Hippocampal Sclerosis in Frontotemporal Dementia:When Vascular Pathology Meets Neurodegeneration

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.</p

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for D-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Individual treatment of hotel and restaurant waste water in rural areas

About 25 hotels, restaurants and pubs in the rural community Heuvelland are situated in the area designated for individual water treatment. In order to meet the legislation by the end of 2015, each business needs to install an individual waste water treatment system (IWTS). To study this situation, three catering businesses were selected for further research. The aim of the study was to quantify the effluent quality and to assess IWTS performance for these catering businesses. First of all, the influence of discharging untreated waste water on the receiving surface water was examined. The results showed a decrease in water quality after the discharge point at every business. With the collected data, simulations with the software WEST (R) were performed. With this software two types of IWTSs with different (buffer) volumes were modelled and tested for each catering business. The first type is a completely mixed activated sludge reactor and the second type is a submerged aerobic fixed-bed reactor. The results of these simulations demonstrate that purification with an IWTS is possible if the capacity is large enough and if an adequate buffer volume is installed and if regular maintenance is performed

Macht en waarden in de wereldpolitiek : actuele vraagstukken in de internationale politiek

De wereldpolitiek van vandaag is wat zij altijd is geweest: een spel om macht en invloed, waar staten met elkaar wedijveren, soms oorlog voeren, soms samenwerken, waar grote mogendheden oprijzen en vervolgens afkalven. Andere spelers – de publieke opinie, grote ondernemingen, een terreurgroep – kunnen af en toe aan zet zijn, maar het zijn de staten die het laatste woord hebben. Maar de wereldpolitiek draait niet enkel om macht. Brute macht roept onvermijdelijk weerstand op. Een internationale orde veronderstelt ook een aanzienlijke mate van vrijwillige instemming. Die internationale orde bestaat aldus uit twee onlosmakelijk verbonden elementen: macht én waarden. De basisdynamiek van de wereldpolitiek berust op een complex machtsspel, waarin geopolitiek, mondialisering en waarden in elkaar verstrengeld zijn. Maar kan dat ook een wereldorde opleveren, die stabiel is – en daarenboven legitiem? Elke generatie heeft steeds weer het gevoel in een heel nieuw wereld te leven, met nooit eerder geziene nieuwe ontwikkelingen, nieuwe actoren, nieuwe thema’s. Bij nader toezien echter is veel wat een generatie als ‘nieuw’ aanvoelt en bestempelt, door vorige generaties op dezelfde manier ervaren. Met die vergelijkingen tussen gisteren en vandaag moet echter altijd voorzichtig worden omgesprongen. De geschiedenis bereidt haar gerechten immers nooit tweemaal op dezelfde manier. Maar de ingrediënten zijn wel vaak dezelfde. Met een blik op het verleden werpt dit handboek bij de colleges 'Langetermijnontwikkelingen in de wereldpolitiek' een blik op de toekomst van de wereldpolitiek

Evaluation of virtual grid processed clinical chest radiographs

Objectives We evaluated the different Virtual Grid software ratios (Fujifilm, Tokyo, Japan) on gridless clinical chest radiographs with visual grading analysis (VGA). In addition, we investigated the 2 image quality assessment algorithms (IQAAs). Materials and Methods Gridless chest radiographs of 50 different intensive care unit patients were collected and afterward processed with Virtual Grid software. Different software (SW) grid ratios-6:1, 10:1, 13:1, 17:1, and 20:1-were applied to investigate the image quality (IQ) improvement. Image quality improvement was assessed by 4 radiologists in a relative VGA study where the reference image was processed with SW grid ratio of 10:1. One of the IQAAs used to analyze the radiographs was implemented in our department but was originally developed by the research group of the Duke University Medical Center. A general IQ score (IQS) was calculated based on contrast, detail, and noise. Another IQAA-NIQE (naturalness image quality evaluator)-available in Matlab (MATLAB Research R2019b; the MathWorks, Inc) was evaluated. Both methods were compared with VGA. Results Visual grading analysis scores of gridless radiographs are significantly lower (P < 0.001). Image quality increases with increasing SW grid ratios, up to grid ratio of 17:1. However, some anatomical structures-spine and ribs-are negatively affected by the higher grid ratios. A correlation coefficient of 0.99 between the VGA and the IQS was observed. The correlation coefficient between VGA and NIQE was 1.00. Conclusions Virtual Grid with SW grid ratio of 6:1 improves the IQ of gridless chest bedside radiographs. The grid ratios 17:1 and 20:1 should be considered carefully as the SW negatively affects parts of the ribs and spine. Therefore, grid ratios up to 13:1 can be advised. The IQAAs are promising and could be used to detect differences in IQ when different scatter correction SW settings are used

TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, Shows In Vitro an Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors ▿ †

TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC50], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC50, >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC50 was ≤4 for 82% of isolates and ≤10 for 96% of isolates. The FC in TMC310911 EC50 was ≤4 and ≤10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively. In vitro resistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC50 = 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC50 = 258). The activity against a comprehensive panel of PI-resistant mutants and the limited in vitro selection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance