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Background Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage in elderly adults; however, presymptomatic diagnosis of CAA is difficult. Hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA‐D) is a rare autosomal‐dominant disease that leads to pathology similar to sporadic CAA. Presymptomatic HCHWA‐D mutation carriers provide a unique opportunity to study CAA‐related changes before any symptoms have occurred. In this study we investigated early CAA‐related alterations in the white matter. Methods and Results We investigated diffusion magnetic resonance imaging (dMRI) data for 15 symptomatic and 11 presymptomatic HCHWA‐D mutation carriers and 30 noncarrier control participants using 4 different approaches. We looked at (1) the relation between age and global dMRI measures for mutation carriers versus controls, (2) voxel‐wise dMRI, (3) independent component‐clustered dMRI measures, and (4) structural connectomics between presymptomatic or symptomatic carriers and controls. Fractional anisotropy decreased, and mean diffusivity and peak width of the skeletonized mean diffusivity increased significantly over age for mutation carriers compared with controls. In addition, voxel‐wise and independent component‐wise fractional anisotropy, and mean diffusivity, and structural connectomics were significantly different between HCHWA‐D patients and control participants, mainly in the periventricular frontal and occipital regions and in the occipital lobe. We found no significant differences between presymptomatic carriers and control participants. Conclusions The dMRI technique is sensitive in detecting alterations in symptomatic HCHWA‐d carriers but did not show alterations in presymptomatic carriers. This result indicates that dMRI may be less suitable for identifying early white matter changes in CAA.

Background: Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods: Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results: The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.582, p = 0.078). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.642 (p = 0.032). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.684, p = 0.004). Conclusions: FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter. Keywords: Frontotemporal dementia, MAPT protein human, GRN protein human, C9orf72 human, Diffusion Tensor Imaging, Resting-state functional MRI, Multimodal MRI, classification, machine learning

Author(s): Dineke Westra[sup.1] , Elena B. Volokhina[sup.1] , Renate G. van der Molen[sup.2] , Thea J. A. M. van der Velden[sup.1] , Annelies Jeronimus-Klaasen[sup.1] , Joop Goertz[sup.2] , Valentina Gracchi[sup.3] [...], Background The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. Methods Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, [alpha]FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. Results Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. Conclusions In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.

The purpose of this prospective study was to describe the normal anatomy and provide reference ranges for measurements of thoracic radiography on Squirrel monkeys (n = 13). Thoracic radiography is a common non-invasive diagnostic tool for both cardiac and non-cardiac thoracic structures. Furthermore cardiac disease is a common condition in captive primates. In this study, left-right lateral, right-left lateral and dorsoventral projections of 13 healthy Squirrel monkeys were reviewed during their annual health examinations. The mean Vertebral Heart Score on the left-right and right-left lateral projections were 8,98 ± 0,25 and 8,85 ± 0,35 respectively. The cardio-thoracic ratio on the dorsoventral projection was 0,68 ± 0,03. The trachea to inlet ratio was 0,33 ± 0,04. Other measurements are provided for the skeletal, cardiac and respiratory systems. Knowledge of the normal radiographic thoracic anatomy is fundamental in clinical as well as research settings for accurate diagnosis of diseases.

Reproductive monitoring for captive breeding in giant pandas is based on behavioural observation and non-invasive hormone analysis. In urine, interpretation of results requires normalisation due to an animal's changing hydration. Correction of urinary concentrations based on creatinine is the gold standard. In this study, a largely unexplored, easy-to-perform normalisation technique, based on urinary specific gravity (USpG), was examined and compared to creatinine. To this extent, six cycles from two female pandas (SB741(1) and SB569(5)) were monitored through urine analysis for oestrogen, progesterone, ceruloplasmin and 13,14-dihydro-15-keto-PGF2a (PGFM). The Pearson's correlation between creatinine and USpG was high (r = 0.805-0.894; p < 0.01), indicative for a similar performance of both normalisation methods. However, generally lower values were observed during pro-oestrus and primary (progesterone) rise. This could be associated with huge shifts in appetite, monitored by faecal output (kg) with an averaged > 50% decrease during oestrus and >50% increase during primary progesterone rise. In parallel, respectively highest and lowest creatinine and USpG levels, were measured, with creatinine obviously more affected as a result of linkage with muscle tissue metabolism affected by reproductive hormones. As a consequence, metabolite levels were significantly different between both corrected datasets with significantly higher oestrogen peak levels during oestrus ranging from 2.13-86.93 and 31.61-306.45 ng/mL (USpG correction) versus 2.33-31.20 and 36.36-249.05 ng/mL Cr (creatinine correction) for SB569 and SB741 respectively, and significant lower progesterone levels during primary progesterone rise ranging from 0.35-3.21 and 0.85-6.80 ng/mL (USpG correction) versus 0.52-10.31 and 2.10-272.74 ng/mL Cr (creatinine correction) for SB569 and SB741 respectively. Consequently, USpG correction rendered unbiased profiles, less subject to variation and metabolic artefacts and therefore allowed a more straightforward identification of peak oestrogen and onset of secondary progesterone rise, being potentially advantageous for future studies unravelling key giant panda reproductive events, including (delayed) implantation. The alternative application of USpG as a normalisation factor was further supported by its easy application and environmental and technical robustness.

Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. In addition, access to COVID-19 therapeutics remains limited. Collecting physicians' experiences with off-label use of therapeutics is important to inform global prioritization processes and better target pediatric research and development. A standardized questionnaire was designed to explore the use of therapeutics used to treat COVID-19 and multisystem inflammatory syndrome in children (MIS-C) in pediatric patients globally. Seventy-three physicians from 29 countries participated. For COVID-19, steroids were used by 75.6% of respondents; remdesivir and monoclonal antibodies were prescribed by 48.6% and 27.1% of respondents, respectively. For MIS-C, steroids were prescribed by 79.1% of respondents and intravenous immunoglobulins by 69.6%. The use of these products depended on their pediatric approval and the limited availability of antivirals and most monoclonal antibodies in Africa, South America, Southeast Asia, and Eastern Europe. Off-label prescription resulted widespread due to the paucity of clinical trials in young children at the time of the survey; though, based on our survey results, it was generally safe and led to clinical benefits. Conclusion: This survey provides a snapshot of current practice for treating pediatric COVID-19 worldwide, informing global prioritization efforts to better target pediatric research and development for COVID-19 therapeutics. Off-label use of such medicines is widespread for the paucity of clinical trials under 12 years and 40 kg, though appears to be safe and generally results in clinical benefits, even in young children. However, access to care, including medicine availability, differs widely globally. Clinical development of COVID-19 antivirals and monoclonal antibodies requires acceleration to ensure pediatric indication and allow worldwide availability of therapeutics that will enable more equitable access to COVID-19 treatment. What is Known: • Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. • Access to care differs widely globally, so because of the diversity of national healthcare systems; the unequal availability of medicines for COVID-19 treatment represents an obstacle to the pediatric population's universal right to health care. What is New: • Off-label COVID-19 drug prescription is widespread due to the lack of clinical trials in children younger than 12 years and weighing less than 40 kg, but relatively safe and generally leading to clinical benefit. • The application of the GAP-f framework to COVID-19 medicines is crucial, ensuring widespread access to all safe and effective drugs, enabling the rapid development of age-appropriate formulations, and developing specific access plans (including stability, storage, packaging, and labeling) for distribution in low- and middle-income countries (LMICs). Antivirals and monoclonal antibodies may benefit from the acceleration to reach widespread and equal diffusion. [ABSTRACT FROM AUTHOR]

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse‐free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T‐cell activation‐associated cytokines such as IL‐2, TNF‐α, and IFN‐γ were reduced upon LMS treatment, whereas IL‐4 and IL‐13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas‐mediated apoptosis. LMS treatment resulted in a mid‐S phase cell cycle arrest accompanied by γH2AX‐foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53‐dependent DNA damage response. [ABSTRACT FROM AUTHOR]

Grade two through six elementary school Dutch children were asked to perform a lexical decision task including 90 pseudowords constructed by changing one or two letters in a Dutch word. Subsequently, the children were asked about the meaning of pseudowords they had not crossed out and that they, apparently, had considered to be words. Multiple regression analyses on the lexical decision task showed that the older children were more hindered by the morphemic structure of a pseudoword than by its orthographic neighbors. The younger children, in contrast, were less hindered by the morphemic structure of a pseudoword and more hindered by its orthographic neighbors. Word length was a (small) predictor only for grade 6. Moreover, the answers of the children reflected that in their construction of meanings for the pseudowords they were hindered both by the morphemic structure and by the orthographic neighbors of the pseudowords. (Contains 1 footnote and 3 tables.)

Individuals with Prader-Willi syndrome (PWS) are at risk for excessive daytime sleepiness (EDS) and disruptive behavior. This pilot study explores temporal characteristics of EDS and severe disruptive behavior across time of day and day of week in seven individuals with PWS (aged between 33 and 49 years) of whom five were matched to controls. Direct care staff and/or parents used a scatter plot (i.e., 2-h partial interval recording) to collect data during 28 successive days. Overall frequency of EDS and severe disruptive behavior was low in both groups. Individuals with PWS generally showed more EDS when there were no scheduled activities compared to when activities were scheduled, specifically in the afternoon and in the evening and during the weekend. Scatter plot methodology may be useful in identifying situations that evoke excessive sleepiness and severe disruptive behaviors in people with PWS. (Contains 4 figures.)

This study focused on the relationship between both achievement level and diagnostic label and sociometric status and self-image of students in Dutch elementary education. In particular, differences between students with specific learning disabilities (SLD) and students with general learning disabilities (GLD) were studied, in regular as well as in special education. A total of 1,300 students participated, 861 in general and 439 in (separate) special education schools. Students with GLD were more often rejected and had a lower self-image than students with SLD. These results seemed to hold mainly for girls and for students with GLD in general education. No argument in favor of or against inclusive education can be advanced based on the results of this study, but the findings highlight the potential role of low achievement in peers' dislike of girls. Moreover, the results suggest the importance of investigating subgroups of students with LD in future research. (Contains 7 tables.)

Background A prediction model for graft survival including donor and recipient characteristics could help clinical decision-making and optimize outcomes. The aim of this study was to develop a risk assessment tool for graft survival based on essential pre-transplantation parameters. Methods The data originated from the national Dutch registry (NOTR; Nederlandse OrgaanTransplantatie Registratie). A multivariable binary logistic model was used to predict graft survival, corrected for the transplantation era and time after transplantation. Subsequently, a prediction score was calculated from the β-coefficients. For internal validation, derivation (80%) and validation (20%) cohorts were defined. Model performance was assessed with the area under the curve (AUC) of the receiver operating characteristics curve, Hosmer–Lemeshow test and calibration plots. Results In total, 1428 transplantations were performed. Ten-year graft survival was 42% for transplantations before 1990, which has improved to the current value of 92%. Over time, significantly more living and pre-emptive transplantations have been performed and overall donor age has increased (P  < .05).The prediction model included 71 829 observations of 554 transplantations between 1990 and 2021. Other variables incorporated in the model were recipient age, re-transplantation, number of human leucocyte antigen (HLA) mismatches and cause of kidney failure. The predictive capacity of this model had AUCs of 0.89, 0.79, 0.76 and 0.74 after 1, 5, 10 and 20 years, respectively (P  < .01). Calibration plots showed an excellent fit. Conclusions This pediatric pre-transplantation risk assessment tool exhibits good performance for predicting graft survival within the Dutch pediatric population. This model might support decision-making regarding donor selection to optimize graft outcomes. Trial registration ClinicalTrials.gov Identifier: NCT05388955 [ABSTRACT FROM AUTHOR]