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Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.
Methods
In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.
Results
In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).
Conclusions
This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.
We present the serendipitous radio-continuum discovery of a likely Galactic supernova remnant (SNR) G305.4–2.2. This object displays a remarkable circular symmetry in shape, making it one of the most circular Galactic SNRs known. Nicknamed Teleios due to its symmetry, it was detected in the new Australian Square Kilometre Array Pathfinder (ASKAP) Evolutionary Map of the Universe (EMU) radio–continuum images with an angular size of 1 320$^{\prime\prime}$$\times$1 260$^{\prime\prime}$ and PA = 0$^\circ$. While there is a hint of possible H$\alpha$ and gamma-ray emission, Teleios is exclusively seen at radio–continuum frequencies. Interestingly, Teleios is not only almost perfectly symmetric, but it also has one of the lowest surface brightnesses discovered among Galactic SNRs and a steep spectral index of $\alpha$=–0.6$\pm$0.3. Our best estimates from Hi studies and the $\Sigma$–D relation place Teleios as a type Ia SNR at a distance of either $\sim$2.2 kpc (near-side) or $\sim$7.7 kpc (far-side). This indicates two possible scenarios, either a young (under 1 000 yr) or a somewhat older SNR (over 10 000 yr). With a corresponding diameter of 14/48 pc, our evolutionary studies place Teleios at the either early or late Sedov phase, depending on the distance/diameter estimate. However, our modelling also predicts X-ray emission, which we do not see in the present generation of eROSITA images. We also explored a type Iax explosion scenario that would point to a much closer distance of $\lt$1 kpc and Teleios size of only $\sim$3.3 pc, which would be similar to the only known type Iax remnant SN1181. Unfortunately, all examined scenarios have their challenges, and no definitive Supernova (SN) origin type can be established at this stage. Remarkably, Teleios has retained its symmetrical shape as it aged even to such a diameter, suggesting expansion into a rarefied and isotropic ambient medium. The low radio surface brightness and the lack of pronounced polarisation can be explained by a high level of ambient rotation measure (RM), with the largest RM being observed at Teleios’s centre.
Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment.
Methods
In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores from the Patient Health Questionnaire-9 (depression symptoms), Generalized Anxiety Disorder-7 (anxiety symptoms), and Work and Social Adjustment Scale (functional impairment). Genome-wide association analyses were performed with REGENIE. Heritability was estimated using GCTA-GREML and genetic correlations with bivariate-GREML.
Results
The phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50–0.69). All three scales were found to be under low but significant genetic influence (single-nucleotide polymorphism-based heritability [h2SNP] = 0.11–0.19) with high genetic correlations between them (rg = 0.79–0.87).
Conclusions
Among individuals with lifetime depression or anxiety from the GLAD Study, the genetic variants that underlie symptom severity largely overlap with those influencing functional impairment. This suggests that self-reported functional impairment, while clinically relevant for diagnosis and treatment outcomes, does not reflect substantial additional genetic liability beyond that captured by symptom-based measures of depression or anxiety.
Poor iron status is one of the most prevalent problems facing infants worldwide, in both developing and developed countries(1). A complex interplay of both dietary and non-dietary factors affects iron intake, absorption, and requirements, and subsequently iron status(2). We aimed to describe iron status in an ethnically diverse cohort of urban-dwelling infants. Data were collected from 364 infants aged 7.0 to 10.0 months living in two main urban centres in New Zealand (Auckland and Dunedin) between July 2020 and February 2022. Participants were grouped by total ethnicity, with any participants who did not identify as either Māori or Pacific categorised into a single ‘others’ group. Haemoglobin, plasma ferritin, soluble transferrin receptor (sTfR), C-Reactive protein, and alpha-1-acid-glycoprotein were obtained from a non-fasting venous blood sample. Inflammation was adjusted for using the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) method(3). Body iron concentration (mg/kg body weight) was calculated using the ratio of sTfR and ferritin. A total of 96.3% of Pacific infants were iron sufficient, defined as body iron ≥0 mg/kg body weight and haemoglobin (Hb) ≥105 g/L, compared to 82.3% of Māori and 76.0% of ‘other’ (i.e. neither Māori nor Pacific) infants. ‘Other’ infants had the highest prevalence of iron deficiency overall, with 2.8% categorised with iron-deficiency anaemia (IDA) (body iron <0 mg/kg, haemoglobin <105 g/L), 11.8% with early ‘functional’ iron deficiency (body iron <0 mg/kg, haemoglobin ≥105 g/L), and 9.4% with iron depletion (ferritin <15 µg/L, in the absence of early ‘functional’ iron deficiency and iron deficiency anaemia). For Māori infants, 3.2% and 6.5% had IDA and early ‘functional’ iron deficiency respectively, and 8.1% were iron depleted. One (3.7%) Pacific infant was iron depleted, and the remainder were iron sufficient. Plasma ferritin and body iron concentration were, on average, higher in Pacific compared to non-Pacific infants. These findings give an up-to-date and robust understanding of the iron status of infants by ethnicity, highlighting an unexpected finding that infants who are neither Māori nor Pacific may be at higher risk of poor iron status in NZ.
Food security constitutes a worldwide concern closely correlated with population growth. By 2050, the global population is expected to reach 9.3 billion(1). The rising population, along with increasing life expectancy and shifts toward Western dietary patterns, is expected to drive higher food demand and contribute to a rise in metabolic conditions(2). In this context, looking for alternative and sustainable food and protein sources is imperative. Pasture legumes including lucerne (Medicago sativa) and red clover (Trifolium pratense) are becoming popular as they can be used as an alternative protein and functional food source. Both crops play an important role in New Zealand’s agriculture. Their seeds can be used in human nutrition as alternative food and protein options; however, the presence of anti-nutritional factors (ANF) and their distinct taste make them less favourable for human consumption. Fermentation can be used as a possible strategy to mitigate these limitations. Lactobacillus fermentation was conducted using Lactocillus plantarum, Lactobacillus. acidophilus and Lactobacillus. casei. Proximate composition and mineral content were determined following Association of Official Analytical Chemists (AOAC) methods. Total phenol content (TPC), total flavonoid content (TFC) and antioxidant activity (2,2-Diphenyl-1-picrylhydrazyl and 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid) and ANF including phytic acid, trypsin, and chymotrypsin inhibition were assessed using colourimetric techniques. For the enzyme inhibition assays, enzyme-substrate reactions were performed with sample extracts before measurement. All the experiments were replicated three times, and the results were expressed as mean ± SD. A factorial analysis of variance (ANOVA) was conducted (4 legume seed samples × 3 LAB cultures) with a Tukey’s post-hoc test for mean comparison at P < 0.05 using IBM SPSS Statistics 29.0. All the legume seeds demonstrated high nutritional content, with crude protein and fibre levels around 40 and 16% respectively. The seeds were also rich in minerals, particularly magnesium, phosphorus, iron and zinc. In addition, fermentation led to an increase (P < 0.05) in TPC, TFC and antioxidant activity, while significantly reducing ANF. For instance, fermentation led to an increase in TPC (18.8 to 47.1% increase), TFC (9.6 to 34.5% increase) and AOA via DPPH and ABTS. Lactobacillus fermentation has proven to be an effective processing technique to enhance the nutritional value of lucerne and red clover seeds. These findings support the potential of using fermentation to develop novel and sustainable protein sources, contributing to improved dietary quality and nutrition. Moreover, further work to study the effect of fermentation on the nutrient digestibility of lucerne and red clover seeds is warranted.
New Zealand and Australian governments rely heavily on voluntary industry initiatives to improve population nutrition, such as voluntary front-of-pack nutrition labelling (Health Star Rating [HSR]), industry-led food advertising standards, and optional food reformulation programmes. Research in both countries has shown that food companies vary considerably in their policies and practices on nutrition(1). We aimed to determine if a tailored nutrition support programme for food companies improved their nutrition policies and practices compared with control companies who were not offered the programme. REFORM was a 24-month, two-country, cluster-randomised controlled trial. 132 major packaged food/drink manufacturers (n=96) and fast-food companies (n=36) were randomly assigned (2:1 ratio) to receive a 12-month tailored support programme or to the control group (no intervention). The intervention group was offered a programme designed and delivered by public health academics comprising regular meetings, tailored company reports, and recommendations and resources to improve product composition (e.g., reducing nutrients of concern through reformulation), nutrition labelling (e.g., adoption of HSR labels), marketing to children (reducing the exposure of children to unhealthy products and brands) and improved nutrition policy and corporate sustainability reporting. The primary outcome was the nutrient profile (measured using HSR) of company food and drink products at 24 months. Secondary outcomes were the nutrient content (energy, sodium, total sugar, and saturated fat) of company products, display of HSR labels on packaged products, company nutrition-related policies and commitments, and engagement with the intervention. Eighty-eight eligible intervention companies (9,235 products at baseline) were invited to participate, of whom 21 accepted and were enrolled in the REFORM programme (delivered between September 2021 and December 2022). Forty-four companies (3,551 products at baseline) were randomised to the control arm. At 24 months, the model-adjusted mean HSR of intervention company products was 2.58 compared to 2.68 for control companies, with no significant difference between groups (mean difference -0.10, 95% CI -0.40 to 0.21, p-value 0.53). A per protocol analysis of intervention companies who enrolled in the programme compared to control companies with no major protocol violation also found no significant difference (2.93 vs 2.64, mean difference 0.29, 95% CI -0.13 to 0.72, p-value 0.18). We found no significant differences between the intervention and control groups in any secondary outcome, except in total sugar (g/100g) where the sugar content of intervention company products was higher than that of control companies (12.32 vs 6.98, mean difference 5.34, 95% CI 1.73 to 8.96, p-value 0.004). The per-protocol analysis for sugar did not show a significant difference (10.47 vs 7.44, mean difference 3.03, 95% CI -0.48 to 6.53, p-value 0.09).In conclusion, a 12-month tailored nutrition support for food companies did not improve the nutrient profile of company products.
Cardiometabolic diseases, including type 2 diabetes (T2DM) and cardiovascular disease (CVD), are common. Approximately one in three deaths annually are caused by CVD in Aotearoa New Zealand (AoNZ)(1). The Mediterranean dietary pattern is associated with a reduced risk of cardiometabolic disease in epidemiological and interventional studies(2,3). However, implementing the Mediterranean diet into non-Mediterranean populations can be challenging(4). Some of these challeanges include facilitating consumption of unfamiliar foods and the cultural and social context of food consumption. AoNZ produces a rich source of high-quality foods consistent with a Mediterranean dietary pattern. He Rourou Whai Painga is collaborative project combining contributions from food industry partners into a Mediterranean Diet pattern and providing foods, recipes and other support to whole household/whānau. The aim was to test if a New Zealand food-based Mediterranean diet (NZMedDiet) with behavioural intervention improves cardiometabolic health and wellbeing in individuals at risk. This presentation will review the background to the research, the process of forming a collaboration between researchers and the food industry, the design and implementation of a complex study design (see protocol paper)(5), with results from the initial randomised controlled trial. We conducted several pilot studies(6,7,8) to inform the final design of the research, which was a combination of two randomised controlled trials (RCT 1 and 2) and a longitudinal cohort study. RCT-1 compared 12-weeks of the NZMedDiet to usual diet in participants with increased cardiometabolic risk (metabolic syndrome severity score (MetSSS) >0.35). The intervention group were provided with food and recipes to meet 75% of their energy requirements, supported by a behavioural intervention to improve adherence. The primary outcome measure was MetSSS after 12 weeks. Two hundred individuals with mean (SD) age 49.9 (10.9)yrs with 62% women were enrolled with their household/whānau. After 12 weeks, the mean (SD) MetSSS was 1.0 (0.7) in the control (n = 98) and 0.8 (0.5) in the intervention (n = 102) group; estimated difference (95% CI) of -0.05 (-0.16 to 0.06), p=0.35. A Mediterranean diet score (PyrMDS) was greater in the intervention group 1.6 (1.1 to 2.1), p<0.001, consistent with a change to a more Mediterranean dietary pattern. Weight reduced in the NZMedDiet group compared with control (-1.9 kg (-2.0 to -0.34)), p=0.006 and wellbeing, assessed by the SF-36 quality of life questionnaire, improved across all domains p<0.001. In participants with increased cardiometabolic risk, food provision with a Mediterranean dietary pattern and a behavioural intervention did not improve a metabolic risk score but was associated with reduced weight and improved quality of life.
Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.
Methods
T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).
Results
PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).
Conclusions
PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.
Plasmodium simium, a parasite of platyrrhine monkeys, is known to cause human malaria outbreaks in Southeast Brazil. It has been hypothesized that, upon the introduction of Plasmodium vivax into the Americas at the time of the European colonization, the human parasite adapted to neotropical anophelines of the Kerteszia subgenus and to local monkeys, along the Atlantic coast of Brazil, to give rise to a sister species, P. simium. Here, to obtain new insights into the origins and adaptation of P. simium to new hosts, we analysed whole-genome sequence (WGS) data from 31 P. simium isolates together with a global sequence dataset of 1086 P. vivax isolates. Population genomic analyses revealed that P. simium comprises a discrete parasite lineage with greatest genetic similarity to P. vivax populations from Latin America – especially those from the Amazon Basin of Brazil – and to ancient European P. vivax isolates, consistent with Brazil as the most likely birthplace of the species. We show that P. simium displays half the amount of nucleotide diversity of P. vivax from Latin America, as expected from its recent origin. We identified pairs of sympatric P. simium isolates from monkeys and from humans as closely related as meiotic half-siblings, revealing ongoing zoonotic transmission of P. simium. Most critically, we show that P. simium currently causes most, and possibly all, malarial infections usually attributed to P. vivax along the Serra do Mar Mountain Range of Southeast Brazil.
We compare the Emory 10-item, 4-choice Rey Complex Figure (CF) Recognition task with the Meyers and Lange (M&L) 24-item yes/no CF Recognition task in a large cohort of healthy research participants and in patients with heterogeneous movement disorder diagnoses. While both tasks assess CF recognition, they differ in key aspects including the saliency of target and distractor responses, self-selection versus forced-choice formats, and the length of the item sets.
Participants and Methods:
There were 1056 participants from the Emory Healthy Brain Study (EHBS; average MoCA = 26.8, SD = 2.4) and 223 movement disorder patients undergoing neuropsychological evaluation (average MoCA = 24.3, SD = 4.0).
Results:
Both recognition tasks differentiated between healthy and clinical groups; however, the Emory task demonstrated a larger effect size (Cohen’s d = 1.02) compared to the M&L task (Cohen’s d = 0.79). d-prime scoring of M&L recognition showed comparable group discrimination (Cohen’s d = 0.81). Unidimensional two-parameter logistic item response theory analysis revealed that many M&L items had low discrimination values and extreme difficulty parameters, which contributed to the task’s reduced sensitivity, particularly at lower cognitive proficiency levels relevant to clinical diagnosis. Dimensionality analyses indicated the influence of response sets as a potential contributor to poor item performance.
Conclusions:
Emory CF Recognition task demonstrates superior psychometric properties and greater sensitivity to cognitive impairment compared to the M&L task. Its ability to more precisely measure lower levels of cognitive functioning, along with its brevity, suggests it may be more effective for diagnostic use, especially in clinical populations with cognitive decline.
Background: TERT promoter mutation (TPM) is an established biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival (PFS). TERT expression, however, has also been observed even in tumours with wildtype TERT promoters (TP-WT). This study aimed to examine TERT expression and clinical outcomes in meningiomas. Methods: TERT expression, TPM status, and TERT promoter methylation of a multi-institutional cohort of meningiomas (n=1241) was assessed through nulk RNA sequencing (n=604), Sanger sequencing of the promoter (n=1095), and methylation profiling (n=1218). 380 Toronto meningiomas were used for discovery, and 861 external institution samples were compiled as a validation cohort. Results: Both TPMs and TERTpromoter methylation were associated with increased TERT expression and may represent independent mechanisms of TERT reactivation. TERT expression was detected in 30.4% of meningiomas that lacked TPMs, was associated with higher WHO grades, and corresponded to shorter PFS, independent of grade and even among TP-WT tumours. TERT expression was associated with a shorter PFS equivalent to those of TERT-negative meningiomas of one higher grade. Conclusions: Our findings highlight the prognostic significance of TERT expression in meningiomas, even in the absence of TPMs. Its presence may identify patients who may progress earlier and should be considered in risk stratification models.
Background: Our prior six-year review (n=2165) revealed 24% of patients undergoing posterior decompression surgeries (laminectomy or discectomy) sought emergency department (ED) care within three months post-surgery. We established an integrated Spine Assessment Clinic (SAC) to enhance patient outcomes and minimize unnecessary ED visits through pre-operative education, targeted QI interventions, and early post-operative follow-up. Methods: We reviewed 13 months of posterior decompression data (n=205) following SAC implementation. These patients received individualized, comprehensive pre-operative education and follow-up phone calls within 7 days post-surgery. ED visits within 90 days post-surgery were tracked using provincial databases and compared to our pre-SAC implementation data. Results: Out of 205 patients, 24 (11.6%) accounted for 34 ED visits within 90 days post-op, showing a significant reduction in ED visits from 24% to 11.6%, and decreased overall ED utilization from 42.1% to 16.6% (when accounting for multiple visits by the same patient). Early interventions including wound monitoring, outpatient bloodwork, and prescription adjustments for pain management, helped mitigate ED visits. Patient satisfaction surveys (n=62) indicated 92% were “highly satisfied” and 100% would recommend the SAC. Conclusions: The SAC reduced ED visits after posterior decompression surgery by over 50%, with pre-operative education, focused QI initiatives, and its individualized, proactive approach.
Background: Deep brain stimulation (DBS) in Parkinson’s disease (PD) requires extensive trial-and-error programming, often taking over a year to optimize. An objective, rapid biomarker of stimulation success is needed. Our team developed a functional magnetic resonance imaging (fMRI)-based algorithm to identify optimal DBS settings. This study prospectively compared fMRI-guided programming with standard-of-care (SoC) clinical programming in a double-blind, crossover, non-inferiority trial. Methods: Twenty-two 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 under SoC and fMRI-determined stimulation conditions. Results: fMRI optimization significantly reduced the time required to determine optimal settings (1.6 vs. 5.6 months, p<0.001). Unified Parkinson’s Disease Rating Scale (UPDRSIII) improved comparably with both approaches (23.8 vs. 23.6, p=0.9). Non-inferiority was demonstrated within a predefined margin of 5 points (p=0.0018). SoC led to greater tremor improvement (p=0.019), while fMRI showed greater bradykinesia improvement (p=0.040). Conclusions: This is the first prospective evaluation of an algorithm able to suggest stimulation parameters solely from the fMRI response to stimulation. It suggests that fMRI-based programming may achieve equivalent outcomes in less time than SoC, reducing patient burden while potentially enhancing bradykinesia response.
Background: The WHO grade of meningioma was updated in 2021 to include homozygous deletions of CDKN2A/B and TERT promotor mutations. Previous work including the recent cIMPACT-NOW statement have discussed the potential value of including chromosomal copy number alterations to help refine the current grading system. Methods: Chromosomal copy number profiles were inferred from from 1964 meningiomas using DNA methylation. Regularized Cox regresssion was used to identify CNAs independenly associated with post-surgical and post-RT PFS. Outcomes were stratified by WHO grade and novel CNAs to assess their potential value in WHO critiera. Results: Patients with WHO grade 1 tumours and chromosome 1p loss had similar outcomes to those with WHO grade 2 tumours (median PFS 5.83 [95% CI 4.36-Inf] vs 4.48 [4.09-5.18] years). Those with chromosome 1p loss and 1q gain had similar outcomes to those with WHO grade 3 cases regardless of initial grade (median PFS 2.23 [1.28-Inf] years WHO grade 1, 1.90 [1.23-2.25] years WHO grade 2, compared to 2.27 [1.68-3.05] years in WHO grade 3 cases overall). Conclusions: We advocate for chromosome 1p loss being added as a criterion for a CNS WHO grade of 2 meningioma and addition of 1q gain as a criterion for a CNS WHO grade of 3.
Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation model compatible with newer methylation arrays. Methods: The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. A nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection. Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and a retrospective cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperformed 2021 WHO grade in predicting postoperative recurrence. Dichotomizing into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (log-rank p<0.05). Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. This will help improve prognostication and inform patient selection for RT.
Background: Glial fibrillary acidic protein (GFAP), a brain-specific biomarker, shows promise in differentiating intracerebral hemorrhage (ICH) from acute ischemic stroke (IS) and stroke mimics (SM). A novel point-of-care platform measures GFAP in minutes, yet requires centrifugation to obtain plasma. We aim to determine whether participants recruited in an ongoing prospective biomarker study (during working hours) differ from non-recruited patients. Methods: An exploratory analysis of undifferentiated stroke <24h from onset, where plasma GFAP levels (pg/ml) are measured (i-STAT Alinity) at hospital arrival. Clinical characteristics are compared among recruited and non-recruited patients. Results: Among the first 101 patients recruited, mean (±SD) age (70.8±14.5 years), % females (48%), and median (IQR) NIHSS (9(3-20) were similar to the 270 non-recruited patients (70.3±16.3 years, 51% females, NIHSS 7 (3-17), respectively) in the same time period. Median ASPECTS was slightly lower in recruited patients (10(9-10) vs (10(10-10)) (p=0.03). ICH and SM were more common among non-recruited (52% IS/13% ICH/32% SM) compared to recruited patients (67% IS/5% ICH/29% SM, p=0.002), while large-vessel occlusion was more common among those recruited (44% vs 19%, p=0.001). Conclusions: Clinical characteristics do not differ among recruited vs. non-recruited patients in an ongoing biomarker study, yet sampling bias exists regarding underlying stroke condition, with efforts to mitigate this going forward.
Background: The complement component C5 inhibitor, ravulizumab, is approved in Canada for the treatment of adults with AQP4-Ab+ NMOSD. Updated efficacy and safety results from the ongoing CHAMPION-NMOSD (NCT04201262) trial are reported. Methods: Participants received IV-administered, weight-based dosing of ravulizumab, with loading on day 1 and maintenance doses on day 15 and every 8 weeks thereafter. Following a primary treatment period (PTP; up to 2.5 years), patients could enter a long-term extension (LTE). Outcome measures included safety, time to first adjudicated on-trial relapse (OTR), risk reduction, and disability scores. Results: 56/41 patients entered/completed the LTE as of June 14, 2024. Median follow-up was 170.3 weeks (186.6 patient-years). No patients experienced an OTR. 94.8% (55/58 patients) had stable or improved Hauser Ambulation Index scores. 89.7% (52/58 patients) had no clinically important worsening in Expanded Disability Status Scale scores. Treatment-emergent adverse events (98.4%) were predominantly mild and unrelated to ravulizumab. Serious adverse events occurred in 25.9% of patients. Two cases of meningococcal infection occurred during the PTP, and none in the LTE. One unrelated death (cardiovascular) occurred during the LTE. Conclusions: Ravulizumab demonstrated long-term clinical benefit in AQP4-Ab+ NMOSD relapse prevention while maintaining or improving disability measures, with no new safety concerns.