Background: Inflammatory bowel disease is an autoimmune disease that affects the gut. T. spiralis larvae (E/S Ags) loaded on calcium-benzene-1,3,5-tricarboxylate metal-organic frameworks (Ca-BTC MOFs) were tested to determine whether they might prevent or cure acetic acid-induced murine colitis. Methods: T. spiralis larvae E/S Ags/Ca-BTC MOFs were used in prophylactic and therapeutic groups to either precede or follow the development of murine colitis. On the seventh day after colitis, mice were slaughtered. The effect of our target antigens on the progress of the colitis was evaluated using a variety of measures, including survival rate, disease activity index, colon weight/bodyweight, colon weight/length) ratios, and ratings for macroscopic and microscopic colon damage. The levels of inflammatory cytokines (interferon-γ and interleukin-4), oxidative stress marker malondialdehyde, and glutathione peroxidase in serum samples were evaluated. Foxp3 T-reg expression was carried out in colonic and splenic tissues. Results: T. spiralis larvae E/S Ags/Ca-BTC MOFs were the most effective in alleviating severe inflammation in murine colitis. The survival rate, disease activity index score, colon weight/length and colon weight/bodyweight ratios, and gross and microscopic colon damage scores have all considerably improved. A large decrease in proinflammatory cytokine (interferon-γ) and oxidative stress marker (malondialdehyde) expression and a significant increase in interleukin-4 and glutathione peroxidase expression were obtained. The expression of Foxp3+ Treg cells was elevated in colonic and splenic tissues. Conclusion: T. spiralis larvae E/S Ags/Ca-BTC MOFs had the highest anti-inflammatory, antioxidant, and cytoprotective capabilities against murine colitis and might be used to develop new preventative and treatment strategies.

The International Political Science Association (IPSA) is a unique case against the common perception that Beijing has the upper hand when the two regimes by the Taiwan Strait contest to join international (non-governmental) organisations. Beijing relentlessly pushes international organisations to acknowledge the One China principle; Taipei also relentlessly denies this principle while it seeks to join. In the 1980s, Chinese and Taiwanese political scientists, representing their own regimes, applied Track II diplomacy to compete over membership of this organisation. IPSA membership mattered to both regimes and their political scientists. After many years of Track II competition, The Chinese Association of Political Science in Taipei became a “collective” member without compromising on how to name itself in April 1989. As a result, Beijing's counterpart withdrew from the IPSA. This situation has now persisted for over thirty years. The IPSA case not only challenges the current understanding of Cross-Strait relations but also throws light on the theoretical understanding of Track II diplomacy.

Background: Brain metastases indicate an advanced tumour stage for many cancers. We sought to investigate the incidence change of tissue-sampled brain metastases and its relation to staging challenges during the COVID-19 pandemic in Newfoundland and Labrador. Methods: We reviewed all brain metastasis cases from 2015-2022 requiring first-time tissue sampling according to pathology reports from the St. John’s Health Sciences Centre. Incidence rates were calculated using yearly population data by regional health authorities and standardized using the 2011 Canadian standard population. Results: We included 173 cases. The average annual age-standardized incidence rate of brain metastases requiring tissue sampling per 100,000 increased from 2.5 (95% CI: 2.0-3.1) pre-COVID-19 to 4.1 (95% CI: 3.3-5.0) post-COVID-19. Brain metastases from lung primaries accounted for 69% of this increase. While incidence declined to near-baseline in the Eastern provincial population by 2022 (3.3; 95% CI: 1.5-5.1), incidence rose into 2022 in the Western population (8.6; 95% CI: 3.9-13.2). Conclusions: These data suggest a delayed presentation of malignancies during the COVID-19 pandemic and underscore the importance of prioritized staging during times of strain on healthcare systems. Regional, temporal trends suggest regions distant from tertiary care centres could face challenges in resolving cases with delayed presentation post-COVID-19.

Background: We performed a network meta-analysis of randomized controlled trials to assess the comparative effectiveness of available pharmacological prophylaxis for migraines. Methods: We searched MEDLINE, EMBASE, Web of Science, Scopus, PsycINFO and Cochrane CENTRAL up to October 2023 for trials that: (1) enrolled adults diagnosed with chronic migraine, and (2) randomized them to any prophylactic medication vs. another medication or placebo. We performed a random-effects frequentist network meta-analysis for patient-important outcomes. Results: We included 193 randomized trials. Compared to placebo, CGRP monoclonal antibodies (mean difference [MD] -1.7, 95%CI: -1.1 to -2.2), injection of botulinum toxin (MD -1.8, 95%CI: -0.7 to -2.9), calcium channel blockers (MD -1.8, 95%CI: -0.5 to -3.0), beta-blockers (MD -1.4, 95%CI: -0.2 to -2.6), and anticonvulsants (MD -1.1, 95%CI: -0.4 to -1.8) were among the most effective treatments in reducing average number of headache days per months. Anticonvulsants (Risk Ratio [RR] 2.3, 95%CI: 1.8 to 3.0), calcium channel blockers (RR 1.8, 95% CI: 1.1 to 3.1), and tricyclic antidepressants (RR 2.3, 95% CI: 1.3 to 3.8) showed the highest risk of discontinuation due to adverse events. Conclusions: Our findings suggest that CGRP inhibitors, botulinum toxin, and beta-blockers may provide the greatest benefit, and tolerability, for reducing the frequency of migraine headaches.

Background: Since 2018, several CGRP-targeted therapies have entered the migraine market, including eptinezumab. Minimal evidence exists evaluating the real-world effectiveness of switching from a subcutaneous to an intravenous anti-CGRP mAb. Methods: An observational, multi-site (n=4), US-based study, REVIEW evaluated real-world experiences of patients with chronic migraine (CM) treated with eptinezumab using a chart review, patient survey, and physician interviews. Adults (≥18 years) with a diagnosis of CM who had completed ≥2 consecutive eptinezumab infusion cycles were eligible. Results: Enrolled patients were primarily female (83%, 78/94), had a mean age of 49 years and a mean migraine diagnosis duration of 15.4 years. All patients (94/94) self-reported prior preventive therapy with 89% (84/94) reporting prior subcutaneous anti-CGRP mAb use (i.e., fremanezumab, galcanezumab, or erenumab). Regardless of prior exposure to a CGRP ligand or receptor blocker, the number of “good” days/month more than doubled following eptinezumab. Patients experienced a similar mean change in the number of “good” days/month regardless of the number and type of previous subcutaneous anti-CGRP mAb used. Conclusions: This real-world, patient survey showed that patients with prior exposure to subcutaneous anti-CGRP mAbs had high overall satisfaction with the effectiveness of eptinezumab treatment regardless of the number and type of previous therapies used.

Background: Reporting extent of resection (EOR) in pituitary adenoma (PA) surgery via endoscopic endonasal approaches (EEA) is not standardized. The use of 3-dimensional volumetric analysis is proposed for measurement of tumor volumes and EOR. Their relationship with visual outcomes is explored. Methods: A retrospective analysis of PA patients presenting with visual disturbances and treated surgically via EEA by a single surgeon between 2006 and 2021. The main outcome was visual function at 12 months post-operatively. Results: 142 patients were included. Majority were male, with mean age of 57.1 years. Most (58.2%) presented with bitemporal hemianopsia. The mean tumor size was 11.3 cm3. The mean EOR was 84.5% (range 21.5-99.8%), with a mean post-operative tumor volume of 1.9 cm3. Visual function improved in 92.2%. Re-resection for visual deterioration was performed in 5.7% of patients, (mean time 2.4 years). No clinical, pathologic, or imaging factors were significantly associated with visual outcome. A significant association was found between EOR and re-resection (mean EOR 66.7% vs 85.6%, p=0.002). Conclusions: For patients with PA presenting with visual deficits, treatment with EEA led to improvement in visual function in the majority of patients, without the need for gross total resection. EOR was significantly associated with the need for re-resection.

Background: This study aimed to investigate the effect of impulsivity on the planning & decision-making of individuals with OCD compared to a control group, focusing on amplitude and latency during the Tower of London (TOL) task. Methods: A sample of a total of 76 (dominantly right-handed & aged between 18-30 yrs) participated. Participants with OCD were assessed with the Y-BOCS & symptom checklist, BIS-11, and the HCs were screened with the GHQ-12. ERP components were measured by using TOL on E-prime 3.0. The amplitude and latency along with the spectral power for each problem-solving task were measured and analyzed. Results: Statistically significant differences were found in the Latency variable in the left frontal area of the brain, indicating distinctive latency patterns in individuals with OCD compared to controls. No statistically significant differences were observed in amplitude or latency for other move sequences. High spectral activity was detected in individuals with OCD for an extended period. Conclusions: Individuals with OCD exhibit higher activity indicative of ambivalence during decision-making which indicates that to overcome impulsive urges, thus they need to put more cognitive effort to maintain the same outcomes. To maintain error-free results obsessive & compulsive behaviors are a necessary evil.

Background: High grade gliomas (HGG) are incurable, aggressive brain malignances that carry poor prognoses. Significant scientific advances have uncovered many of the features of these diseases; however, it remains unclear how mutations and transcriptional changes drive glioma growth and progression. Methods: We used a Nestin-Cre mouse model in combination with an extrinsic chemical mutagen (N-ethyl-N-nitrosurea, ENU), to model HGG. We combined our mouse model with live animal in vivo magnetic resonance imaging to track tumor growth over time, and sample discrete lesions during premalignant, early stage tumor, and end stage tumor phases. Results: We show that the somatic mutations, copy number changes, and transcriptional profiles of tumors vary depending on the stage of growth, and that the Raf/Ras pathway is key for tumor growth with a recurring Braf mutation occurring in early stage lesions. Gene set enrichment analysis (GSEA) shows that end stage tumors have increased immunogenic/inflammatory activity, and increased signaling through Raf/Ras. Conclusions: The combination of genetic and nongenetic insults results in activating mutations in early lesions, which continue to be biologically active and underlie key differences between early and end stage tumors. Overall, this work sheds light on important differences between early and late stage tumors.

Background: Success of deep brain stimulation (DBS) in Parkinson’s disease (PD) relies on time-consuming trial-and-error testing of stimulation settings. Here, we prospectively compared an fMRI-based stimulation optimization algorithm with >1 year of standard-of-care (SoC) programming in a double-blind, crossover, non-inferiority trial. Methods: Twenty-seven PD-DBS patients were prospectively enrolled for fMRI using a 30-sec DBS-ON/OFF cycling paradigm. Optimal settings were identified using our published classification algorithm. Subjects then underwent >1 year of SoC programming. Clinical improvement was assessed, after an overnight medication washout period, under SoC and fMRI-determined stimulation conditions. A predefined non-inferiority margin was -5 points on the Unified Parkinson’s Disease Rating Scale (UPDRSIII). Results: UPDRSIII improved from 45.3 (SD=14.6) at baseline to 24.9 (SD=10.9) and 24.1 (SD=10.9) during SoC and fMRI-determined stimulation, respectively. The mean difference in scores was 0.8 (SD=8.5; 95% CI -4.5 to 6.2). The non-inferiority margin was not contained within the 95% confidence interval, establishing non-inferiority (p=0.013). Conclusions: This is the first prospective evaluation of an algorithm able to suggest stimulation parameters solely from the fMRI response to stimulation. It suggests equivalent outcomes may be achieved in 3 hours of fMRI scanning immediately after surgery compared to SoC requiring 6 or more in-person clinic visits throughout >1 year.

Background: This post hoc analysis evaluated the efficacy of eptinezumab vs placebo across 24 weeks of treatment in the placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure. Methods: DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100 mg, 300 mg, or placebo intravenous infusion every 12 weeks. Eligible patients needed documented evidence of 2–4 prior preventive treatment failures within the past 10 years. This post hoc analysis focused on subgroups of patients with prior treatment failure on topiramate, beta blockers, amitriptyline, and/or flunarizine. Results: The full analysis set included 890 patients: 633 previously failed topiramate, 538 failed beta blockers, 508 failed amitriptyline, and 333 failed flunarizine; within each subgroup, most patients had 2 prior treatment failures (51–56%). Across Weeks 1–12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo, with larger reductions observed over Weeks 13–24. Similarly, ≥50% MRRs were higher with eptinezumab than with placebo and increased following a second infusion. Conclusions: Eptinezumab demonstrated greater reductions in MMDs compared with placebo across all subgroups of prior preventive treatment failure, with evidence to suggest that a second dose provides additional benefit.

Background: Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, the integration of multiple molecular platforms has yielded novel insights into disease biology and heterogeneity. We hypothesise that applying contemporary multi-omic approaches to liquid biopsies will improve the power of current models. Methods: We have compiled a cohort of 51 patients with glioblastoma, brain metastasis, and primary CNS lymphoma who underwent CSF sampling as part of clinical care. Cell free methylated DNA and shotgun proteomic profiling was obtained from the CSF of each patient and used to build tumour-specific classifiers. Integrated classifiers were compared with single platform classifiers using multiple approaches. Results: In this study, we show that the DNA methylation and protein profiles of cerebrospinal fluid can be combined to fully discriminate lymphomas from their major diagnostic counterparts with perfect AUCs of 1 (95% confidence interval 1-1) and 100% specificity. Each integrated lymphoma classifier significantly outperforms single-platform classifiers, suggesting synergistic biology is obtained using multiple molecular platforms. Conclusions: We present the most specific and accurate CNS lymphoma classifier to date by integrating the methylome and proteome of CSF. This has important implications for the future of cancer diagnostics and generates immediate utility for patients with CNS lymphoma.

Background: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) is a rare, acquired polyneuropathy, especially in children, affecting the peripheral nervous system. It most commonly presents in a symmetric, proximal and distal, sensorimotor fashion. Immunosuppression and immunomanipulation are treatment modalities. We present a case of a 14 year old male with severe progressive CIDP who became refractory to steroid and IVIg but responded to Rituximab. Methods: Case presentation: A 14-year-old male with a history of asymmetric quadriparesis was diagnosed with CIDP. He had an initial partial response to IVIG and prednisone but then rapidly became refractory to even weekly IVIG and prednisone. Rituximab was therefore started. Results: Within 12 weeks his strength improved from quadriplegia to walker-assisted gait. By 22 weeks he achieved independent ambulation. His JAMAR hand grip increased from 0 to 28 kg. His worst recordable median conduction velocity (CV) improved from a nadir (MRC 0/5) of 14% of normal to 52% at full recovery (MRC 5/5). Conclusions: This case highlights several important clinical points. Dramatic improvement is possible in cases of quadriplegic CIDP. Strength recovery is not linearly related to CV recovery. There appears to be a role for polytherapy.

Background: The lateral prefrontal cortex (LPFC) is uniquely found in primates and has been associated with contextual learning. This function is thought to be subserved by neurons that are tuned to abstract concepts and the combination of those concepts. LPFC neuron tuning remains to be fully investigated in naturalistic conditions. Methods: Two macaques were trained to perform a context-colour association task while using a joystick to navigate in an X-shaped maze. They were implanted with two 96-channel microelectrode arrays, targeting the LPFC. Mean firing rates were computed and multivariate linear regressions were used to determine tuning. Results: LPFC neurons were tuned to context (12.4%), color position (6.2%), target side (17.2%), and were selective to more than one feature (21.2%). LPFC neurons acquired tuning to task features in an ordered manner, starting with context (130.1±27.4ms), followed by the colour position (296.2±21.4ms) and then target side (493.3±19.3ms). Furthermore, most neurons (54%) changed their tuning over time. Conclusions: We demonstrate that single neurons can encode relevant features embedded in a naturalistic virtual environment. Our results support previous observations that LPFC neurons combine individual features and suggest that these features are also combined temporally. These findings contribute towards understanding the LPFC and have potential practical implications.

Background: We tested the hypothesis that delivering remote ischemic conditioning (RIC) with an adjunct tissue reflectance sensor (TRS) device may be feasible in patients with acute ischemic stroke (AIS) and cerebral small vessel disease (cSVD). Methods: AIS patients with neurological deficits within 7 days of symptom onset were screened for moderate to severe cSVD. Eligible patients were randomized 2:1 to receive intervention RIC or sham RIC (7 days). The primary outcome measure was intervention feasibility. It was assessed as an intervention-related comfort by a 5-point Likert scale during each session (1-very uncomfortable, 5-very comfortable). The secondary outcome measure was assessment of TRS derived dermal blood concentration and blood oxygenation changes during RIC. Results: Forty-seven (32 intervention, 15 sham) patients were enrolled at a median (IQR) 39.7 (25-64) hours after symptom onset, with mean±SD age of 75±12 years, 22 (46.8%) were females and median baseline NIHSS of 5(3-7). The Likert scale was 3.5 (3-4) in the intervention group and 4 (4-5) in the sham group. The TRS derived blood concentration and blood oxygenation changes were proportionate in the intervention arm and absent in the sham arm. Conclusions: RIC treatment with TRS is feasible in patients with AIS+cSVD. The efficacy of RIC needs further assessment.

Background: Frontotemporal dementia (FTD) often presents with varying neuropsychiatric symptoms (NPS), which may differ based on genetic mutations. We hypothesized distinct NPS trajectories in FTD progression among carriers of chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) mutations. Methods: We analyzed 1662 participants from ALLFTD, including 342 C9orf72, 148 GRN, 168 MAPT mutation carriers, and 1004 noncarriers. We categorized participants into four stages based on CDR plus NACC FTLD global scores: 1) Presymptomatic (consistent CDR=0), 2) Early conversion (CDR increasing from 0 to 0.5), 3) Advanced conversion (CDR increasing from 0.5 to ≥1.0), and 4) Symptomatic (CDR>1.0). The Neuropsychiatric Inventory-Questionnaire (NPI-Q) assessed NPS changes, analyzed using a mixed-effects model, accounting for age and baseline scores. Results: Our results indicated similar NPS trajectories in the presymptomatic stage for all groups. Notably, during early conversion, C9orf72 and GRN carriers exhibited significantly higher NPI-Q score increases than MAPT carriers, primarily in psychosis and hyperactivity domains. In later stages, increases in NPS were similar across groups. Conclusions: This study suggests familial FTD progression, particularly in TDP-43 pathology, may involve more severe NPS like psychosis or hyperactivity, differing from tau pathology or sporadic FTD. Further research is needed to explore these distinct trajectories.

Background: Electrophysiological tests such as the tapping test are used to distinguish functional and organic tremors, in which patients with functional tremor commonly show entrainment and amplitude reduction (>50% decrease relative to baseline) of contralateral tremor during tapping. While these features are suggested to be specific to functional tremor, the tapping test in Parkinson’s disease (PD) tremor has not been tested. Methods: We evaluated 18 PD patients (2F, age 64.17±7.30 [mean±SD] years) with rest and postural tremors using surface electromyography and triaxial accelerometry. Patients were recorded while tapping at 1, 3 and 5 Hz with the contralateral arm at rest or outstretched. Tremor amplitude and frequency were calculated using power spectrum analysis from accelerometer recordings. Results: Reduction of rest tremor amplitude was observed in 3/18 patients during 1 and 3 Hz tapping. Reduction was seen in 3/16 and 1/16 patients with postural tremors at 1 and 3 Hz tapping, respectively. Frequency shifts (>1.5 Hz) were observed in 3/18 rest tremors and 6/16 postural tremors. Seven patients exhibited rest and/or postural tremor entrainment during 3 or 5 Hz tapping. Conclusions: Distractibility and entrainment can be found in PD tremor. The tapping test may not reliably distinguish between PD tremor and functional tremor.