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BackgroundThe key Alzheimer’s disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aβ42and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers.MethodsParticipants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months.ResultsOverall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up tor=0.50 (pr=0.43 (p=0.002) among tau, andr=−0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers.ConclusionThe implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.

The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Background: It is currently inconclusive whether different intracytoplasmic sperm injection (ICSI) timings post oocyte retrieval (POR) lead to altered chance of clinical pregnancy and live birth following in vitro fertilization (IVF) treatment. This study, therefore, aimed to synthesize literature-based evidence for better clinical guidance regarding ICSI practice. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines. Studies were searched for in PubMed, MEDLINE, EMBASE, and the Cochrane Library. Outcome endpoints included clinical pregnancy and live birth rates (LBRs). Results: A total of 605 records were retrieved in the initial search. After exclusion, 30 articles were included for further screening for eligibility. For meta-analysis, 1 prospective and 5 retrospective cohort studies were included for pooled analysis, from which clinical pregnancy rates (CPRs) were evaluated in 6 studies while LBRs were evaluated in 3 studies. CPRs were comparable when ICSI was performed at (a) [Formula: see text] hours POR (risk ratio or RR = 1.00, [Formula: see text] confidence interval [CI] 0.94–1.08) vs [Formula: see text] hours, (b) [Formula: see text] hours (RR = 1.01, [Formula: see text] CI 0.88–1.16) vs [Formula: see text] hours, (c) [Formula: see text] hours (RR = 0.99, [Formula: see text] CI 0.93–1.05) vs [Formula: see text] hours, (d) [Formula: see text] hours (RR = 0.98, [Formula: see text] CI 0.93–1.02) vs [Formula: see text] hours, and (e) [Formula: see text] hours (RR = 1.05, [Formula: see text] CI 0.90–1.23) vs [Formula: see text] hours. However, LBR was reduced when ICSI was performed [Formula: see text] hours POR vs [Formula: see text] hours (RR = 0.94, [Formula: see text] CI 0.89–0.99), but such reduction disappeared when comparing [Formula: see text] hours POR (RR = 1.09, [Formula: see text] CI 0.85–1.38) vs [Formula: see text] hours. Conclusions: CPRs remain comparable when ICSI is performed at a range of timings up to 6-hour POR. However, LBR may benefit slightly by scheduling ICSI between 5- and 6-hour POR.

Background Crohn’s disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. Methods Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric (“GenePy”). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. Results Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged Conclusions A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.

Recent evidence has shown that the marker of reactive astrogliosis, glial fibrillary acidic protein (GFAP), has a stronger relationship with cerebral amyloid beta (Aβ) pathology in blood than in cerebrospinal fluid (CSF). This study investigates if pre-analytical treatment of blood and CSF contribute to these unexpected findings.Paired CSF and serum samples from 49 individuals (Aβ-negative = 28; Aβ-positive = 21) underwent a series of seven freeze-thaw cycles (FTCs). All samples were analyzed for GFAP and neurofilament light (NfL) using single molecule array technology including a fresh unfrozen sample from each patient.FTC significantly affected CSF GFAP concentration (-188.12 pg/ml per FTC) but not serum GFAP. In the same samples, NfL remained stable. Serum GFAP had a higher discrimination of Aβ burden than CSF GFAP, irrespective of FTC, which also included unfrozen samples.This study demonstrates large stability differences of GFAP in CSF and serum. However, this disparity does not seem to fully explain the stronger association of serum GFAP with Aβ pathology. Further work should investigate mechanisms of GFAP release into the bloodstream under pathological conditions.

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886–0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835–0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642–0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320–0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

Studies of Crohn’s disease have consistently implicated NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Thereafter, genome-wide association, next-generation sequencing and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalized diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2 research, based on recently published evidence, and suggest methods that may meet these requirements.

To determine how the use of biological therapy is associated with surgical intervention for paediatric inflammatory bowel disease (PIBD) at a population level.Hospital Episode Statistics data were obtained for all admissions within England (1997-2015), in children aged 0-18 years, with an ICD-10 code for diagnosis of Crohn disease (CD), ulcerative colitis (UC), or inflammatory bowel disease-unclassified (IBD-U). Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures codes for major surgical resection associated with PIBD and for biological therapy were also obtained. Data are presented as median values (interquartile range).In total, 22,645 children had a diagnosis of PIBD of which 13,722 (61%) had CD, 7604 (34%) had UC, and 1319 (5.8%) cases had IBD-U. Biological therapy was used in 4054 (17.9%) cases. Surgical resection was undertaken in 3212 (14%) cases, more commonly for CD than UC (17.5 vs 10.3%, P0.0001). Time from diagnosis to major surgical resection was 8.3 (1.2-28.2) months in CD and 8.2 (0.8-21.3) months in UC. As the time-frame of the dataset progressed, there was a decreased rate of surgical intervention ( P = 0.04) and an increased use of biological therapy ( P0.0001). Additionally, the number of new diagnoses of PIBD increased.The introduction of biologic agents has been associated with a reduction in cases undergoing surgery in children with a known diagnosis of PIBD. As time progresses we will be able to determine whether biological therapies prevent the need for surgery altogether or just delay this until adulthood.

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.

Background and objectives:Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relation between kidney function, blood, cerebrospinal fluid (CSF), and structural brain MRI markers of neurodegeneration, in a sample including individuals with and without CKD.Methods:Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma-neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR) and structural brain MRI were included. Participants were invited to also have CSF collected. The primary endpoint of the present study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR and cerebrospinal fluid (CSF)- and MRI-derived markers of neurodegeneration and Alzheimer’s disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3; 6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model.Results:We included 744 participants, 668 without CKD (Age 71 (70; 71) years, 50% males) and 76 with CKD (age 71 (70;71) years, 39% males). Biomarkers from cerebrospinal fluid (CSF) were analysed in 313 participants. 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 (76; 77), 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 versus 14.0 pg/mL, pDiscussion:In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with two main subtypes: Crohn’s disease (CD) and Ulcerative Colitis (UC). Prompt subtype diagnosis enables the correct treatment to be administered. Using genomic data, we aimed to assess machine learning (ML) to classify patients according to IBD subtype. Methods Whole exome sequencing from paediatric/adult IBD patients was processed using an in-house bioinformatics pipeline. This data was condensed into the per-gene, per-individual genomic burden score, GenePy. Data was split into training and testing datasets (80/20). Feature selection with a linear support vector classifier, and hyperparameter tuning with Bayesian Optimisation was performed (training data). The supervised ML method random forest was utilised to classify patients as CD or UC using three panels: I) all available genes, 2) autoimmune genes, 3) ‘IBD’ genes. ML results were assessed using AUROC, sensitivity and specificity on the testing dataset. Results 906 patients were included in analysis (600 CD, 306 UC). Training data included 488 patients, balanced according to the minority class of UC. The autoimmune gene panel generated the best performing ML model (AUROC=0.68), outperforming an IBD gene panel (AUROC =0.61). NOD2 was the top gene for discriminating CD and UC, regardless of the gene panel used. Lack of variation in genes with high GenePy scores in CD patients was the best classifier of a diagnosis of UC. Discussion We demonstrate promising classification of patients by subtype utilising random forest and WES data. Focussing on specific subgroups of patients, with larger datasets may result in better classification.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176). We show that: 1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns towards a younger profile, and 3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

Abstract The rise of machine learning in healthcare has significant implications for paediatrics. Long-term conditions with significant disease heterogeneity comprise large portions of the routine work performed by paediatricians. Improving outcomes through discovery of disease and treatment prediction models, alongside novel subgroup clustering of patients, are some of the areas in which machine learning holds significant promise. While artificial intelligence has percolated into routine use in our day to day lives through advertising algorithms, song or movie selections and sifting of spam emails, the ability of machine learning to utilise highly complex and dimensional data has not yet reached its full potential in healthcare. In this review article, we discuss some of the foundations of machine learning, including some of the basic algorithms. We emphasise the importance of correct utilisation of machine learning, including adequate data preparation and external validation. Using nutrition in preterm infants and paediatric inflammatory bowel disease as examples, we discuss the evidence and potential utility of machine learning in paediatrics. Finally, we review some of the future applications, alongside challenges and ethical considerations related to application of artificial intelligence. Impact Machine learning is a widely used term; however, understanding of the process and application to healthcare is lacking. This article uses clinical examples to explore complex machine learning terms and algorithms. We discuss limitations and potential future applications within paediatrics and neonatal medicine.

Purpose: glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. Methods: we included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages). Results: plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. Conclusions: higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes. The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17–519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013–13054). MSC receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva programme grant IJC2018-037478-I). CM receives funding within the context of EURO-FINGERS, an EU Joint Programme—Neurodegenerative Disease Research (JPND) project. The EURO-FINGERS project is supported through the following funding organizations under the aegis of JPND—www.jpnd.eu: Finland, Academy of Finland; Germany, Federal Ministry of Education and Research; Spain, National Institute of Health Carlos III; Luxembourg, National Research Fund; Hungary, National Research, Development and Innovation Office; and the Netherlands, Netherlands Organisation for Health Research and Development (ZonMW-Memorabel #733051102). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532); the European Research Council (#681712); the Swedish State Support for Clinical Research (#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862); the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21–831376-C, #ADSF-21–831381-C, and #ADSF-21–831377-C); the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228); the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017–00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809–2016615); the Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466–236); and the National Institute of Health (NIH), USA (grant #1R01AG068398-01).

Introduction Frontotemporal dementia (FTD) encompasses a wide spectrum of genetic, clinical, and histological findings. Sex is emerging as a potential biological variable influencing FTD heterogeneity; however, only a few studies explored this issue with nonconclusive results. Objective To estimate the role of sex in a single-center large cohort of FTD patients. Methods Five hundred thirty-one FTD patients were consecutively enrolled. Demographic, clinical, and neuropsychological features, survival rate, and serum neurofilament light (NfL) concentration were determined and compared between sex. Results The behavioral variant of FTD was more common in men, whereas primary progressive aphasia was overrepresented in women (p p = 0.003), semantic fluency (p = 0.03), Short Story Recall Test (p = 0.003), and the copy of Rey Complex Figure (p = 0.005). On the other hand, men exhibited more personality/behavioral symptoms (Frontal Behavior Inventory [FBI] AB, p = 0.003), displaying higher scores in positive FBI subscales (FBI B, p p = 0.02), irritability (p = 0.006), poor judgment (p = 0.033), aggressivity (p = 0.008), and hypersexuality (p = 0.006) were more common in men, after correction for disease severity. NfL concentration and survival were not statistically different between men and women (p = 0.167 and p = 0.645, respectively). Discussion The present study demonstrated that sex is a potential factor in determining FTD phenotype, while it does not influence survival. Although the pathophysiological contribution of sex in neurodegeneration is not well characterized yet, our findings highlight its role as deserving biological variable in FTD.

Objective: The incidence of paediatric inflammatory bowel disease (IBD) has been increasing over 25 years; however, contemporary trends are not established and the impact of COVID-19 on case rates is unclear. Methods: Data from Southampton Children's hospital prospective IBD database were retrieved for 2002-2021. Incidence rates were calculated based on referral area populations and temporal trends analysed. Disease prevalence for those aged -6, driven by Crohn's disease, β = 0.732, P = 0.00024 and ulcerative colitis, β = 0.816, P = 0.000011. There was no change in IBDU incidence, β = 0.230, P = 0.33. From 2002-2021, 51 patients were diagnosed -7). There was no significant change in incidence of IBD in

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer’s disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer’s disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer’s Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer’s disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer’s disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03–1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50–5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02–1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03–1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer’s disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02–1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01–1.10). There was higher discrimination accuracy for Alzheimer’s disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer’s disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer’s disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer’s disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer’s disease.

Gold-standard diagnosis of Alzheimer’s disease (AD) relies on histopathological staging systems. Using the topographical information from [18F]MK6240 tau positron-emission tomography (PET), we applied the Braak tau staging system to 324 living individuals. We used PET-based Braak stage to model the trajectories of amyloid-β, phosphorylated tau (pTau) in cerebrospinal fluid (pTau181, pTau217, pTau231 and pTau235) and plasma (pTau181 and pTau231), neurodegeneration and cognitive symptoms. We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau-PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III–IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, whereas Braak stages V–VI were incompatible with normal cognition. In 159 individuals with follow-up tau-PET, progression beyond stage III took place uniquely in the presence of amyloid-β positivity. Our findings support PET-based Braak staging as a framework to model the natural history of AD and monitor AD severity in living humans.

While chest tube placement with pleural fibrinolytic medication is the established treatment of pediatric empyema, treatment failure is reported in up to 20% of these children.Standardizing fibrinolytic administration among interventional radiology (IR) physicians to improve patient outcomes in pediatric parapneumonic effusion.We introduced a hospital-wide clinical pathway for parapneumonic effusion (1-2 mg tissue plasminogen activator [tPA] twice daily based on pleural US grade); we then collected prospective data for IR treatment May 2017 through February 2020. These data included demographics, co-morbidities, pediatric intensive care unit (PICU) admission, pleural US grade, culture results, daily tPA dose average, twice-daily dose days, skipped dose days, pleural therapy days, need for chest CT/a second IR procedure/surgical drainage, and length of stay. We compared the prospective data to historical controls with IR treatment from January 2013 to April 2017.Sixty-three children and young adults were treated after clinical pathway implementation. IR referrals increased (P = 0.02) and included higher co-morbidities (P = 0.005) and more PICU patients (P = 0.05). Mean doses per day increased from 1.5 to 1.9 (P lt; 0.001), twice-daily dose days increased from 38% to 79% (P lt; 0.001) and median pleural therapy days decreased from 3.5 days to 2.5 days (P = 0.001). No IR patients needed surgical intervention. No statistical differences were observed for gender/age/weight, US grade, need for a second IR procedure or length of stay. US grade correlated with greater positive cultures, need for chest CT/second IR procedure, and pleural therapy days.Interventional radiology physician standardization improved on a clinical pathway for fibrinolysis of parapneumonic effusion. Despite higher patient complexity, pleural therapy duration decreased. There were no chest tube failures needing surgical drainage.

Background and ObjectivesTo evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.MethodsIndividuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,APOEε4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation–mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.ResultsThere were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% wereAPOEε4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aβ42/Aβ40 (22% vs 43% positive;p= 0.003). The receiver operating characteristic area under the curve of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% CI 0.79–0.92); p-tau181, 0.76 (0.68–0.84); p-tau231, 0.69 (0.60–0.78); and NfL, 0.64 (0.55–0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex,APOEε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aβ42/Aβ40 positivity (odds ratio 0.31 [95% CI 0.13–0.73], 0.30 [0.13–0.71], and 0.27 [0.12–0.64], respectively). Models of amyloid PET status yielded similar findings.DiscussionModels predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1β, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10

[Introduction] Clinical trials targeting tau in Alzheimer's disease (AD) need to recruit individuals at risk of tau accumulation. Here, we studied cerebrospinal fluid (CSF) biomarkers and plasma phosphorylated tau (p-tau)181 as predictors of tau accumulation on positron emission tomography (PET) to evaluate implications for trial designs., [Methods] We included older individuals who had serial tau-PET scans, baseline amyloid beta (Aβ)-PET, and baseline CSF biomarkers (n = 163) or plasma p-tau181 (n = 74). We studied fluid biomarker associations with tau accumulation and estimated trial sample sizes and screening failure reductions by implementing these markers into participant selection for trials., [Results] P-tau181 in CSF and plasma predicted tau accumulation (r > 0.36, P < .001), even in AD-continuum individuals with normal baseline tau-PET (A+T–; r > 0.37, P < .05). Recruitment based on CSF biomarkers yielded comparable sample sizes to Aβ-PET. Prescreening with plasma p-tau181 reduced up to ≈50% of screening failures., [Discussion] Clinical trials testing tau-targeting therapies may benefit from using fluid biomarkers to recruit individuals at risk of tau aggregation., AM is supported by Gamla Tjänarinnor. TKK was funded by the BrightFocus Foundation (#A2020812F), the International Society for Neurochemistry's Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-940244), the Swedish Brain Foundation (Hjärnfonden; #FO2021-0298), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson's Foundation. MJG is supported by the “Miguel Servet” program (CP19/00031) and a research grant (PI20/00613) of the Spanish Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). AS is supported by the Paulo Foundation and the Orion Research Foundation sr. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). MS is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine; KAW 2014.0363), the Swedish Research Council (#2017-02869), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-813971), and the Swedish Alzheimer Foundation (#AF-740191). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).

Background/Objective– Heterogeneity and chronicity of Crohn’s disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient’s disease course, preventing assessment and integration into predictive modelling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score.Methods– Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a paediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children’s Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov).Results– Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/faecal/radiological/endoscopic results, medication usage, surgery, growth parameters and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration.PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/faecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5), data were normally distributed (p=0.2) with 25% of patients having a PCD-MI Conclusions– PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimised scores and validation on external cohorts.