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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.

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

Abstract Both regular flow and infrequent outburst floods shape the mountain landscape, but their relative contributions have been widely debated, in part due to the paucity of quantitative data on historical outburst floods. In June 2000, an outburst flood was triggered by a landslide-dam failure in a rapidly exhumed region of the Eastern Himalaya. To investigate the role of this kind outburst flood on landscape evolution, we employ topographic differencing, satellite imagery, and 2D hydraulic simulations to quantify the equivalent erosion and deposition within ~ 80 km flood route downstream of the breach. The flood lasted for ~ 10 h, with a peak discharge of 105 m3/s, leading to average erosion of 10 m, and contributed ~ 1–2 × 103 times more sediment than over long-term mean fluvial processes. The flood produced extensive lateral erosion, which triggered a threefold widening of the valley floor and abundant subsequent landslides. The ubiquitous boulder bars deposited in the channel inhibited incision, and facilitated lateral erosion after the flood. The resulting channel configuration and extensive bank erosion continue to affect fluvial dynamics until the next catastrophic flood that remobilizes the boulders. Our quantitative findings highlight the profound importance of recurrent outburst floods for gorge development and landscape evolution in Eastern Himalaya.

Abstract Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.

Abstract Background 18F-FDG brain PET is clinically used for differential diagnosis in cognitive dysfunction of unclear etiology and for exclusion of a neurodegenerative cause in patients with cognitive impairment in late-life psychiatric disorders. 18F-FDG PET measures regional glucose metabolism, which represents a combination of neuronal/synaptic activity but also astrocytic activity and neuroinflammation. Recently, imaging of synaptic vesicle protein 2 A (SV2A) has become available and was shown to be a proxy of synaptic density. This prospective study will investigate the use of 18F-SynVesT-1 for imaging SV2A and its discriminative power for differential diagnosis in cognitive disorders in a head-to-head comparison to 18F-FDG PET. In addition, simultaneous PET/MR allows an evaluation of contributing factors and the additional value of advanced MRI imaging to FDG/SV2A PET imaging will be investigated. In this work, the study design and protocol are depicted. Methods In this prospective, multimodal imaging study, 110 patients with uncertain diagnosis of cognitive impairment who are referred for 18F-FDG PET brain imaging in their diagnostic work-up in a tertiary memory clinic will be recruited. In addition, 40 healthy volunteers (HV) between 18 and 85 years (M/F) will be included. All study participants will undergo simultaneous 18F-SynVesT-1 PET/MR and an extensive neuropsychological evaluation. Amyloid status will be measured by PET using 18FNAV4694, in HV above 50 years of age. Structural T1-weighted and T2-weighted fluid-attenuated inversion recovery MR images, triple-tagging arterial spin labeling (ASL) and resting-state functional MRI (rs-fMRI) will be obtained. The study has been registered on ClinicalTrials.gov (NCT05384353) and is approved by the local Research Ethics Committee. Discussion The main endpoint of the study will be the comparison of the diagnostic accuracy between 18F-SynVesT-1 and 18F-FDG PET in cognitive disorders with uncertain etiology and in exclusion of a neurodegenerative cause in patients with cognitive impairment in late-life psychiatric disorders. The strength of the relationship between cognition and imaging data will be assessed, as well as the potential incremental diagnostic value of including MR volumetry, ASL perfusion and rs-fMRI.

Background: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by recurrent abdominal pain related to defecation and/or associated to a change in bowel habits. According to the stool type, four different IBS subtypes can be recognized, constipation predominant (IBS-C), diarrhea predominant (IBS-D), mixed (IBS-M), and undefined (IBS-U). Patients report that their IBS symptoms are exacerbated by food. Thus, it is important to find a nutritional approach that could be effective in reducing IBS symptoms. Objective: The present work is a post hoc analysis of the previously published DOMINO trial. It aimed to evaluate the effects of a self-instructed FODMAP-lowering diet smartphone application on symptoms and psychosocial aspects in primary care IBS stratifying the results for each IBS subtypes. Design: Post hoc analysis. Methods: Two hundred twenty-two primary care IBS patients followed a FODMAP-lowering diet for 8 weeks with the support of a smartphone application. Two follow-up visits were scheduled after 16 and 24 weeks. IBS–Symptoms Severity Score (IBS-SSS), quality of life (QoL), and adherence and dietary satisfaction were evaluated. Results: After 8 weeks, IBS-SSS improved in all IBS subtypes ( p

Abstract Background The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. Methods A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. Results The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). Conclusions The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.

Background: To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 μs) over conventional pulse width DBS (cDBS; ≥60 μs) in movement disorders. Objective: To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. Methods: We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. Results: Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p

Abstract Background Although a new generation of tomographs with a longer axial field-of-view called total-body PET have been developed, they are not widely utilized due to their high cost compared to conventional scanners. The newly designed walk-through total-body PET scanner is introduced as a high-throughput and cost-efficient alternative to total-body PET scanners, by making use of a flat panel geometry and lower cost, depth-of-interaction capable, monolithic BGO detectors. The main aim of the presented study is to evaluate through Monte Carlo simulation the system characteristics of the walk-through total-body PET scanner by comparing it with a Quadra-like total-body PET of similar attributes to the Siemens Biograph Vision Quadra. Methods The walk-through total-body PET is comprised of two flat detector panels, spaced 50 cm apart. Each panel, 70 $$\times$$ × 106 cm $$^2$$ 2 in size, consists of 280 BGO-based monolithic detectors. The Quadra-like TB-PET has been simulated based on the characteristics of the Biograph Vision Quadra, one of the most common total-body PET scanners with 106 cm of axial field-of-view, which is constructed with pixelated LSO scintillation crystals. The spatial resolution, sensitivity, count rate performance, scatter fractions, and image quality of both scanners are simulated in the GATE simulation toolkit for comparison. Results Due to the DOI-capable detectors used in the walk-through total-body PET, the values of the spatial resolution of this scanner were all below 2 mm along directions parallel to the panels, and reached a maximum of 3.36 mm in the direction perpendicular to the panels. This resolution is a large improvement compared to the values of the Quadra-like TB-PET. The walk-through total-body PET uses its maximum sensitivity (154 cps/kBq) for data acquisition and image reconstruction. Conclusion Based on the combination of very good spatial resolution and high sensitivity of the walk-through total-body PET, along with a 2.2 times lower scintillation crystal volume and 1.8 times lower SiPM surface, this scanner can be a very cost-efficient alternative for total-body PET scanners in cases where concomitant CT is not required.

Abstract Background The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer’s disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. Methods Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. Results 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = − 0.22, OR = 0.80, p

Abstract Background Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.

In this theoretical study, we compare electrostatically doped metal-transition metal dichalcogenide (TMD) edge-contacts versus substitutionally doped edge-contacts in terms of their contact resistance. Our approach involves the utilization of electrostatic doping achieved by applying back-gate bias to the metal-TMD edge contacts, where carrier injection is primarily governed by the Schottky barrier at the interface. To analyze these contacts, we employ the Wentzel-Kramers-Brillouin (WKB) approximation to calculate the transmission coefficient and use density functional theory (DFT)-derived band structures. We numerically solve the Poisson equation to capture the electrostatic potential. We also account for the impact of the image force using Green's function for the Poisson equation with boundary conditions appropriate to our specific geometry. Our findings reveal that electrostatically doped TMD edge contacts exhibit higher contact resistance compared to impurity-doped edge contacts at equivalent carrier concentrations. At the same time, we find that, among the electrostatically doped edge contacts, a low-κ back-gate oxide in conjunction with low-κ top oxide is preferable in terms of improvement in contact resistance. For instance, in a metal-TMD edge contact scenario involving a monolayer MoS_{2} as the channel, SiO_{2} as the infinitely thick top oxide, and a SiO_{2} back-gate oxide with an equivalent oxide thickness (EOT) of 1nm, we demonstrate that it is possible to achieve an impressively low contact resistance of 50Ωµm when the back-gate bias exceeds or equals 2 V.

Scintigraphy and Positron Emission Tomography (PET) are both nuclear medicine imaging techniques, providing functional information of the imaged areas. Scintigraphy is a two-dimensional projected imaging technique that was introduced in equine imaging in the late 1970s. Scintigraphy allows imaging of large body parts and can cover multiple areas, remaining the only technique commonly used in horses for whole body imaging. PET is a cross-sectional imaging technique, first used in horses in 2015, allowing higher resolution three-dimensional functional imaging of the equine distal limb. This manuscript will cover current use and values of these two modalities in equine lameness diagnosis.

PARVAX is a genetic vaccine platform based on an adeno-associated vector that has demonstrated to elicit potent, durable, and protective immunity in nonhuman primates (NHPs) after a single dose. Here, we assessed vaccine immunogenicity following a PARVAX prime-boost regimen against SARS-CoV-2. In mice, a low-dose prime followed by a higher-dose boost elicited potent neutralizing antibody responses and distinct cross-reactivity profiles, depending on the antigen used in the booster vaccine. However, the potent neutralizing anti-vector antibody responses developed in mice limited the dose that could be administered as a prime. We further explored the re-administration efficacy in NHPs primed with a SARS-CoV-2 Delta vaccine and boosted with an Omicron BA.1 vaccine at week 15, after the primary response peak antibody levels were reached. The boost elicited an increase in antibodies against several Omicron variants, but no increase was detected in the antibody titers for other variants. The anti-vector responses were low and showed some increased subsequent boosts but generally declined over time. The potent prime vaccination limited the detection of the boosting effect, and therefore, the effect of anti-vector immunity was not fully elucidated. These data show that PARVAX can be effectively re-administered and induce a novel antigenic response.