Differentiation between viral and autoimmune limbic encephalitis: a prospective cohort study with development and validation of a diagnostic model.

BACKGROUND: Distinguishing between viral encephalitis (VE) and autoimmune limbic encephalitis (ALE) presents a clinical challenge due to the overlap in symptoms. We aimed to develop and validate a diagnostic prediction model to differentiate VE and ALE. METHODS: A prospective observational multicentre cohort study, which continuously enrolled patients diagnosed with either ALE or VE from October 2011 to April 2023. The demographic data, clinical features, and laboratory test results were collected and subjected to logistic regression analyses. The model was displayed as a web-based nomogram and then modified into a scored prediction tool. Model performance was assessed in both derivation and external validation cohorts. RESULTS: A total of 2423 individuals were recruited, and 1001 (496 VE, 505 ALE) patients were included. Based on the derivation cohort (389 VE, 388 ALE), the model was developed with eight variables including age at onset, acuity, fever, headache, nausea/vomiting, psychiatric or memory complaints, status epilepticus, and CSF white blood cell count. The model showed good discrimination and calibration in both derivation (AUC 0.890; 0.868-0.913) and external validation (107 VE, 117 ALE, AUC 0.872; 0.827-0.917) cohorts. The scored prediction tool had a total point that ranged from - 4 to 10 also showing good discrimination and calibration in both derivation (AUC 0.885, 0.863-0.908) and external validation (AUC 0.868, 0.823-0.913) cohorts. CONCLUSIONS: The prediction model provides a reliable and user-friendly tool for differentiating between the VE and ALE, which would benefit early diagnosis and appropriate treatment and alleviate economic burdens on both patients and society.

Intestinal dysbiosis exacerbates susceptibility to the anti-NMDA receptor encephalitis-like phenotype by changing blood brain barrier permeability and immune homeostasis.

Changes in the intestinal microbiota have been observed in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). However, whether and how the intestinal microbiota is involved in the pathogenesis of NMDARE susceptibility needs to be demonstrated. Here, we first showed that germ-free (GF) mice that underwent fecal microbiota transplantation (FMT) from NMDARE patients, whose fecal microbiota exhibited low short-chain fatty acid content, decreased abundance of Lachnospiraceae, and increased abundance of Verrucomicrobiota, Akkermansia, Parabacteroides, Oscillospirales, showed significant behavioral deficits. Then, these FMT mice were actively immunized with an amino terminal domain peptide from the GluN1 subunit (GluN1356-385) to mimic the pathogenic process of NMDARE. We found that FMT mice showed an increased susceptibility to an encephalitis-like phenotype characterized by more clinical symptoms, greater pentazole (PTZ)-induced susceptibility to seizures, and higher levels of T2 weighted image (T2WI) hyperintensities following immunization. Furthermore, mice with dysbiotic microbiota had impaired blood-brain barrier integrity and a proinflammatory condition. In NMDARE-microbiota recipient mice, the levels of Evan's blue (EB) dye extravasation increased, ZO-1 and claudin-5 expression decreased, and the levels of proinflammatory cytokines (IL-1, IL-6, IL-17, TNF-α and LPS) increased. Finally, significant brain inflammation, mainly in hippocampal and cortical regions, with modest neuroinflammation, immune cell infiltration, and reduced expression of NMDA receptors were observed in NMDARE microbiota recipient mice following immunization. Overall, our findings demonstrated that intestinal dysbiosis increased NMDARE susceptibility, suggesting a new target for limiting the occurrence of the severe phenotype of NMDARE.

Ambient Aqueous Synthesis of Imine-Linked Covalent Organic Frameworks (COFs) and Fabrication of Freestanding Cellulose Nanofiber@COF Nanopapers.

Covalent organic frameworks (COFs) are usually synthesized under solvothermal conditions that require the use of toxic organic solvents, high reaction temperatures, and complicated procedures. Additionally, their insolubility and infusibility present substantial challenges in the processing of COFs. Herein, we report a facile, green approach for the synthesis of imine-linked COFs in an aqueous solution at room temperature. The key behind the synthesis is the regulation of the reaction rate. The preactivation of aldehyde monomers using acetic acid significantly enhances their reactivity in aqueous solutions. Meanwhile, the still somewhat lower imine formation rate and higher imine breaking rates in aqueous solution, in contrast to conventional solvothermal synthesis, allow for the modulation of the reaction equilibrium and the crystallization of the products. As a result, highly crystalline COFs with large surface areas can be formed in relatively high yields in a few minutes. In total, 16 COFs are successfully synthesized from monomers with different molecular sizes, geometries, pendant groups, and core structures, demonstrating the versatility of this approach. Notably, this method works well on the gram scale synthesis of COFs. Furthermore, the aqueous synthesis facilitates the interfacial growth of COF nanolayers on the surface of cellulose nanofibers (CNFs). The resulting CNF@COF hybrid nanofibers can be easily processed into freestanding nanopapers, demonstrating high efficiency in removing trace amounts of antibiotics from wastewater. This study provides a route to the green synthesis and processing of various COFs, paving the way for practical applications in diverse fields.

Efficacy of immunotherapy and prognosis in anti-LGI1 encephalitis patients: A meta-analysis.

OBJECTIVE: To assess the efficacy and safety of immunotherapy for LGI1 antibody encephalitis, and consider the predictors of poor outcomes following immunotherapy. METHODS: We searched PubMed and Embase for articles reporting the immunotherapy data of anti-LGI1 encephalitis patients. The proportions of patients with poor outcomes (modified Rankin Scale [mRS] score > 2) at 3 months, 12 months, and the last follow-up, as well as the odds ratio [OR] of predictors were pooled. RESULTS: The review included 162 articles with 1066 patients. The proportion of patients with poor functional outcomes was 21% at 3 months, 14% at 12 months, and 14% at the last follow-up after receiving immunotherapy. The proportion of patients with reported relapse was 16.6%. The mean duration from onset to the first relapse was 15.6 months. Predictors significantly associated with poor outcomes were age (increase of 1 year), the presence of cognitive impairment, and CSF LGI1 antibody positive. We did not find a statistically significant association between the worst mRS score in the acute phase, the presence of faciobrachial dystonic seizures (FBDS), days from symptom onset to immunotherapy, second-line treatment, maintenance immunotherapy, or follow-up time and outcomes. INTERPRETATION: Although most patients respond to immunotherapy, a minority of patients still have poor outcomes. Advanced age, cognitive impairment, and CSF LGI1 antibody positive are associated with an increased risk of poor outcomes. However, due to the insufficiency of the data, these conclusions need to be interpreted with caution.

Combined Catalysis for Engineering Bioinspired, Lignin-Based, Long-Lasting, Adhesive, Self-Mending, Antimicrobial Hydrogels.

The engineering of multifunctional biomaterials using a facile sustainable methodology that follows the principles of green chemistry is still largely unexplored but would be very beneficial to the world. Here, the employment of catalytic reactions in combination with biomass-derived starting materials in the design of biomaterials would promote the development of eco-friendly technologies and sustainable materials. Herein, we disclose the combination of two catalytic cycles (combined catalysis) comprising oxidative decarboxylation and quinone-catechol redox catalysis for engineering lignin-based multifunctional antimicrobial hydrogels. The bioinspired design mimics the catechol chemistry employed by marine mussels in nature. The resultant multifunctional sustainable hydrogels (1) are robust and elastic, (2) have strong antimicrobial activity, (3) are adhesive to skin tissue and various other surfaces, and (4) are able to self-mend. A systematic characterization was carried out to fully elucidate and understand the facile and efficient catalytic strategy and the subsequent multifunctional materials. Electron paramagnetic resonance analysis confirmed the long-lasting quinone-catechol redox environment within the hydrogel system. Initial in vitro biocompatibility studies demonstrated the low toxicity of the hydrogels. This proof-of-concept strategy could be developed into an important technological platform for the eco-friendly, bioinspired design of other multifunctional hydrogels and their use in various biomedical and flexible electronic applications.

Synthesis of Porous Organic Polymers with Tunable Amine Loadings for CO2 Capture: Balanced Physisorption and Chemisorption.

The cross-coupling reaction of 1,3,5-triethynylbenzene with terephthaloyl chloride gives a novel ynone-linked porous organic polymer. Tethering alkyl amine species on the polymer induces chemisorption of CO2 as revealed by the studies of ex situ infrared spectroscopy. By tuning the amine loading content on the polymer, relatively high CO2 adsorption capacities, high CO2-over-N2 selectivity, and moderate isosteric heat (Qst) of adsorption of CO2 can be achieved. Such amine-modified polymers with balanced physisorption and chemisorption of CO2 are ideal sorbents for post-combustion capture of CO2 offering both high separation and high energy efficiencies.

Cellulose Nanofiber @ Conductive Metal-Organic Frameworks for High-Performance Flexible Supercapacitors.

Conductive metal-organic frameworks (c-MOFs) show great potential in electrochemical energy storage thanks to their high electrical conductivity and highly accessible surface areas. However, there are significant challenges in processing c-MOFs for practical applications. Here, we report on the fabrication of c-MOF nanolayers on cellulose nanofibers (CNFs) with formation of nanofibrillar CNF@c-MOF by interfacial synthesis, in which CNFs serve as substrates for growth of c-MOF nanolayers. The obtained hybrid nanofibers of CNF@c-MOF can be easily assembled into freestanding nanopapers, demonstrating high electrical conductivity of up to 100 S cm-1, hierarchical micromesoporosity, and excellent mechanical properties. Given these advantages, the nanopapers are tested as electrodes in a flexible and foldable supercapacitor. The high conductivity and hierarchical porous structure of the electrodes endow fast charge transfer and efficient electrolyte transport, respectively. Furthermore, the assembled supercapacitor shows extremely high cycle stability with capacitance retentions of >99% after 10000 continuous charge-discharge cycles. This work provides a pathway to develop flexible energy storage devices based on sustainable cellulose and MOFs.

Metal-organic framework derived leaf-like CoSNC nanocomposites for supercapacitor electrodes.

The designed construction of micro-/nano-structures and multi-composites on electrodes showed a promising prospect to improve electrochemical properties in supercapacitors. Herein, a facile carbonizing strategy was adopted for fabricating leaf-like CoSNC nanocomposites, which possess both the sheet structure and multi-composites of well-dispersed CoS2 nanoparticles in N-doped carbon frameworks. First, the leaf-like nanocomposites with high aspect ratios effectively shortened the ion/electron transmission paths and exposed more faradaic redox sites. Second, the N-doped carbon frameworks could stabilize the electrode structure during charge/discharge processes. Third, the well-dispersed CoS2 nanoparticles could also enhance the electrochemical kinetics. Hence, leaf-like CoSNC nanocomposites as electrode materials exhibited high specific capacitance, good rate capacity and cycling stability.

P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia.

Objective Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model. Methods P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis. Results Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons. Conclusions These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia-neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.

Testing of diagnosis criteria of tension-type headache: A multicenter clinical study.

Objective Tension-type headache is *These authors contributed equally to this work. usually manifested as head pain without associated symptoms, and the validation of diagnostic criteria presented are lacking and highly required in the International Classification of Headache Disorders. The aim of the present study was to explore the diagnosis criteria of tension-type headache in a multicenter-based sample from Chongqing, China. Methods Clinical characteristics and demographics were systematically and prospectively collected between March 2014 and December 2015 from 15 participating hospitals in Chongqing, using a semi-structured face-to-face interview. All patients were asked to complete a headache diary for at least 4 weeks. Results Out of 1832 patients with headache, 150 patients (97 female/53 male, 44.56 ± 11.9 years old) were diagnosed with tension-type headache based on the standard International Classification of Headache Disorders, 3rd edition beta version, and interestingly, 114 (76%) patients were diagnosed with tension-type headache based on the alternative criteria. One patient was excluded because only two of the four characteristics were fulfilled. Thirty-five (23.3%) patients did not meet the alternative criteria because of associated symptoms, including mild nausea (n = 6), photophobia (n = 1), and phonophobia (n = 28). All patients with TTH had mild or moderate headaches, 98.0% of patients suffered from non-pulsating headaches, 99.3% of patients said their headaches were not aggravated by routine physical activity, and 77.3% of patients had bilateral headache. Conclusions Non-pulsating headaches and headaches that are not aggravated by routine physical activity may represent core criteria for screening patients with tension-type headache. Nausea might not be an exclusion feature for diagnosis of TTH, but an important criterion for screening. Further studies are needed.

Field testing of the ICHD-3ß and expert opinion criteria for chronic migraine.

BACKGROUND: Chronic headache (CrH) occurs commonly in the population, and chronic migraine (CM) accounts for much of the CrH. Diagnostic criteria for CM remain controversial, and this could lead to undertreatment of CM. The purpose of this study was to analyze the clinical profiles of CM and to field test the International Classification of Headache Disorders-3ß criteria (ICHD-3ß) and Expert Opinion criteria (EO) for CM application. METHODS: We retrospectively reviewed the medical records of CrH patients in our headache clinic during the period. Eligible patients were selected from CrH population based on Silberstein and Lipton criteria (S-L) for CM, and meanwhile fulfilled with migraine days at least 8 days/month. Then we evaluated the characteristics of clinic profiles and outcomes between patients diagnosed CM using ICHD-3ß and EO criteria. Field tested the CM criteria Of ICHD-3ß and EO. RESULTS: In a total of 710 CrH patients , 261 (36.8 %) were recruited with CM based on both S-L criteria and fulfilled at least 8 migraine days/month. Be understandable, all the 261 patients met the EO criteria, and only 185 (70.9 %) met ICHD-3ß for CM. For the 76 patients who met EO but not ICHD-3ß, 70 had atypical migraine attacks (probable migraine, PM), and another 6 had typical migraine attacks but less than a total history of 5 attacks. Although 173 (66.3 %) were concurrent with medication overuse, just one patient overused triptans and none used ergot agents. Clinical features were not significantly different between the ICHD-3ß and EO criteria groups (P > 0.05), and neither were outcomes of prophylaxis (P = 0.966). Total migraine prophylaxis effectiveness was 73 %. CONCLUSION: Migraine-specific analgesics are rarely used in China, permitting patients with PM to avail themselves of "migraine days" is a reasonable accommodation for this difficult condition. In our hands, use of the new EO criteria for diagnosis of CM increases the sensitivity and maintains the specificity of decision making, and therefore should be adopted in CM management practice.