Search

IntroductionAlthough frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype.MethodsRetrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments.ResultsCommon symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations.DiscussionThis study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients.HighlightsThis project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Healthcare is a huge business sector in many countries, focusing on the social function of delivering quality health when people develop illness. The system is essentially financed by public funds based on the solidarity principle. With a large financial outlay, the sector must use economic evaluation methods to achieve better efficiency. The objective of our study was to evaluate and to understand how health economics is used today, taking Belgium as an example of a high-income country. The evaluation started with a historical view of healthcare development and ended with potential projections for its future. A literature review focused on country-specific evaluation reports to identify the health economic methods used, with a search for potential gaps. The first results indicated that Belgium in 2021 devoted 11% of its GDP, 17% of its total tax revenue, and 30% of the national Social Security Fund to health-related activities, totalizing EUR 55.5 billion spending. The main health economic method used was a cost-effectiveness analysis linked to budget impact, assigning reimbursable monetary values to new products becoming available. However, these evaluation methods only impacted at most 20% of the money circulating in healthcare. The remaining 80% was subject to financial regulations (70%) and budgeting (10%), which could use many other techniques of an economic analysis. The evaluation indicated two potentially important changes in health economic use in Belgium. One was an increased focus on budgeting with plans, time frames, and quantified treatment objectives on specific disease problems. Economic models with simulations are very supportive in those settings. The other was the application of constrained optimization methods, which may become the new standard of practice when switching from fee-for-service to pay-per-performance as promoted by value-based healthcare and value-based health management. This economic refocusing to a more constrained approach may help to keep the healthcare system sustainable and affordable in the face of the many future challenges including ageing, climate change, migration, pandemics, logistical limitations, and financial instability.

Background: Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently, a white matter tract termed the hyperdirect pathway (HDP), directly connecting the motor cortex to STN, has gained interest as HDP stimulation is hypothesized to drive DBS therapeutic effects. Previously, we have investigated EEG-based evoked potentials (EPs) to better understand the neuroanatomical origins of the DBS clinical effect. We found a 3-ms peak (P3) relating to clinical benefit, and a 10-ms peak (P10) suggesting nigral side effects. Here, we aimed to investigate the neuroanatomical origins of DBS EPs using probabilistic mapping. Methods: EPs were recorded using EEG whilst low-frequency stimulation was delivered at all DBS-contacts individually. Next, EPs were mapped onto the patients’ individual space and then transformed to MNI standard space. Using voxel-wise and fiber-wise probabilistic mapping, we determined hotspots/hottracts and coldspots/coldtracts for P3 and P10. Topography analysis was also performed to determine the spatial distribution of the DBS EPs. Results: In all 13 patients (18 hemispheres), voxel- and fiber-wise probabilistic mapping resulted in a P3-hotspot/hottract centered on the posterodorsomedial STN border indicative of HDP stimulation, while the P10-hotspot/hottract covered large parts of the substantia nigra. Conclusion: This study investigated EP-based probabilistic mapping in PD patients during STN-DBS, revealing a P3-hotspot/hottract in line with HDP stimulation and P10-hotspot/hottract related to nigral stimulation. Results from this study provide key evidence for an electrophysiological measure of HDP and nigral stimulation.

Abstract Background Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. Methods We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. Results ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. Conclusions Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

Abstract The market for microbial gums such as xanthan, gellan, dextran, and curdlan is continuously expanding, driven by their increasing application in various industries including petroleum, pharmaceuticals, cosmetics, and food, with the latter accounting for approximately 50% of global usage. To meet the growing demand and improve sustainability, there is a need to enhance production efficiency and reduce costs. This article addresses these issues by examining recent advancements and emerging trends in microbial gum production and application. By highlighting patented technologies and innovative approaches, the article aims to provide a comprehensive understanding of how the industry can achieve higher yields and economic viability. Despite being produced by different microorganisms, these gums are synthesized under similar conditions, such as pH, temperature, and medium composition. The purification or downstream processes for these gums are also comparable, primarily involving solvent precipitation, centrifugation for separation, and drying. Significant advances in gum production include genetic improvement of microbial strains to improve biopolymer performance. Additionally, alternative media are being explored, either by optimizing nutrient availability or deprivation, or by using agroindustrial by-products to reduce production costs. Engineering improvements are another strategy: bioreactor characteristics, fermentation conditions and modes of operation, and advances in downstream process are highlighted. Furthermore, the text explores emerging trends in the application of microbial gums in the food sector. Microbial gums applications are not limited to their traditional action as emulsifiers and stabilizers, but expands to new uses in biodegradable packaging films and as antioxidant and prebiotic food ingredient.

Abstract Background Sophorolipids (SLs) are a class of natural, biodegradable surfactants that found their way as ingredients for environment friendly cleaning products, cosmetics and nanotechnological applications. Large-scale production relies on fermentations using the yeast Starmerella bombicola that naturally produces high titers of SLs from renewable resources. The resulting product is typically an extracellular mixture of acidic and lactonic congeners. Previously, we identified an esterase, termed Starmerella bombicola lactone esterase (SBLE), believed to act as an extracellular reverse lactonase to directly use acidic SLs as substrate. Results We here show based on newly available pure substrates, HPLC and mass spectrometric analysis, that the actual substrates of SBLE are in fact bola SLs, revealing that SBLE actually catalyzes an intramolecular transesterification reaction. Bola SLs contain a second sophorose attached to the fatty acyl group that acts as a leaving group during lactonization. Conclusions The biosynthetic function by which the Starmerella bombicola ‘lactone esterase’ converts acidic SLs into lactonic SLs should be revised to a ‘transesterase’ where bola SL are the true intermediate. This insights paves the way for alternative engineering strategies to develop designer surfactants.

Abstract Background There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established. Methods Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aβ groups (CL 50 = Aβ+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample. Results Participants included 765 Aβ- (61%, Mdn age = 66.0, IQR age = 61.0–71.0; 59% women), 301 Aβ± (24%; Mdn age = 69.0, IQR age = 64.0–75.0; 53% women) and 194 Aβ+ individuals (15%, Mdn age = 73.0, IQR age = 68.0–78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (b CL*Time = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (b CL*Time = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aβ+ CN individuals (HR Aβ+ vs Aβ- = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (b Aβ+ vs Aβ- = 0.137/year, 95% CI [0.069,0.206], p

Abstract Anaphylactic reactions at the time of chimeric antigen receptor T (CAR‐T) cell infusion are adverse events that have not been reported in pivotal clinical trials or in real‐world series. We report the case of patient with severe anaphylaxis with cardiac arrest after tisagenlecleucel injection for Diffuse Large B cell Lymphoma, who recovered after resuscitation and intensive care treatment; we also conducted a Food and Drug Administration Adverse Event Reporting System database analysis and found several cases of severe anaphlyaxis after CAR‐T cell injection. Although not reported in pivotal CAR‐T cell studies, anaphylaxis can occur after CAR‐T cell injection, highlighting the need to include anaphylaxis as a possible side effect in future studies.

Abstract Background Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare primary immunodeficiency, with only 256 cases reported globally. This study aimed to explore the disease burden of APDS from the perspective of individuals with APDS and their caregivers. Methods Qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers, to explore the symptoms and health-related quality of life (HRQoL) impact of APDS. Some individuals and caregivers also completed a narrative account exercise. All interviews were audio recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded. Results Semi-structured qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers. Individuals and caregivers had the option of completing a narrative account exercise. Six HCPs participated in an interview. Seven participants completed the narrative account exercise (N = 5 caregivers and N = 2 individuals with APDS) and 12 took part in an interview (N = 4 caregivers and N = 8 individuals with APDS). Themes identified from HCPs interviews included symptoms, clinical manifestations, HRQoL impacts and treatments/management of APDS. The narrative account exercise identified similar themes, but with the addition to the journey to diagnosis. These themes were explored during the individual/caregiver interviews. Reported clinical manifestations and symptoms of APDS included susceptibility to infections, lymphoproliferation, gastrointestinal (GI) disorders, fatigue, bodily pain, and breathing difficulties. HRQoL impacts of living with APDS included negative impacts to daily activities, including work, education and social and leisure activities, physical functioning, as well as emotional well-being, such as concern for the future, and interpersonal relationships. Impacts to caregiver HRQoL included negative impacts to physical health, work, emotional well-being, interpersonal relationships and family life and holidays. The management of APDS included the use of healthcare services and medications including immunoglobulin replacement therapy (IRT), rapamycin, prophylactic antibiotics, leniolisib, as well as medical procedures due to complications. Conclusions APDS has a high disease burden and there is an unmet need for licensed, more targeted treatments which modify disease progression. This study was the first to describe the day-to-day experience and HRQoL impact of APDS from the perspective of individuals living with the condition, caregivers and treating physicians.

Abstract Background This study evaluates the lesion contrast in a cost-effective long axial field of view (FOV) PET scanner, called the walk-through PET (WT-PET). The scanner consists of two flat detector panels covering the entire torso and head, scanning patients in an upright position for increased throughput. High-resolution, depth-of-interaction capable, monolithic detector technology is used to provide good spatial resolution and enable detection of smaller lesions. Methods Monte Carlo GATE simulations are used in conjunction with XCAT anthropomorphic phantoms to evaluate lesion contrast in lung, liver and breast for various lesion diameters (10, 7 and 5 mm), activity concentration ratios (8:1, 4:1 and 2:1) and patient BMIs (18–37). Images were reconstructed iteratively with listmode maximum likelihood expectation maximization, and contrast recovery coefficients (CRCs) were obtained for the reconstructed lesions. Results Results shows notable variations in contrast recovery coefficients (CRC) across different lesion sizes and organ locations within the XCAT phantoms. Specifically, our findings reveal that 10 mm lesions consistently exhibit higher CRC compared to 7 mm and 5 mm lesions, with increases of approximately 54% and 330%, respectively, across all investigated organs. Moreover, high contrast recovery is observed in most liver lesions regardless of diameter or activity ratio (average CRC = 42%), as well as in the 10 mm lesions in the lung. Notably, for the 10 mm lesions, the liver demonstrates 42% and 62% higher CRC compared to the lung and breast, respectively. This trend remains consistent across lesion sizes, with the liver consistently exhibiting higher CRC values compared to the lung and breast: 7 mm lesions show an increase of 96% and 41%, while 5 mm lesions exhibit approximately 294% and 302% higher CRC compared to the lung and breast, respectively. Conclusion A comparison with a conventional pixelated LSO long axial FOV PET shows similar performance, achieved at a reduced cost for the WT-PET due to a reduction in required number of detectors.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

INTRODUCTION: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). METHODS: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. RESULTS: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. DISCUSSION: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. HIGHLIGHTS: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline.

Background: Pregnant women are more vulnerable to the severe effects of COVID-19 compared to their non-pregnant peers. Early in the pandemic, there was a rise in cesarean deliveries and preterm births among infected pregnant women. This study aims to evaluate whether there were any changes in obstetric interventions during the first two waves of the pandemic in Belgium. Methods: Between March 2020 and February 2021, the Belgian Obstetric Surveillance System (B.OSS) conducted an extensive, nationwide population-based registry study, that included nearly all births to women with a confirmed SARS-CoV-2 infection within six weeks before hospitalization in Belgium. The perinatal outcomes of these women were analyzed and compared with pre-pandemic regional perinatal data. Results: A total of 923 SARS-CoV-2 infected pregnant women were admitted to the hospital; 9.3 % were hospitalized for severe COVID-19, while the remaining were hospitalized for obstetric reasons. Infected women had a higher median BMI, a higher incidence of diabetes, and a greater proportion were overweight or obese compared to the reference group (p

Abstract The pathogenic effect of SNCA gene multiplications indicates that elevation of wild-type α-synuclein levels is sufficient to cause Parkinson’s disease (PD). Mitochondria have been proposed to be a major target of α-synuclein-induced damage. PINK1/parkin/DJ-1-mediated mitophagy is a defense strategy that allows cells to selectively eliminate severely damaged mitochondria. Here, we quantified mitophagic flux and non-mitochondrial autophagic flux in three models of increased α-synuclein expression: 1/Drosophila melanogaster that transgenically express human wild-type and mutant α-synuclein in flight muscle; 2/human skin fibroblasts transfected with α-synuclein or β-synuclein; and 3/human induced pluripotent stem cell (iPSC)-derived neurons carrying an extra copy of wild-type SNCA under control of a doxycycline-inducible promoter, allowing titratable α-synuclein upregulation. In each model, elevated α-synuclein levels potently suppressed mitophagic flux, while non-mitochondrial autophagy was preserved. In human neurons, a twofold increase in wild-type α-synuclein was already sufficient to induce this effect. PINK1 and parkin activation and mitochondrial translocation of DJ-1 after mitochondrial depolarization were not affected by α-synuclein upregulation. Overexpression of the actin-severing protein cofilin or treatment with CK666, an inhibitor of the actin-related protein 2/3 (Arp2/3) complex, rescued mitophagy in neurons with increased α-synuclein, suggesting that excessive actin network stabilization mediated the mitophagy defect. In conclusion, elevated α-synuclein levels inhibit mitophagic flux. Disruption of actin dynamics may play a key role in this effect.

Abstract Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p