Electroencephalographic signals are obtained by amplifying and recording the brain’s spontaneous biological potential using electrodes positioned on the scalp. While proven to help find changes in brain activity with a high temporal resolution, such signals are contaminated by non-stationary and frequent artefacts. A plethora of noise reduction techniques have been developed, achieving remarkable performance. However, they often require multi-channel information and additional reference signals, are not fully automated, require human intervention and are mostly offline. With the popularity of Brain-Computer Interfaces and the application of Electroencephalography in daily activities and other ecological settings, there is an increasing need for robust, online, near real-time denoising techniques, without additional reference signals, that is fully automated and does not require human supervision nor multi-channel information. This research contributes to the body of knowledge by introducing onEEGwaveLAD, a novel, fully automated, ONline, EEG wavelet-based Learning Adaptive Denoiser pipeline for artefact identification and reduction. It is a specific framework that can be instantiated for various types of artefacts paving the path towards real-time denoising. As the first of its kind, it is described and instantiated for the particular problem of blink detection and reduction, and evaluated across a general and a specific analysis of the signal to noise ratio across 30 participants.

Refractory Focal Epilepsy can be treated by the surgical resection of the Seizure Onset Zone (SOZ), the region in the brain from which seizures originate. To remove the SOZ, precise localization must be performed to identify this region, and to minimize the risk of removing eloquent cortex. StereoEEG is a valuable method to localize the SOZ, by recording the propagation of epileptic signals using a series of implanted depth electrodes. This allows the origin of the seizure signals to be determined based on the time at which they are detected at known electrode contact coordinates along the implanted electrodes. The automation of the localization of the SOZ using stereo-EEG, CT and MRI data is becoming increasingly relevant in the neurosurgical literature, as it offers an opportunity for increased accuracy and efficiency. This study proposes a novel method to localize the SOZ by using multimodal image processing. The method allows a statistical representation of the SOZ to be constructed on the cortical surface model, by using a series of spatial transformations. In a clinical case of MRI-positive focal epilepsy, the proposed pipeline was able to correctly identify the SOZ whilst using electrophysiological input from distant electrodes with 80-90% of the pipeline’s result being within the resection cavity. In an MRI-negative patient’s result, 60-75% of the SOZ determination was also within the resective cavity. In both cases, the pipeline showed greater than 50% reduction in SOZ volume determination. Such precise localization may allow for smaller resection volumes to achieve seizure freedom and reduce neurological complications. This method may therefore offer a more accurate solution to SOZ localization with a reduced clinical workload.

BACKGROUND AIMS:Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism.METHODS:We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment.RESULTS:Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted.CONCLUSIONS:This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.

Introduction We recently showed in a large pediatric tri-institutional cohort of patients receiving a first allogeneic hematopoietic cell transplantation (allo-HCT) for a hematologic malignancy, that, in addition to recovery of CD4 > 50 cells/uL, also recovery of B cells > 25 cells/uL was found to be a predictor for outcomes. The impact of B cell immune reconstitution (IR) in a purely ex vivo T-cell depleted (TCD) setting has not been described. Objectives We analyzed the impact of B cell IR in a cohort of patients who received an ex vivo TCD allo-HCT for either a non-malignant or malignant indication. Methods We retrospectively analyzed data from consecutive patients receiving their first ex vivo CD34+ TCD allo-HCT for any indication at our institution for the period 2008-2018. Statistical analyses involved linearity evaluation using martingale residuals plots, as well as maximally selected log-rank statistics to identify cutoffs related to outcomes. For statistical analyses cox proportional hazard models and Fine-Gray competing risk methods were used. All statistical analyses were done using R statistical software, version 4.3.1. Results 326 patients with sufficient CD4 and B cell data in the first 100 days after allo-HCT were included. Median age for the full cohort was 40.3 (range 0.1-73.3) years; 84 (25.8%) patients were <18 years old. Diagnoses included acute myeloid leukemia (n=125), acute lymphoblastic leukemia (n=71), myelodysplastic syndrome (n=55), non-malignant (n=34), and other malignant (n=41) conditions. There was non-linearity between maximum B cell count before day 100 after HCT and non-relapse mortality (NRM). Log rank statistics demonstrated a B cell count of 199 cells/uL as the best cut-off to discriminate for risk of NRM (fig 1a); based on which we defined B cell IR as B cell > 200 cells/uL before day 100 for this cohort. Achieving both CD4 and B cell IR was associated with higher 5-year overall survival (OS) compared to only CD4 IR (86.8% versus 72.4%, p=0.036; fig 1b), but with similar 2-year cumulative incidence of NRM (2.3% versus 3.7%, p=0.062; fig 1c) and relapse (17.1% versus 21.3%, p=0.55; fig 1d). Compared to only CD4 IR, patients with only B cell IR had lower 5-year OS (56.6% versus 72.4%, p=0.018; fig 1b) and higher NRM (27.6% versus 3.7%, p<0.001; fig 1c). Conclusion In our analyses we show that B cell IR was not an additional predictor for outcomes in this cohort of mostly adult patients undergoing ex vivo CD34+ TCD allo-HCT. This was in contrast with our previous results in a cohort of pediatric/young adult patients, that included mainly T-replete allo-HCT, highlighting the importance of separately evaluating the impact of IR on outcomes in different allo-HCT platforms.

EBV+ lymphomas constitute a significant cause of morbidity and mortality in recipients of allogeneic hematopoietic cell (HCT) and solid organ transplants (SOT). Phase I and II trials have shown that in HCT recipients, adoptive transfer of EBV-specific T-cells from the HCT donor can safely induce durable remissions of EBV+ lymphomas including 70->90% of patients who have failed to respond to treatment with Rituximab. More recently, EBV-specific T-cells generated from allogeneic 3rd party donors have also been shown to induce durable remission of EBV+ lymphomas in Rituximab refractory HCT and SOT recipients. In this review, we compare results of phase I and II trials of 3rd party and donor derived EBV-specific T-cells. We focus on the attributes and limitations of each product in terms of access, safety, responses achieved and durability. The limited data available regarding donor and host factors contributing to T cell persistence is also described. We examine factors contributing to treatment failures and approaches to prevent or salvage relapse. Lastly, we summarize strategies to further improve results for virus-specific immunotherapies for post-transplant EBV lymphomas.

Abstract Background Midlife risk factors such as Type 2 Diabetes Mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life, with executive function, memory and attention domains often affected first. Spatiotemporal gait characteristics are increasingly recognised as biomarkers of neurocognitive function and later dementia risk. Methods Using an automated walkway, 24 spatiotemporal gait parameters were examined across 5 domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions. Neurocognitive function was measured using a neuropsychological assessment battery. Linear regression was used assess the relationship between each gait parameter across the three walks and cognitive function. Results 102 middle-aged adults underwent assessment, 65 with uncomplicated T2DM (57.5 ± 8.0 years; 40% female) and 37 healthy controls (57.0 ± 8.3 years; 62.1% female). T2DM was associated with significant changes in gait phases and rhythm domains at usual-pace, and greater gait variability observed during maximal-pace and dual-task. In the overall cohort, both gait pace and rhythm domains were associated with memory and executive function during usual pace walking. At maximal-pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual-task, associations between gait variability and delayed memory and executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Conclusion This supports the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals. Discrete associations were seen between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms, in addition to single-task usual-pace gait, may be important in cognitively unimpaired populations with risk factors for later cognitive decline - with the aim of identifying individuals who may benefit most from potential preventative interventions.

Background Although type 2 diabetes mellitus (T2DM) is an established risk factor for cognitive impairment, the underlying mechanisms remain poorly explored. One potential mechanism may be through effects of T2DM on cerebral perfusion. The current study hypothesized that T2DM is associated with altered peripheral and central hemodynamic responses to orthostasis, which may in turn be associated with cognitive impairment in T2DM.Methods A novel use of function-on-scalar regression, which allows the entire hemodynamic response curve to be modeled, was employed to assess the association between T2DM and hemodynamic responses to orthostasis. Logistic regression was used to assess the relationship between tissue saturation index (TSI), T2DM, and cognitive impairment. All analyses used cross-sectional data from Wave 3 of The Irish Longitudinal Study on Ageing (TILDA).Results Of 2 984 older adults (aged 64.3 +/- 8.0; 55% female), 189 (6.3%) had T2DM. T2DM was associated with many features that are indicative of autonomic dysfunction including a blunted peak heart rate and lower diastolic blood pressure. T2DM was associated with reduced TSI and also with greater odds of impaired performance on the Montreal Cognitive Assessment (odds ratio [OR]: 1.62; confidence interval [CI: 1.07, 2.56]; p = .019). Greater TSI was associated with lower odds of impaired performance (OR: 0.90, CI [0.81-0.99]; p = .047).Conclusions T2DM was associated with impaired peripheral and cerebral hemodynamic responses to active stand. Both T2DM and reduced cerebral perfusion were associated with impaired cognitive performance. Altered cerebral perfusion may represent an important mechanism linking T2DM and adverse brain health outcomes in older adults.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline—with the aim of identifying individuals who may benefit from potential preventative interventions.

Objectives: Evidence is limited on the comparative impact of specific anesthetic agents used in electroconvulsive therapy (ECT) on outcomes in treatment-resistant depression (TRD). Our study aimed to compare the efficacy of methohexital vs propofol by examining the number of treatment sessions needed to transition from acute to maintenance ECT (NTS) (i.e., change from minimum of two to one or fewer treatments per week), missed treatment sessions, and seizure durations.Methods: We conducted a retrospective cohort study via chart review of patients with TRD receiving ECT from October 2017 to October 2019. We included adult patients (3 18 years) diagnosed with TRD who received at least six ECT sessions. We analyzed our data using multilevel structural equation modeling(MSEM).Results: We included 149 patients (36.9% or 55/149 were ³ 65 years): 54 were methohexital-treated (mean age 59 ± 17 years; 41% male) and 95 were propofol-treated (mean age 55 ± 17 years; 36% male). No significant differences between methohexital vs propofol groups were found in NTS (mean ± SD: 12.6 ± 6.6 vs 11.5 ± 6.1; p = 0.3) and missed treatment sessions (0.63 ± 1.2 vs 0.69 ± 1.2; p = 0.75). Patients receiving methohexital manifested longer motor (25.5 ± 10.6s vs 19.9 ± 8.4s; p < .001) and electroencephalographic (EEG) seizure durations (42 ± 17.5s vs .9± 13.1s; p < .001) vs propofol. MSEM revealed that (1) methohexital was associated with longer first-session seizure durations (motor seizure: b = 6.28, p < 0.05; EEG seizure: b = 8.03, p < 0.05) and more rapid decline in motor seizure duration across sessions (b = –.38, p < .05) over propofol, while accounting for relevant covariates; (2) regardless of anesthesia used, faster reductions in seizure durations across sessions predicted fewer NTS; and (3) methohexital was associated with fewer NTS adjusted for covariates which were driven by two indirect effects: (a) sharper decline in motor duration across sessions and (b) the association between a sharper decline in motor duration across sessions with fewer missed treatments. The outcomes were not influenced by age, indicating that the findings are relevant to older adults.Conclusions: Our findings suggest that methoxexital had fewer NTS and longer seizure durations than propofol, indicating better ECT outcomes using methohexital for TRD. Further research is warranted to verify methohexital’s effects on cognitive and additional recovery outcomes within clinical practice.

Objectives The defining achievement of a multi-marathoner is completing 100 marathons. This study aimed to comprehensively document the phenomenon of multi-marathoning, addressing its demographics, culture and participatory nature, filling a gap in peer-reviewed research on the topic. Additionally, it aimed to provide recommendations for multi-marathon governing bodies, event organisers, health professionals and participants to address identified issues. Methods A global survey was distributed to participants and individuals interested in multi-marathoning. It was distributed with support from major national and international multi-marathon clubs through their social media channels, email groups and newsletters. The survey was conducted anonymously and online. Results The survey garnered responses from 830 participants across 40 countries, with an average marathon completion count of 146.54 (SD 201.83) per respondent. Gender distribution showed 60.69% men, 39.3% women and 0.1% gender variant/non-conforming. Respondents’ average ages were 51.6 (SD 9.96) years for men, 48.83 (SD 9.15) years for women and 35.00 (SD 8.76) years for gender variant/non-conforming. As participants age, social and travel motivations surpass competitiveness. A majority (57%) of respondents had at least one contravention to the pre-participation screening questionnaire PARQ-+ and 67% reported taking pain relief medication around events. Notably, 93% of respondents reported multi-marathoning as beneficial for their mental health. Discussion Multi-marathoning accommodates older athletes, but a significant gender imbalance exists in participation levels. Long-term health implications warrant attention from governing bodies, event organisers, health professionals and participants alike. Multi-marathoners should seek medical advice before participation, utilise modern equipment for health monitoring and optimise training accordingly. Conclusion Recommendations include encouraging diversity at events, ensuring event directors have well-resourced health plans and promoting participants’ proactive health management before and during their involvement in the sport. This study not only advances our understanding of multi-marathoning as a sport but also contributes to theoretical frameworks such as SDT and HBM.

In the European Union, the introduction of the Medical Device Regulation (MDR) 2017/745 in 2021 increased the regulatory requirements for 'in-hospital' manufacture of medical devices. Depending on the exact scenario, a hospital manufacturing devices will need to consider applying one of three sets of regulatory requirements defined in the MDR: a reduced set of rules called the 'health institution exemption', which can be availed of under certain conditions; rules that apply for the manufacture of custom-made devices; or, exceptionally and most onerously, the same 'full' set of rules that apply to commercial medical device manufacturers. The purpose of this discussion is to provide an introductory guide to compliance with the MDR for in-hospital manufacture, highlighting the main regulatory requirements and the factors which determine which of the three 'routes' is the most appropriate.

Abstract Objectives: Multi-marathoners, athletes dedicated to completing 100 or more marathons, represent a unique subculture within endurance sports. This study uses the Ten Item Personality Inventory (TIPI) test to explore their psychological traits. The study aims to identify the unique personality profiles of multi-marathoners and understand their implications for participation, performance, and well-being. Methods: TIPI was used to describe personality and provide valuable insights into the tendencies for certain personality traits. TIPI was conducted via an online cross-sectional survey distributed to the multi-marathon community, which received 593 responses, 56% men (n=331, average age = 53.87 years, SD = 9.91), 44% women (n=261, average age = 54.06, SD 10.56) from 22 countries. One respondent identified as another gender and was not included in the gender-based analysis. Cronbach’s Alpha and Guttman’s Lambda 6 were calculated to assess the internal consistency of the survey, and the results were statistically analysed using Mann-Whitney U tests, ANOVA Aligned Rank Transform (ART) tests, and Wilcoxon rank-sum post-hoc tests to highlight differences in emotional stability, openness, conscientiousness, extraversion, and agreeableness. Normative TIPI data from the original TIPI study served as a dataset for comparison. Additionally, Spearman's ρ based correlation was used to explore relationships between personality traits and other related variables from the multi-marathoner community collected from a previous study. Results: The findings reveal distinctive personality traits among multi-marathoners. Compared to the general population, results show multi-marathoners displayed higher levels of conscientiousness (F (1,591) = 2.42, p < 0.001 for gender), indicating strong self-discipline, organisation, and goal-oriented behaviour. They exhibited lower levels of emotional stability (F (1,591) = 5.525, p < 0.001 for age group) and openness (F (1,591) = 2.54, p < 0.001 for age group), suggesting challenges in stress management and adaptability. Following significant results from the ANOVA ART tests, the Wilcoxon rank-sum post-hoc analysis revealed a significant gender difference in agreeableness, with women exhibiting higher levels of agreeableness compared to men (W = 50809, p<0.00091). However, after applying the Bonferroni statistical correction, no significant differences were found between genders in conscientiousness or emotional stability. Additionally, there were no significant differences in personality traits across different age groups after applying the statistical correction. These findings suggest that while gender differences in agreeableness are robust, age-related differences in personality traits were not statistically significant in this study. Conclusion: This study offers insights into the psychological traits of multi-marathoners, highlighting their high conscientiousness and lower emotional stability. Contrary to the initial hypotheses, no significant differences were found in openness, and age-related differences in personality traits were not statistically significant after applying the Bonferroni statistical correction. These findings suggest that while multi-marathoners possess distinct personality traits, the relationship between these traits and their engagement in endurance sports is more complex than initially anticipated. These insights can guide the development of interventions to foster resilience and sustained participation, enhancing their overall experience and success in multi-marathoning. Longitudinal studies to track changes in personality traits and explore effective psychological interventions for this unique athletic community would allow further insight. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Trinity College Dublin’s Faculty of Health Sciences Research Ethics Committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable All information will be available after acceptance or earlier if required (and is available immediately)