We study self-similar viscous fingering for the case of divergent flow within a wedge-shaped Hele-Shaw cell. Previous authors have conjectured the existence of a countably infinite number of selected solutions, each distinguished by a different value of the relative finger angle. Interestingly, the associated solution branches have been posited to merge and disappear in pairs as the surface tension decreases. For the first time, we demonstrate how the selection mechanism can be derived based on exponential asymptotics. Asymptotic predictions of the finger-to-wedge angle are additionally given for different sized wedges and surface-tension values. The merging of solution branches is explained; this feature is qualitatively different to the case of classic Saffman–Taylor viscous fingering in a parallel channel configuration. Moreover, because the asymptotic framework does not highly depend on specifics of the wedge geometry, the proposed theory for branch merging in our self-similar problem likely relates much more widely to tip-splitting instabilities in time-dependent flows in circular and other geometries, where the viscous fingers destabilise and divide in two.

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.

Background: Pituitary apoplexy is a rare clinical syndrome resulting from infarction or hemorrhage of a pituitary tumor. Here, we present a large single center retrospective cohort study of patients with apoplexy. Methods: Patients with symptomatic apoplexy treated from January 2000 to October 2022 were isolated from the Halifax Neuropituitary Program’s database, containing prospectively entered data. Patients treated surgically typically presented with vision deterioration or decreased consciousness. Patient demographics, tumor size, endocrinologic values, and clinical outcomes were analyzed. Results: Eighty-three patients met our inclusion criteria. Seventy-two percent of tumours (n=60) were biochemically non-functioning adenomas. Sixty (72.3%) patients were treated surgically, while twenty-three (27.7%) were treated conservatively. At time of presentation, patients treated surgically had a tumor size in maximum dimension of 2.7±1.4 cm versus 1.6±0.5 cm for those treated conservatively (p=0.0003). There were no significant differences in endocrinological values at time of presentation between groups. Fifteen percent (n=9) of patients treated surgically underwent an additional surgery (mean 2.8±2.0 years from index), of which 67% (n=6) were secondary to tumor recurrence. Conclusions: This is one of the largest reported series of apoplexy with long-term follow up. A subset of surgically treated patients will require additional intervention, highlighting the importance of ongoing follow up in this population.

Background: Quality of life (QoL) is the awareness of individuals’ well-being in life in physical, personal, mental and social wellbeing and needs to be addressed in brain tumor patients. Methods: A retrospective study conducted in 2017 in a single academic center that included patients diagnosed with brain tumors in a 10 year period. The assessment of the QoL was done using the European Organization for Research and Treatment of Cancer (EORTC), a standardized model (QLQ-C30) that assess several domains (Global Health, Physical function, Role functioning, Emotional Functioning, Cognitive functioning, social functioning and symptoms domain) and Brain cancer model (BN20) to assess symptoms to evaluate all aspects of wellbeing. Results: The total number of patients included in this study is 76 patients with no gender predilection. The most common brain tumor was meningioma by 40% followed by glioma/ others. More than half of the brain tumor patients had a WHO grade I (65%), intermediate grading grade II (15%) and higher grading grade III/IV (20%). The scales and measurements of functioning in life were low in all types of brain tumors. Conclusions: Quality of life in brain tumor patients seemed poor regardless of the type. Further prospective studies are needed to assess QoL worldwide.

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

The twentieth and twenty-first centuries have witnessed a literary revival in the Indigenous languages of the region known canonically as “Latin America.” Across this varied corpus, a major theme is the cultural significance of maize. This article compares the depiction of maize in four bilingual poems, each written in a different Indigenous language alongside Spanish: Nahuatl (Ethel Xochitiotzin Pérez), Yucatec Maya (María Dolores Dzul Barboza), Central Quechua (César Vargas Arce), and Southern Quechua (Emilio Corrales). Through close textual analysis and by recourse to theoretical perspectives such as “literary cartography,” the “textual continuum,” “deep mapping,” and “trans-indigeneity,” the article argues that each poem communicates culturally specific ways of understanding geography that, when set in dialogue, challenge hegemonic definitions of the Western Hemisphere such as North, South, or Latin “America.” Rather, the poems in combination weave an interconnected yet multiperspectival cartographic tapestry with maize as the common thread.

Background: People with epilepsy experience higher rates of cardiac arrhythmia and sudden death than the general population, with the highest risk in genetic epilepsies. Despite growing evidence of a possible cardiac contribution, routine cardiac screening for epilepsy patients is rarely performed. Methods: We performed a single center, retrospective review of patients with developmental epileptic encephalopathies caused by genetic variants expressed in the heart and brain. Clinical history, medications, age, and cardiac evaluation data were extracted. Results: Among 67 patients (56% female), 54 (81%) had at least one ECG. Twenty (37%) had an abnormal ECG. Forty-one had a repeat ECG: 8 showed persistent abnormalities, 7 resolution of abnormalities, and 7 a new abnormality. Five patients with an abnormality did not receive a follow up ECG. Two patients each had histories of cardiac arrest, syncope, and sudden death in a family member. Cardiac phenotypes differed in patients who experienced generalized tonic-clonic seizures and patients with epilepsy for 3+ years. Conclusions: Almost 1/3 of our high-risk epilepsy cohort had history of cardiac events or abnormalities on cardiac testing. Seizure type and epilepsy duration were associated with altered cardiac phenotypes. Since some findings were potentially clinically significant, routine cardiac screening of high-risk epilepsy patients may be warranted.

In this paper, we investigate the twisted GGP conjecture for certain tempered representations using the theta correspondence and establish some special cases, namely when the L-parameter of the unitary group is the sum of conjugate-dual characters of the appropriate sign.