Tetrodotoxin-resistant mechanosensitivity and L-type calcium channel-mediated spontaneous calcium activity in enteric neurons.

Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high- and low-frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic-motility stages E18.5-P3 showed that CaV1.2-positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2-aminoethoxydiphenyl borate (2-APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2-APB resistant. We extended our results on L-type channel-dependent spontaneous activity and TTX-resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro-mechanical sensitivity in the enteric nervous system. HIGHLIGHTS: What is the central question of this study? What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity? What is the main finding and its importance? ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L-type calcium channels and IP3R receptors, and the enteric nervous system exhibits a tetrodotoxin-resistant mechanosensitive response. Abstract figure legend Tetrodotoxin-resistant Ca2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum.

A Comprehensive Head-to-Head Comparison of Key Plasma Phosphorylated Tau 217 Biomarker Tests.

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarkers for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-ß (Aß)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217 WashU ]and p-tau217 WashU ) as well as with immunoassays (p-tau217 Lilly , p-tau217 Janssen , p-tau217 ALZpath ). CSF biomarkers included p-tau217 Lilly , and the FDA-approved p-tau181/Aß42 Elecsys and p-tau181 Elecsys . All plasma p-tau217 tests exhibited high ability to detect abnormal Aß-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217 WashU had the highest performance, with significantly higher AUCs than all the immunoassays ( P diff <0.007). For detecting Aß-PET status, %p-tau217 WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217 Lilly and plasma p-tau217 ALZpath had higher AUCs than plasma p-tau217 Janssen for Aß-PET status ( P diff <0.006), and p-tau217 Lilly outperformed plasma p-tau217 ALZpath for tau-PET status ( P diff =0.025). Plasma %p-tau217 WashU exhibited higher associations with all PET load outcomes compared to immunoassays; baseline Aß-PET load (R 2 : 0.72; immunoassays: 0.47-0.58; P diff <0.001), baseline tau-PET load (R 2 : 0.51; immunoassays: 0.38-0.45; P diff <0.001), longitudinal Aß-PET load (R 2 : 0.53; immunoassays: 0.31-0.38; P diff <0.001) and longitudinal tau-PET load (R 2 : 0.50; immunoassays: 0.35-0.43; P diff <0.014). Among immunoassays, plasma p-tau217 Lilly was more strongly associated with Aß-PET load than plasma p-tau217 Janssen ( P diff <0.020) and with tau-PET load than both plasma p-tau217 Janssen and plasma p-tau217 ALZpath (all P diff <0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R 2 %p-tau217 WashU : 0.33; immunoassays: 0.27-0.30; P diff <0.024). The main results were replicated in an external cohort from Washington University in St Louis ( n =219). Finally, p-tau217 Nulisa showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS-and immunoassay-based p-tau217 tests generally perform well in identifying Aß-PET, tau-PET, and cognitive abnormalities, but %p-tau217 WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test.

Opioid use disorder and role of yoga as an adjunct in management (OUDARYAM): Study protocol for a randomized controlled trial.

Background: The proposed research aims to test the effects and mechanisms of a six-month yoga-based intervention as an add-on to standard treatment in opioid use disorder (OUD) by conducting a randomized controlled study with the following primary outcome variables: 1) clinical: abstinence (opioid negative urine test), and reductions in pain and craving, and 2) mechanisms: reward circuit activation in response to opioid visual cue craving paradigm, activation in response to a cognitive control task, and resting state functional connectivity through fMRI, and plasma beta-endorphin levels. Secondary outcome variables are perceived stress, anxiety, sleep quality, cognitive performance, pain threshold, buprenorphine dosage and side effects, withdrawal symptoms, socio-occupational functioning, vedic personality traits, heart rate variability, serum cortisol, and brain GABA levels through magnetic resonance spectroscopy (MRS). Methods: In this single-blinded, randomized, controlled, parallel-group superiority trial with 1:1 allocation ratio, 164 patients with OUD availing the outpatient/ inpatient clinical services at a tertiary mental healthcare hospital in India will be enrolled after giving informed consent. Consecutive consenting patients will be randomly allotted to one of the two groups - yoga arm (standard treatment + yoga-based intervention), or waitlist group (standard treatment alone). Allocation concealment will be followed, the clinicians, outcome assessors and data analysts will remain blind to subject-group allocation. A validated and standardized yoga program for OUD will be used as an intervention. Participants in the yoga arm will receive 10 supervised in-person sessions of yoga in the initial two weeks followed by tele-yoga sessions thrice a week for the next 22 weeks. The wait-list control group will continue the standard treatment alone for 24 weeks. Assessments will be done at baseline, two weeks, 12 weeks, and 24 weeks. Data from all randomized subjects will be analysed using intent-to-treat analysis and mixed model multivariate analysis. Dissemination: Findings will be disseminated through peer-reviewed publication, conference presentations, and social media. Trial registration number: The trial has been registered under Clinical Trials Registry-India with registration number CTRI/2023/03/050737.

Getting the right tail right: Modeling tails of health expenditure distributions.

Health expenditure data almost always include extreme values, implying that the underlying distribution has heavy tails. This may result in infinite variances as well as higher-order moments and bias the commonly used least squares methods. To accommodate extreme values, we propose an estimation method that recovers the right tail of health expenditure distributions. It extends the popular two-part model to develop a novel three-part model. We apply the proposed method to claims data from one of the biggest German private health insurers. Our findings show that the estimated age gradient in health care spending differs substantially from the standard least squares method.

CSF neurofilament light chain profiling and quantitation in neurological diseases.

Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury.

Robust Classical and Quantum Polarimetry with a Single Nanostructured Metagrating.

We formulate a new conceptual approach for one-shot complete polarization state measurement with nanostructured metasurfaces applicable to classical light and multiphoton quantum states by drawing on the principles of generalized quantum measurements based on positive operator-valued measures. Accurate polarization reconstruction from a combination of photon counts or correlations from several diffraction orders is robust with respect to even strong fabrication inaccuracies, requiring only a single classical calibration of the metasurface transmission. Furthermore, this approach operates with a single metagrating without interleaving, allowing for a reduction in metasurface size while preserving high transmission efficiency and output beam quality. We theoretically obtained original metasurface designs, fabricated the metasurface from amorphous silicon nanostructures deposited on glass, and experimentally confirmed accurate polarization reconstruction of laser beams. We also anticipate robust operation under changes in environmental conditions, opening new possibilities for space-based imaging and satellite optics.

Comparison of cerebrospinal fluid, plasma and neuroimaging biomarker utility in Alzheimer's disease.

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer's disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aß40lumi and Aß42/Aß40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer's disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aß40lumi and t-tau/Aß40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aß40lumi, p-tau181/Aß40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer's disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer's disease clinical practice and trials.

Disease staging of Alzheimer's disease using a CSF-based biomarker model.

Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aß42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0-5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aß-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.

Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset.

OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.

Is thermal sensitivity affected by predation risk? A case study in tadpoles from ephemeral environments.

Changes in environmental temperature may induce variations in thermal tolerance and sensitivity in ectotherm organisms. These variations generate plastic responses that can be analyzed by examining their Thermal Performance Curves (TPCs). Additionally, some performance traits, like locomotion, could be affected by other factors such as biological interactions (e.g., predator-prey interaction). Here, we evaluate if the risk of predation modifies TPCs in Mendoza four-eyed frog (Pleurodema nebulosum, Burmeister, 1861) and Guayapa's four-eyed frog (Pleurodema guayapae, Barrio, 1964), two amphibian species that occur in ephemeral ponds in arid environments. We measured thermal tolerances and maximum swimming velocity at six different temperatures in tadpoles under three situations: control, exposure to predator chemical cues, and exposure to conspecific alarm cues. TPCs were fitted using General Additive Mixed Models. We found that curves of tadpoles at risk of predation differed from those of control mainly in thermal sensitivity parameters. Our work confirms the importance of biotic interactions have in thermal physiology.

Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests.

With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-ß (Aß) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aß42/40 and p-tau181/Aß42. The primary and secondary outcomes were detection of brain Aß or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aß PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89-90% for Aß PET and 87-88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.

Plant-specific environmental and developmental signals regulate the mismatch repair protein MSH6 in Arabidopsis thaliana.

The DNA mismatch repair (MMR) is a postreplicative system that guarantees genomic stability by correcting mispaired and unpaired nucleotides. In eukaryotic nuclei, MMR is initiated by the binding of heterodimeric MutS homologue (MSH) complexes to the DNA error or lesion. Among these proteins, MSH2-MSH6 is the most abundant heterodimer. Even though the MMR mechanism and proteins are highly conserved throughout evolution, physiological differences between species can lead to different regulatory features. Here, we investigated how light, sugar, and/or hormones modulate Arabidopsis thaliana MSH6 expression pattern. We first characterized the promoter region of MSH6. Phylogenetic shadowing revealed three highly conserved regions. These regions were analyzed by the generation of deletion constructs of the MSH6 full-length promoter fused to the ß-glucuronidase (GUS) gene. Combined, our in silico and genetic analyses revealed that a 121-bp promoter fragment was necessary for MSH6 expression and contained potential cis-acting elements involved in light- and hormone-responsive gene expression. Accordingly, light exposure or sugar treatment of four-day old A. thaliana seedlings triggered an upregulation of MSH6 in shoot and root apical meristems. Appropriately, MSH6 was also induced by the stem cell inducer WUSCHEL. Further, the stimulatory effect of light was dependent on the presence of phyA. In addition, treatment of seedlings with auxin or cytokinin also caused an upregulation of MSH6 under darkness. Consistent with auxin signals, MSH6 expression was suppressed in the GATA23 RNAi line compared with the wild type. Our results provide evidence that endogenous factors and environmental signals controlling plant growth and development regulate the MSH6 protein in A. thaliana.

Posterior Cerebellar Resting-State Functional Hypoconnectivity: A Neural Marker of Schizophrenia Across Different Stages of Treatment Response.

BACKGROUND: Identifying stable and consistent resting-state functional connectivity patterns across illness trajectories has the potential to be considered fundamental to the pathophysiology of schizophrenia. We aimed to identify consistent resting-state functional connectivity patterns across heterogeneous schizophrenia groups defined based on treatment response. METHODS: In phase 1, we used a cross-sectional case-control design to characterize and compare stable independent component networks from resting-state functional magnetic resonance imaging scans of antipsychotic-naïve participants with first-episode schizophrenia (n = 54) and healthy participants (n = 43); we also examined associations with symptoms, cognition, and disability. In phase 2, we examined the stability (and replicability) of our phase 1 results in 4 groups (N = 105) representing a cross-sequential gradation of schizophrenia based on treatment response: risperidone responders, clozapine responders, clozapine nonresponders, and clozapine nonresponders following electroconvulsive therapy. Hypothesis-free whole-brain within- and between-network connectivity were examined. RESULTS: Phase 1 identified posterior and anterior cerebellar hypoconnectivity and limbic hyperconnectivity in schizophrenia at a familywise error rate-corrected cluster significance threshold of p < .01. These network aberrations had unique associations with positive symptoms, cognition, and disability. During phase 2, we replicated the phase 1 results while comparing each of the 4 schizophrenia groups to the healthy participants. The participants in 2 longitudinal subdatasets did not demonstrate a significant change in these network aberrations following risperidone or electroconvulsive therapy. Posterior cerebellar hypoconnectivity (with thalamus and cingulate) emerged as the most consistent finding; it was replicated across different stages of treatment response (Cohen's d range -0.95 to -1.44), reproduced using different preprocessing techniques, and not confounded by educational attainment. CONCLUSIONS: Posterior cerebellar-thalamo-cingulate hypoconnectivity is a consistent and stable state-independent neural marker of schizophrenia.

A large therian mammal from the Late Cretaceous of South America.

Theria represent an extant clade that comprises placental and marsupial mammals. Here we report on the discovery of a new Late Cretaceous mammal from southern Patagonia, Patagomaia chainko gen. et sp. nov., represented by hindlimb and pelvic elements with unambiguous therian features. We estimate Patagomaia chainko attained a body mass of 14 kg, which is considerably greater than the 5 kg maximum body mass of coeval Laurasian therians. This new discovery demonstrates that Gondwanan therian mammals acquired large body size by the Late Cretaceous, preceding their Laurasian relatives, which remained small-bodied until the beginning of the Cenozoic. Patagomaia supports the view that the Southern Hemisphere was a cradle for the evolution of modern mammalian clades, alongside non-therian extinct groups such as meridiolestidans, gondwanatherians and monotremes.

Predicting disability and mortality in CV2/CRMP5-IgG associated paraneoplastic neurologic disorders.

BACKGROUND: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND). METHODS: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival. RESULTS: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. INTERPRETATION: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.

Characteristics and Attendance of Patients Eligible for the PASS Clinic: A Transition of Care Model After Acute Symptomatic Seizures.

Background and Objectives: Most acute symptomatic seizure (ASyS) patients stay on antiseizure medications (ASM) long-term, despite low epilepsy development risk. The Post-Acute Symptomatic Seizure (PASS) clinic is a transition of care model for ASyS patients who individualize ASM management with the goal of a safe deprescription. We evaluated patients discharged on ASMs after a witnessed or suspected ASyS to analyze their PASS clinic visit attendance and its predictors. Methods: A single-center, retrospective cohort study of adults without epilepsy who were discharged from January 1, 2019, to September 30, 2019, on first-time ASMs due to witnessed or suspected ASyS (PASS clinic-eligible). We fit a cause-specific Cox proportional hazards model to analyze factors associated with PASS clinic attendance, which depends on survival in this patient population that has a high early postdischarge mortality (a competing risk). We checked for multicollinearity and the assumption of proportional hazards. Results: Among 307 PASS clinic-eligible patients, 95 (30.9%) attended the clinic and 136 (44.3%) died during a median follow-up of 14 months (interquartile range = 2-34). ASyS occurred in 60.2% (convulsive 47%; electrographic 26.7%) of patients. ASMs were continued in the absence of ASyS or epileptiform abnormalities (EAs) in 27% of patients. Multivariable analysis revealed that the presence of EAs (HR = 1.69, 95% CI 1.10-2.59), PASS clinic appointments provided before discharge (HR = 3.39, 95% CI 2.15-5.33), and less frequently noted ASyS etiologies such as autoimmune encephalitis (HR = 2.03, 95% CI 1.07-3.86) were associated with an increased clinic attendance rate. Medicare/Medicaid insurance (HR = 0.43, 95% CI 0.24-0.78, p = 0.005) and the presence of progressive brain injury (i.e., tumors; HR = 0.55, 95% CI 0.32-0.95, p = 0.032) were associated with reduced rate of PASS clinic attendance. Discussion: Our real-world data highlight the need for appropriate postdischarge follow-up of ASyS patients, which can be fulfilled by the PASS clinic model. Modest PASS clinic attendance can be significantly improved by adhering to a structured discharge planning process whereby appointments are provided before discharge. Future research comparing patient outcomes, specifically safe ASM discontinuation in a PASS clinic model to routine clinical care, is needed.

Longitudinal Disability, Cognitive Impairment, and Mood Symptoms in Patients With Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Longitudinal outcomes in anti-NMDA receptor encephalitis (anti-NMDARe) are still not fully understood and may not be adequately captured with the modified Rankin Scale (mRS), often the sole reported outcome. We aim to characterize longitudinal outcomes in anti-NMDARe using multiple outcome measures. METHODS: This single-center, retrospective, observational study examined outcome measures (mRS and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]) in adults with NMDA receptor-IgG in CSF at short- and long-term follow-ups using linear and logistic regression modeling. Patients with evaluations for cognitive impairment (Montreal Cognitive Assessment/Mini-Mental State Examination), depression (Patient Health Questionnaire-9), and anxiety (General Anxiety Disorder-7) >6 months from symptom onset were correlated with final CASE scores. RESULTS: Thirty-eight patients (76% female, median disease onset age = 28 years, range = 1-75 years) were included. The majority received first-line immunosuppressants (97%) at a median of 3.9 weeks (interquartile range [IQR] = 2.1-9.7) from symptom onset and 68% received second-line therapies. At baseline, median/mean mRS and CASE were 4 (IQR = 3-5) and 12.9 (SD = 7.2), respectively. At short-term follow-up (median = 10 weeks, IQR = 6-17), factors associated with higher CASE and mRS included dysautonomia, coma/lethargy, seizures/status epilepticus, and intensive care unit admission (p < 0.05). At long-term follow-up (median = 70 weeks, IQR = 51-174), median/mean mRS and CASE were 2 (IQR = 1-3) and 4.4 (SD = 4.2), respectively. Only weakness at symptom onset predicted higher mRS scores (odds ratio = 5.6, 95% confidence interval 1.02-30.9, p = 0.047). Despite both mRS and CASE improving from baseline (p < 0.001), only 9 patients (31%) returned to their premorbid function. Among patients with cognitive and mood evaluations >6 months from onset, moderate-severe cognitive impairment (42%), depression (28%), and anxiety (30%) were frequent. Cognitive and depression measures were associated with final CASE subscores (including memory, language, weakness, and psychiatric). DISCUSSION: Multiple clinical factors influenced short-term outcomes, but only onset weakness influenced long-term mRS, highlighting that mRS is predominantly affected by global motor function. Although mRS and CASE improved over time for most patients, these outcome measures did not capture the full extent of long-term functional impairment in terms of mood, cognition, and the ability to return to premorbid function. This emphasizes the need for increased utilization of more nuanced cognitive and mood outcome measures.

Direct Observation of the Mutual Coupling Effect in the Protein-Water-Glycerol Mixture by Combining Neutron Scattering and Selective Deuteration.

Numerous studies have discussed the impact of cosolvents on the structure, dynamics, and stability of proteins in aqueous solutions. However, the dynamics of cosolvents in the protein-water-cosolvent ternary system is largely unexplored in experiments due to technical difficulty. Consequently, a comprehensive understanding of the interplay among proteins, water, and cosolvents is still lacking. Here, we employed selective deuteration and neutron scattering techniques to characterize the individual motions of each component in the protein/water/glycerol (GLY) mixture across various temperatures. The consistent dynamic onset temperatures and the correlation between the MSD of the protein and the viscosity of solvents revealed the mutual coupling effects among the three components. Furthermore, our experimental and simulation results showed that the hydrogen bond relaxation energy barrier in the ternary system is ∼43 kJ/mol, whereas in the protein-water binary system it is merely ∼35 kJ/mol. Therefore, we suggest that GLY can enhance hydrogen bond interactions in the ternary system through the mutual coupling effect, thereby serving as one of the protective mechanisms of protein preservation by GLY.