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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

BackgroundThe impact of missing data on individual continuous glucose monitoring (CGM) data is unknown but can influence clinical decision-making for patients. ObjectiveWe aimed to investigate the consequences of data loss on glucose metrics in individual patient recordings from continuous glucose monitors and assess its implications on clinical decision-making. MethodsThe CGM data were collected from patients with type 1 and 2 diabetes using the FreeStyle Libre sensor (Abbott Diabetes Care). We selected 7-28 days of 24 hours of continuous data without any missing values from each individual patient. To mimic real-world data loss, missing data ranging from 5% to 50% were introduced into the data set. From this modified data set, clinical metrics including time below range (TBR), TBR level 2 (TBR2), and other common glucose metrics were calculated in the data sets with and that without data loss. Recordings in which glucose metrics deviated relevantly due to data loss, as determined by clinical experts, were defined as expert panel boundary error (εEPB). These errors were expressed as a percentage of the total number of recordings. The errors for the recordings with glucose management indicator

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

BackgroundOnly a small group of patients with glioblastoma multiforme (GBM) survives more than 36 months, so-called long-term survivors. Recent studies have shown that chromosomal instability (CIN) plays a prognostic and predictive role among different cancer types. Here, we compared histological (chromosome missegregation) and bioinformatic metrics (CIN signatures) of CIN in tumors of GBM typical survivors (≤36 months overall survival), GBM long-term survivors and isocitrate dehydrogenase (IDH)-mutant grade 4 astrocytomas.MethodsTumor sections of all gliomas were examined for anaphases and chromosome missegregation. Further CIN signature activity analysis in the The Cancer Genome Atlas (TCGA)-GBM cohort was performed.ResultsOur data show that chromosome missegregation is pervasive in high grade gliomas and is not different between the 3 groups. We find only limited evidence of altered CIN levels in tumors of GBM long-term survivors relative to the other groups, since a significant depletion in CIN signature 11 relative to GBM typical survivors was the only alteration detected. In contrast, within IDH-mutant grade 4 astrocytomas we detected a significant enrichment of CIN signature 5 and 10 activities and a depletion of CIN signature 1 activity relative to tumors of GBM typical survivors.ConclusionsOur data suggest that CIN is pervasive in high grade gliomas, however this is unlikely to be a major contributor to the phenomenon of long-term survivorship in GBM. Nevertheless, further evaluation of specific types of CIN (signatures) could have prognostic value in patients suffering from grade 4 gliomas.

BackgroundGlioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied. Age and dexamethasone administration in glioblastoma patients have been hypothesized to limit the effectiveness of immunotherapy, but their effects remain unclear. We compared peripheral blood immune composition in patients with different types of brain tumor to determine the influence of age, dexamethasone treatment, and tumor volume.MethodsHigh-dimensional mass cytometry was used to characterise peripheral blood mononuclear cells of 169 patients with glioblastoma, lower grade astrocytoma, metastases and meningioma. We used blood from medically-refractory epilepsy patients and healthy controls as control groups. Immune phenotyping was performed using FlowSOM and t-SNE analysis in R followed by supervised annotation of the resulting clusters. We conducted multiple linear regression analysis between intracranial pathology and cell type abundance, corrected for clinical variables. We tested correlations between cell type abundance and survival with Cox-regression analyses.ResultsGlioblastoma patients had significantly fewer naive CD4+ T cells, but higher percentages of mature NK cells than controls. Decreases of naive CD8+ T cells and alternative monocytes and an increase of memory B cells in glioblastoma patients were influenced by age and dexamethasone treatment, and only memory B cells by tumor volume. Progression free survival was associated with percentages of CD4+ regulatory T cells and double negative T cells.ConclusionHigh-dimensional mass cytometry of peripheral blood in patients with different types of intracranial tumor provides insight into the relation between intracranial pathology and peripheral immune status. Wide immunosuppression associated with age and pre-operative dexamethasone treatment provide further evidence for their deleterious effects on treatment with immunotherapy.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

BackgroundCommunity-acquired pneumonia (CAP) represents a major health burden worldwide. Dysregulation of the immune response plays an important role in adverse outcomes in patients with CAP.MethodsWe analyzed peripheral blood mononuclear cells by 36-color spectral flow cytometry in adult patients hospitalized for CAP (n=40), matched control subjects (n=31), and patients hospitalized for COVID-19 (n=35).ResultsWe identified 86 immune cell metaclusters, 19 of which (22.1%) were differentially abundant in patients with CAP versus matched controls. The most notable differences involved classical monocyte metaclusters, which were more abundant in CAP and displayed phenotypic alterations reminiscent of immunosuppression, increased susceptibility to apoptosis, and enhanced expression of chemokine receptors. Expression profiles on classical monocytes, driven by CCR7 and CXCR5, divided patients with CAP into two clusters with a distinct inflammatory response and disease course. The peripheral immune response in patients with CAP was highly similar to that in patients with COVID-19, but increased CCR7 expression on classical monocytes was only present in CAP.ConclusionCAP is associated with profound cellular changes in blood that mainly relate to classical monocytes and largely overlap with the immune response detected in COVID-19.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

Abstract Background: What combination of risk factors for Alzheimer’s disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-β pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. Methods: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-β status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-β status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-β status, and their interaction on changes in cognitive functioning over time. Results: Fifty-two participants (19%) had abnormal amyloid-β, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-β status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-β status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-β×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE β(SE)=-0.05(0.02); AD-PRS β(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-β status and AD-PRS predicted a steeper decline in memory functioning (amyloid-β β(SE)=-0.07(0.04); AD-PRS β(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-β status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-β abnormal individuals only (β(SE)=-0.13(0.06); β(SE)=-0.22(0.07), respectively). Conclusion: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-β only. Furthermore, independent of amyloid-β status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

In South-West Uganda, manure is highly valued for sustaining yields of East African Highland Banana, but it is in short supply. As a result, banana growers import manure from rangelands up to 50 km away. We aimed to explore the potential of this regional banana-livestock integration to meet crop nutrient requirements for sustainable intensification of banana cropping systems. We used a mixed-methods approach supported by detailed data collection. Multiple spatial levels were integrated: field-level modelling to determine long-term nutrient requirements, a household-level survey to characterize farmer practices, and a regional-level spatial analysis to map banana production and manure source areas. For median to 90th percentile banana yields (37-52 t FW/ha/year), minimum K requirements were 118–228 kg/ha/year. To supply this with manure, 10.5–20.5 t DM manure/ha/year would be needed, requiring 47–91 tropical livestock units and 27–52 ha of rangeland, far more than what is potentially available currently. However, using only manure to satisfy potassium requirements increases the risk of N losses due to nutrient imbalances likely to result from large manure applications. For sustainable intensification, manure supplemented with K-based fertilizers is a better option than manure alone, as it is more cost-effective and reduces potential N losses.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Background/Objectives: Traditional glycemic monitoring in type 2 diabetes is limited, whereas continuous glucose monitoring (CGM) offers better insights into glucose fluctuations. This study aimed to determine the correlations and relative contributions of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to hyperglycemia. Methods: We utilized CGM and recorded carbohydrate intake data from lifestyle diaries of 59 patients enrolled in the Diabetes and Lifestyle Cohort Twente (DIALECT-2). Correlations between FPG and the glucose management indicator (GMI), FPG and Time Above Range (TAR), PPG and GMI, and PPG and TAR were conducted. Daily and mealtime relative contributions of PPG and FPG to glycated hemoglobin (HbA1c) and GMI were determined, considering two ranges: on target (<7.0%, 53 mmol/mol) and not on target (≥7.0%, 53 mmol/mol). Correlations between mealtime PPG and carbohydrate consumption were examined. Results: FPG and PPG correlated with GMI (r = 0.82 and 0.41, respectively, p < 0.05). The relative contribution of PPG in patients with HbA1c, GMI, and TAR values not on target was lower than in patients with HbA1c, GMI, and TAR values on target. When analyzing different mealtimes, patients with target GMI values had a higher PPG (73 ± 21%) than FPG after breakfast (27 ± 21%, p < 0.001). Individuals with elevated GMI levels had lower PPG after lunch (30 ± 20%), dinner (36 ± 23%), and snacks (34 ± 23%) than FPG. PPG after breakfast positively correlated (r = 0.41, p < 0.01) with breakfast carbohydrate intake. Conclusions: Both PPG and FPG contribute to hyperglycemia, with PPG playing a larger role in patients with better glycemic control, especially after breakfast. Targeting PPG may be crucial for optimizing glucose management. [ABSTRACT FROM AUTHOR]

Op 10 juni 2021, meer dan een jaar na de uitbraak van COVID-19 in Europa, heeft de redactie van het Journal of Social Intervention een panelgesprek georganiseerd over de lessen die opleidingen sociaal werk trekken uit de coronacrisis. Studenten, docenten en leidinggevenden van sociaal werk opleidingen in Nederland en Vlaanderen blikten in dit gesprek kritisch terug op de ontwikkelingen in de opleidingen in deze bijzondere tijden en keken hoopvol vooruit naar wat we hieruit kunnen leren voor de toekomst. De snelle omschakeling naar digitaal onderwijs, de zorg voor de kwaliteit van het onderwijs en het welzijn van de studenten werden positief gewaardeerd. Maar in tijden van crisismanagement verliest men de essentie van het sociaal werk soms uit het oog: het belang van fysieke contacten en nabijheid, en vooral de democratische processen van co-creatie van opleiding, professionele praktijk en samenleving. Het dialogisch werken als eigenheid en kracht van het sociaal werk is volgens de panelleden te weinig geprofileerd in deze crisistijden. Die specifieke bijdrage van het sociaal werk zichtbaar maken, is een aandachtspunt voor de toekomst.

Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation. An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer., Author(s): Paula Voabil [sup.1] , Marjolein de Bruijn [sup.2] , Lisanne M. Roelofsen [sup.2] , Sanne H. Hendriks [sup.2] [sup.7] , Simone Brokamp [sup.2] , Marlous van den Braber [sup.2] [...]

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

This study compares the effects of metformin, sulfonylurea derivative (SU) and no treatment in HNF4A-MODY on glycemic control. In two patients with HNF4A-MODY, we changed the existing metformin treatment to SU derivative. The effect on the glycemic control was registered with a Freestyle Libre Flash glucose monitoring device. Each treatment period had a duration of 2 consecutive weeks, and in between, an intermediate period without medication. Data from the first 2 days after changing medications were excluded. We calculated time in range (TIR), and differences in the mean glucose level were tested with a one-way ANOVA test. The 24-h average glucose levels were significantly lower with either metformin (7.7 mmol/L; P < 0.001 and 6.3 mmol/L; P < 0.001) or gliclazide (7.6 mmol/L; P < 0.001 and 5.8 mmol/L; P < 0.001) compared to no treatment (9.4 and 8.9 mmol/L). The TIR with metformin or gliclazide was higher than without treatment (patient 1: 87 and 83 vs 61% and patient 2: 83 and 93 vs 67%). Treatment with either metformin or gliclazide effectively decreases blood glucose, rendering both drugs appropriate for treating HNF4A-MODY.

Abstract Background The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease. Methods Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. Results Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. Conclusions These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.