased significantly more steeply to lower levels in both the TBM and BM patients compared with VM patients. The lowest serum sodium level was in the order of TBM < BM < VM patients, and the change was statistically significant in all subgroups (131.8 ± 6.4, 133.1 ± 5.1, 137.4 ± 3.7, respectively, p < 0.001). Participants with lower serum sodium level were more likely to have a diagnosis of TBM rather than VM, and this association was more pronounced for the lowest sodium level than the initial sodium level [OR 4.6 (95% CI 2.4-8.8, p < 0.001)]. These findings indicate that baseline and longitudinal evaluation of serum sodium level can provide information for differential diagnosis of TBM from BM or VM.