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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.

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.

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 Neuroinflammation, characterized by increased reactivity of microglia and astrocytes in the brain, is known to be present at various stages of the Alzheimer’s disease (AD) continuum. However, its presence and relationship with amyloid pathology in cognitively normal at-risk individuals is less clear. Here, we used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aβ) and their association in cognitively unimpaired homozygotes, heterozygotes, or non-carriers of the APOE ε4 allele, the strongest genetic risk for sporadic AD. Methods Sixty 60–75-year-old APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) were recruited in collaboration with the local Auria biobank. The participants underwent 11C-PK11195 PET (targeting 18-kDa translocator protein, TSPO), 11C-PiB PET (targeting Aβ), brain MRI, and neuropsychological testing including a preclinical cognitive composite (APCC). 11C-PK11195 distribution volume ratios and 11C-PiB standardized uptake value ratios (SUVRs) were calculated for regions typical for early Aβ accumulation in AD. Blood samples were drawn for measuring plasma glial fibrillary acidic protein (GFAP) and plasma Aβ1-42/1.40. Results In our cognitively unimpaired sample, cortical 11C-PiB-binding increased according to APOE ε4 gene dose (median composite SUVR 1.47 (range 1.38–1.66) in non-carriers, 1.55 (1.43–2.02) in heterozygotes, and 2.13 (1.61–2.83) in homozygotes, P = 0.002). In contrast, cortical composite 11C-PK11195-binding did not differ between the APOE ε4 gene doses (P = 0.27) or between Aβ-positive and Aβ-negative individuals (P = 0.81) and associated with higher Aβ burden only in APOE ε4 homozygotes (Rho = 0.47, P = 0.043). Plasma GFAP concentration correlated with cortical 11C-PiB (Rho = 0.35, P = 0.040), but not 11C-PK11195-binding (Rho = 0.13, P = 0.47) in Aβ-positive individuals. In the total cognitively unimpaired population, both higher composite 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, whereas elevated 11C-PiB-binding was associated with lower APCC scores. Conclusions Only Aβ burden measured by PET, but not markers of neuroinflammation, differed among cognitively unimpaired elderly with different APOE ε4 gene dose. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aβ.

Background Alzheimer’s disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement. Methods We developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer’s disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer’s disease from non-AD (p n = 165) and BioFINDER-2 cohorts (n = 563), consisting of patients across the full Alzheimer’s disease continuum, including also young controls ( Results Increased levels of all phosphorylated epitopes were found in Alzheimer’s disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer’s disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC = 98.73%, fold change = 7.64; BioFINDER-2: AUC = 91.89%, fold change = 10.65), pT217 (TRIAD: AUC = 99.71%, fold change = 6.33; BioFINDER-2: AUC = 98.12%, fold change = 8.83) and pT205 (TRIAD: AUC = 99.07%, fold change = 5.34; BioFINDER-2: AUC = 93.51%, fold change = 3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC = 83.26, fold change = 2.39; BioFINDER-2: AUC = 91.05%, fold change = 3.29), pT231 (TRIAD: AUC = 86.25, fold change = 3.80; BioFINDER-2: AUC = 78.69%, fold change = 3.65) and pT205 (TRIAD: AUC = 71.58, fold change = 1.51; BioFINDER-2: AUC = 71.11%, fold change = 1.70). Conclusions While an increase was found for all pTau species examined, the highest fold change in Alzheimer’s disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates.

The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research.We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers.The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures.This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.

Microglial activation and tau accumulation propagate together in patients with Alzheimer's disease, suggesting an interaction that determines disease progression. Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([C-11]PBR28), amyloid-beta (A beta) ([F-18]AZD4694) and tau ([F-18]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [C-11]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of A beta, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A beta and activated microglia sets the pace for tau spread across Braak stages.

Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials. The research leading to these results received funding from ‘la Caixa’ Foundation (ID 100010434), under agreement LCF/PR/GN17/10300004 and the Alzheimer’s Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). E.V. was supported by Flanders Innovation and Entrepreneurship (VLAIO grant no. 140105). C.M. received funding within the context of EURO-FINGERS, a 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 no. 733051102). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (grant no. 2018-02532), the European Research Council (ERC, grant no. 681712), Swedish State Support for Clinical Research (grant no. ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (grant no. 201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (grant nos. 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 (grant no. FO2019-0228), the EU’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 860197 (MIRIADE) and the UK Dementia Research Institute at University College London (UCL). J.D.G. is supported by the Spanish Ministry of Economy and Competitiveness (RYC-2013-13054) and received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD (grant no. 115952) and from Ministerio de Ciencia, Innovación y Universidades (grant no. RTI2018-102261). M.S.C. receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 948677), the Instituto de Salud Carlos III (PI19/00155), and from the ERC under the EU’s ‘la Caixa’ Foundation (ID 100010434) and from the EU’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant (no. 847648, LCF/BQ/PR21/11840004). K.B. is supported by the Swedish Research Council (grant no. 2017-00915), the ADDF, USA (grant no. RDAPB-201809-2016615), the Swedish Alzheimer Foundation (grant no. AF-742881) (grant nos. AF-930351, AF-939721 and AF-968270), Hjärnfonden, Sweden (grant nos. FO2017-0243 and ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (grant nos. ALFGBG-715986 and ALFGBG-965240), the EU Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institutes of Health (grant no. 1R01AG068398-01) and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495).

Background Synaptic dysfunction and degeneration are central to Alzheimer’s disease (AD) and have been found to correlate strongly with cognitive decline. Thus, studying cerebrospinal fluid (CSF) biomarkers reflecting synaptic degeneration, such as the presynaptic protein synaptosomal-associated protein 25 (SNAP-25), is of importance to better understand the AD pathophysiology. Methods We compared a newly developed Single molecule array (Simoa) immunoassay for SNAP-25 with an in-house immunoprecipitation mass spectrometry (IP-MS) method in a well-characterized clinical cohort (n = 70) consisting of cognitively unimpaired (CU) and cognitively impaired (CI) individuals with and without Aβ pathology (Aβ+ and Aβ−). Results A strong correlation (Spearman’s rank correlation coefficient (rs) > 0.88; p < 0.0001) was found between the Simoa and IP-MS methods, and no statistically significant difference was found for their clinical performance to identify AD pathophysiology in the form of Aβ pathology. Increased CSF SNAP-25 levels in CI Aβ+ compared with CU Aβ− (Simoa, p ≤ 0.01; IP-MS, p ≤ 0.05) and CI Aβ− (Simoa, p ≤ 0.01; IP-MS, p ≤ 0.05) were observed. In independent blood samples (n = 32), the Simoa SNAP-25 assay was found to lack analytical sensitivity for quantification of SNAP-25 in plasma. Conclusions These results indicate that the Simoa SNAP-25 method can be used interchangeably with the IP-MS method for the quantification of SNAP-25 in CSF. Additionally, these results confirm that CSF SNAP-25 is increased in relation to amyloid pathology in the AD continuum.

Background Blood phosphorylated tau (p-tau) forms are promising Alzheimer’s disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p-tau231 and p-tau181 in paired plasma and serum samples. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker-positive AD and biomarker-negative control participants. Methods We studied three independent cohorts (n=115 total): cohorts 1 and 2 included individuals with paired plasma and serum, while cohort 3 included paired serum and CSF. Blood-based p-tau231 and p-tau181 were measured using in-house or commercial single molecule array (Simoa) methods. Results Serum and plasma p-tau231 and p-tau181 were two- to three-fold increased in biomarker-positive AD versus biomarker-negative controls (P≤0.0008). Serum p-tau231 separated diagnostic groups with area under the curve (AUC) of 82.2% (cohort 3) to 88.2% (cohort 1) compared with 90.2% (cohort 1) for plasma. Similarly, p-tau181 showed AUC of 89.6% (cohort 1) to 89.8% (cohort 3) in serum versus 85.4% in plasma (cohort 1). P-tau231 and p-tau181 correlated slightly better in serum (rho=0.92 for cohort 1, 0.93 for cohort 3) than in plasma (rho=0.88, cohort 1). Within-individual p-tau181 (Quanterix) and p-tau231 concentrations were twice higher in plasma versus serum, but p-tau181 (in-house, Gothenburg) levels were not statistically different. Bland-Altman plots revealed that the relative difference between serum/plasma was larger in the lower range. P-tau levels in paired plasma and serum correlated strongly with each other (rho=0.75–0.93) as well as with CSF Aβ42 (rho= −0.56 to −0.59), p-tau and total-tau (rho=0.53–0.73). Based on the results, it seems possible that serum p-tau reflects the same pool of brain-secreted p-tau as in CSF; we estimated that less than 2% of CSF p-tau is found in serum, being same for both controls and AD. Conclusions Comparable diagnostic performances and strong correlations between serum versus plasma pairs suggest that p-tau analyses can be expanded to research cohorts and hospital systems that prefer serum to other blood matrices. However, absolute biomarker concentrations may not be interchangeable, indicating that plasma and serum samples should be used independently. These results should be validated in independent cohorts.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2022. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2022 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

Background The prodromal phase of frontotemporal dementia (FTD) is still not well characterized, and conversion rates to dementia and predictors of progression at 1-year follow-up are currently unknown. Methods In this retrospective study, disease severity was assessed using the global CDR plus NACC FTLD. Prodromal FTD was defined to reflect mild cognitive or behavioural impairment with relatively preserved functional independence (global CDR plus NACC = 0.5) as well as mild, moderate and severe dementia (classified as global CDR plus NACC = 1, 2, 3, respectively). Disease progression at 1-year follow-up and serum NfL measurements were acquired in a subgroup of patients. Results Of 563 participants, 138 were classified as prodromal FTD, 130 as mild, 175 as moderate and 120 as severe FTD. In the prodromal and mild phases, we observed an early increase in serum NfL levels followed by behavioural disturbances and deficits in executive functions. Negative symptoms, such as apathy, inflexibility and loss of insight, predominated in the prodromal phase. Serum NfL levels were significantly increased in the prodromal phase compared with healthy controls (average difference 14.5, 95% CI 2.9 to 26.1 pg/mL), but lower than in patients with mild FTD (average difference -15.5, 95% CI -28.4 to -2.7 pg/mL). At 1-year follow-up, 51.2% of patients in the prodromal phase had converted to dementia. Serum NfL measurements at baseline were the strongest predictors of disease progression at 1-year follow-up (OR 1.07, 95% CI 1.03 to 1.11, p < 0.001). Conclusions Prodromal FTD is a mutable stage with high rate of progression to fully symptomatic disease at 1-year follow-up. High serum NfL levels may support prodromal FTD diagnosis and represent a helpful marker to assess disease progression.

Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR p value = 4.6e−13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.

Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study; n = 58 and Hawaiian Ironman Triathlon 2008; n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO2 max) in recreationally active individuals and a triathlon time-to-completion (Hawaiian Ironman Triathlon cohort only). A nominal significance threshold of α

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73–0.87] and 0.92 [95% CI 0.89–0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS., Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.

Background Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. Methods Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P –5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. Results No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile–Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P –5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10–7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P –4) and the validation study (P –6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. Conclusions Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true.

The precise role of periostin, an extra-cellular matrix protein, in inflammatory bowel disease (IBD) is unclear. Here, we investigated periostin in paediatric IBD including its relationship with disease activity, clinical outcomes, genomic variation and expression in the colonic tissue. Plasma periostin was analysed using ELISA in 144 paediatric patients and 38 controls. Plasma levels were assessed against validated disease activity indices in IBD and clinical outcomes. An immuno-fluorescence for periostin and detailed isoform-expression analysis in the colonic tissue was performed in 23 individuals. We integrated a whole-gene based burden metric ‘GenePy’ to assess the impact of variation in POSTN and 23 other genes functionally connected to periostin. We found that plasma periostin levels were significantly increased during remission compared to active Crohn’s disease. The immuno-fluorescence analysis demonstrated enhanced peri-cryptal ring patterns in patients compared to controls, present throughout inflamed, as well as macroscopically non-inflamed colonic tissue. Interestingly, the pattern of isoforms remained unchanged during bowel inflammation compared to healthy controls. In addition to its role during the inflammatory processes in IBD, periostin may have an additional prominent role in mucosal repair. Additional studies will be necessary to understand its role in the pathogenesis, repair and fibrosis in IBD.

Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer’s Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer’s Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer’s Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer’s Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer’s pathology in previous studies.

Background Epithelioid hemangioma is a rare, benign vascular lesion classically presenting with painless nodules in the head and neck region. Hemangioma lesions are typically small, located within the dermis and subcutaneous tissue, and rarely exceed 10 cm in size. Complete surgical excision, with negative margins, is the recommended treatment as local recurrence is common. We describe an unusual presentation of epithelioid hemangioma that, to our knowledge, has not been previously described in the literature, epithelioid. Case presentation We report an atypical case of a large epithelioid hemangioma lesion with deep intramuscular involvement in a 16-year-old male. Ultrasound and MRI showed a hypervascular mass on the patient’s left upper back, and biopsy confirmed the diagnosis. Treatment consisted of preoperative embolization followed by excision and local tissue rearrangement. Conclusions Epithelioid hemangiomas are considered uncommon in the pediatric population. Moreover, it is challenging to diagnose these lesions due to their similarities to other vascular anomalies. We aim to increase awareness of this condition and obtain more precision in diagnosis, thus standardizing the approach for those treating individuals with vascular anomalies.

Background The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer’s disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer’s Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.

A proliferation of recent literature provides substantial direction as to the key ingredients-target groups, messages and methods, and evaluation-of local-level, public interventions to counter stigma and discrimination. This paper provides a selective narrative review of that literature from the perspective or standpoint of anti-stigma experts with lived experience of mental distress, the key findings of which have been synthesised and presented in diagrammatic overviews (infographics). These are intended to guide providers in planning, delivering and evaluating lived experience-directed local-level, public interventions to counter stigma and discrimination in accord with current best practice.

Influences of adenosine 2A receptor (A2AR) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A2AR-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A2AR-sensitive genes modified by A2AR KO (≥1.2-fold change, 4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR

Alzheimer’s disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles and widespread neuronal loss in the brain. In recent years, blood biomarkers have emerged as a realistic prospect to highlight accumulating pathology for secondary prevention trials. Neurofilament light chain (NfL), a marker of axonal degeneration, is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. A strong relationship with cerebrospinal fluid (CSF) NfL suggests that these biomarker modalities reflect the same pathological process. Yet, the connection between blood NfL and brain tissue pathology has not been directly compared. In this study, longitudinal plasma NfL from cognitively healthy controls (n = 12) and AD participants (n = 57) were quantified by the Simoa platform. On reaching post-mortem, neuropathological assessment was performed on all participants, with additional frozen and paraffin-embedded tissue acquired from 26 participants for further biochemical (Aβ1–42, Aβ1–40, tau) and histological (NfL) evaluation. Plasma NfL concentrations were significantly increased in AD and correlated with cognitive decline, independent of age. Retrospective stratification based on Braak staging revealed that baseline plasma NfL concentrations were associated with higher neurofibrillary tangle pathology at post-mortem. Longitudinal increases in plasma NfL were observed in all Braak groupings; a significant negative association, however, was found between plasma NfL at time point 1 and both its rate of change and annual percentage increase. Immunohistochemical evaluation of NfL in the medial temporal gyrus (MTG) demonstrated an inverse relationship between Braak stages and NfL staining. Importantly, a significant negative correlation was found between the plasma NfL measurement closest to death and the level of NfL staining in the MTG at post-mortem. For the first time, we demonstrate that plasma NfL associates with the severity of neurofibrillary tangle pathology and neurodegeneration in the post-mortem brain. Electronic supplementary material The online version of this article (10.1186/s40478-018-0649-3) contains supplementary material, which is available to authorized users.

The gene SMART (genes and the Skeletal Muscle Adaptive Response to Training) Study aims to identify genetic variants that predict the response to both a single session of High-Intensity Interval Exercise (HIIE) and to four weeks of High-Intensity Interval Training (HIIT). While the training and testing centre is located at Victoria University, Melbourne, three other centres have been launched at Bond University, Queensland University of Technology, Australia, and the University of Brighton, UK. Currently 39 participants have already completed the study and the overall aim is to recruit 200 moderately-trained, healthy Caucasians participants (all males 18–45 y, BMI

Paediatric inflammatory bowel disease (PIBD), comprising Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) is a complex and multifactorial condition with increasing incidence. An accurate diagnosis of PIBD is necessary for a prompt and effective treatment. This study utilises machine learning (ML) to classify disease using endoscopic and histological data for 287 children diagnosed with PIBD. Data were used to develop, train, test and validate a ML model to classify disease subtype. Unsupervised models revealed overlap of CD/UC with broad clustering but no clear subtype delineation, whereas hierarchical clustering identified four novel subgroups characterised by differing colonic involvement. Three supervised ML models were developed utilising endoscopic data only, histological only and combined endoscopic/histological data yielding classification accuracy of 71.0%, 76.9% and 82.7% respectively. The optimal combined model was tested on a statistically independent cohort of 48 PIBD patients from the same clinic, accurately classifying 83.3% of patients. This study employs mathematical modelling of endoscopic and histological data to aid diagnostic accuracy. While unsupervised modelling categorises patients into four subgroups, supervised approaches confirm the need of both endoscopic and histological evidence for an accurate diagnosis. Overall, this paper provides a blueprint for ML use with clinical data.

Background Achilles tendinopathy is the most prevalent tendon disorder in people engaged in running and jumping sports. Aetiology of Achilles tendinopathy is complex and requires comprehensive research of contributing risk factors. There is relatively little research focussing on potential biomedical risk factors for Achilles tendinopathy. The purpose of this systematic review is to identify studies and summarise current knowledge of biomedical risk factors of Achilles tendinopathy in physically active people. Methods Research databases were searched for relevant articles followed by assessment in accordance with PRISMA statement and standards of Cochrane collaboration. Levels of evidence and quality assessment designation were implemented in accordance with OCEBM levels of evidence and Newcastle-Ottawa Quality Assessment Scale, respectively. Results A systematic review of the literature identified 22 suitable articles. All included studies had moderate level of evidence (2b) with the Newcastle-Ottawa score varying between 6 and 9. The majority (17) investigated genetic polymorphisms involved in tendon structure and homeostasis and apoptosis and inflammation pathways. Overweight as a risk factor of Achilles tendinopathy was described in five included studies that investigated non-genetic factors. COL5A1 genetic variants were the most extensively studied, particularly in association with genetic variants in the genes involved in regulation of cell-matrix interaction in tendon and matrix homeostasis. It is important to investigate connections and pathways whose interactions might be disrupted and therefore alter collagen structure and lead to the development of pathology. Polymorphisms in genes involved in apoptosis and inflammation, and Achilles tendinopathy did not show strong association and, however, should be considered for further investigation. Conclusions This systematic review suggests that biomedical risk factors are an important consideration in the future study of propensity to the development of Achilles tendinopathy. The presence of certain medical comorbidities and genetic markers should be considered when contemplating the aetiology of Achilles tendinopathy. Further elucidation of biomedical risk factors will aid in the understanding of tendon pathology and patient risk, thereby informing prevention and management strategies for Achilles tendinopathy. Trial Registration PROSPERO CRD42016036558

The causes of childhood brain tumors (CBT) are largely unknown, but gestational diet may influence this risk. The aim of this analysis was to investigate whether maternal coffee or tea consumption during pregnancy was associated with the risk of CBT.The Australian Study of the Causes of Childhood Brain Tumours was a population-based, Australian case-control study conducted between 2005 and 2010. Case children were recruited from 10 pediatric oncology centers and control children by nationwide random-digit dialing, frequency matched to cases on the basis of age, sex and state of residence. Coffee and tea intake were assessed using a food frequency questionnaire.Data on coffee and tea consumption during pregnancy were available from 293 case mothers and 726 control mothers. Odds ratios (ORs) and confidence intervals (CIs) were calculated using multivariable unconditional logistic regression. There was little evidence of an association between gestational consumption of any coffee (OR 1.23, 95% CI 0.92, 1.64) or tea (OR 1.00, 95% CI 0.74, 1.36) and CBT risk. Among children aged under 5 years, the OR for any coffee consumption during pregnancy was 1.76 (95% CI 1.09, 2.84) and for ≥2 cups per day during pregnancy was 2.52 (95% CI 1.26, 5.04). There was little evidence that associations with coffee or tea intake differed by parental smoking status.These results suggest a positive association between coffee intake ≥2 cups per day and risk of CBT in younger children, although some estimates are imprecise. There was no association between maternal tea drinking and risk of CBT.

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992-2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2-1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.

An important anniversary often provides a valuable hook on which to hang a re-assessment of a key theme in international history. In this case, the 70th anniversary of Winston Churchill's Fulton sp...

Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. This study investigated whether household exposure to paints and floor treatments and parental occupational painting were associated with CBT risk in a population-based case-control study conducted between 2005 and 2010.Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing, frequency matched to cases on age, sex, and state of residence. Data were obtained from parents in mailed questionnaires and telephone interviews. Information on domestic painting and floor treatments, and parental occupational exposure to paint, in key periods relating to the index pregnancy and childhood was obtained for 306 cases and 950 controls. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders.Overall, we found little evidence that parental, fetal, or childhood exposure to home painting or floor treatments was associated with risk of CBT. There was, though, some evidence of a positive association between childhood exposure to indoor painting and risk of high-grade glioma [odds ratio (OR) 3.31, 95 % confidence interval (CI) 1.29, 8.52] based on very small numbers. The OR for the association between CBT and paternal occupational exposure to paint any time before the pregnancy was 1.32 (95 % CI 0.90, 1.92), which is consistent with the results of other studies.Overall, we found little evidence of associations between household exposure to paint and the risk of CBT in any of the time periods investigated.

In an ongoing effort to propose biologically protective nutrient criteria, we examined how total nitrogen (TN) and its forms were associated with macroinvertebrate communities in wadeable streams of Maryland. Taxonomic and functional metrics of an index of biological integrity (IBI) were significantly associated with multiple nutrient measures; however, the highest correlations with nutrients were for ammonia-N and nitrite-N and among macroinvertebrate measures were for Beck's Biotic Index and its metrics. Since IBI metrics showed comparatively less association, we evaluated how macroinvertebrate taxa related to proposed nutrient criteria previously derived for those same streams instead of developing nutrient-biology thresholds. We identified one tolerant and three intolerant taxa whose occurrence appeared related to a TN benchmark. Individually, these taxa poorly indicated whether streams exceeded the benchmark, but combining taxa notably improved classification rates. We then extracted major physiochemical gradients using principal components analysis to develop models that assessed their influence on nutrient indicator taxa. The response of intolerant taxa was predominantly influenced by a nutrient-forest cover gradient. In contrast, habitat quality had a greater effect on tolerant taxa. When taxa were aggregated into a nutrient sensitive index, the response was primarily influenced by the nutrient-forest gradient. Multiple lines of evidence highlight the effects of excessive nutrients in streams on macroinvertebrate communities and taxa in Maryland, whose loss may not be reflected in metrics that form the basis of biological criteria. Refinement of indicator taxa and a nutrient-sensitive index is warranted before thresholds in aquatic life to water quality are quantified.

We develop a model based on the notion that prices lead earnings, allowing for a simultaneous estimation of the implied growth rate and the cost of equity capital for US industrial sectors. The major difference between our approach and that in prior literature is that ours avoids the necessity to make assumptions about terminal values and consequently about future growth rates. In fact, growth rates are an endogenous variable, which is estimated simultaneously with the implied cost of equity capital. Since we require only 1-year-ahead forecasts of earnings and no assumptions about dividend payouts, our methodology allows us to estimate ex ante aggregate growth and risk premia over a larger sample of firms than has previously been possible. Our estimate of the risk premium being between 3.1 and 3.9 % is at the lower end of recent estimates, reflecting the inclusion of these short-lived companies. Our estimate of the long run growth is from 4.2 to 4.7 %.

Inactivation of the p53 tumor suppressor pathway allows cell survival in times of stress and occurs in many human cancers; however, normal embryonic stem cells and some cancers such as neuroblastoma maintain wild-type human TP53 and mouse Trp53 (referred to collectively as p53 herein). Here we describe a miRNA, miR-380-5p, that represses p53 expression via a conserved sequence in the p53 3' untranslated region (UTR). miR-380-5p is highly expressed in mouse embryonic stem cells and neuroblastomas, and high expression correlates with poor outcome in neuroblastomas with neuroblastoma derived v-myc myelocytomatosis viral-related oncogene (MYCN) amplification. miR-380 overexpression cooperates with activated HRAS oncoprotein to transform primary cells, block oncogene-induced senescence and form tumors in mice. Conversely, inhibition of endogenous miR-380-5p in embryonic stem or neuroblastoma cells results in induction of p53, and extensive apoptotic cell death. In vivo delivery of a miR-380-5p antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. We demonstrate a new mechanism of p53 regulation in cancer and stem cells and uncover a potential therapeutic target for neuroblastoma.

Southern Africa is at a pivotal point in time for transboundary water cooperation. The number and extent of coverage of existing international water agreements and joint management institutions merits cautious optimism about future water management in the region. Yet, taken alone, a numerical account of water treaties reveals little about the context in which the agreements were negotiated, the nature of the rules and regulations adopted, or the influence of the agreements in addressing problems or enhancing joint governance. Drawing on a database containing all the international freshwater agreements entered into between South Africa and its neighbours since 1910, this article examines trends in the articulation of these treaties and discusses the implications of the rules and regulations they embody. Specific consideration is given to issues of information sharing, water allocation and organizations. This analysis is a first step towards understanding the impact of existing agreements, identifying opportunities for the negotiation of new treaties and enhancing existing systems.

Cardiac ischemia reperfusion leads to oxidative stress and poor physiological recovery. Selenium deficiency down-regulates thioredoxin reductase (Txnrd) and glutathione peroxidase (Gpx) activity, impairing recovery from ischemia-reperfusion. Furthermore, selenium supplementation has been shown to be cardioprotective and lessens oxidative stress in reperfused rat hearts. In this study we have investigated the role of selenium in the mRNA expression of these, and related antioxidant proteins, post ischemia-reperfusion. Male rats were fed varying doses of selenium for five weeks. Hearts were isolated and perfused using the Langendorff method with 22.5 min of global ischemia and 45 min reperfusion. RNA was extracted for quantitative real-time PCR analysis of glutathione peroxidase (Gpx)-1 and 4, glutathione reductase (Gsr), thioredoxin peroxidase-2 (Prdx2), thioredoxin (Txn) and thioredoxin reductase (Txnrd)-1 and 2 gene expression. Selenium deficiency produced significant reductions in Gpx-1, Gpx-4, Prdx2, Txnrd-1 and Txnrd-2 expression. Conversely, selenium supplementation of 1000 μg/kg significantly up-regulated Gpx-1, Gpx-4, Txn, Txnrd-1 and Txnrd-2 transcription. Our results show selenium modulates the cardiac mRNA expression of thioredoxin and glutathione related enzymes post ischemia-reperfusion, and impacts on tolerance to ischemia-reperfusion. (Mol Cell Biochem 270: 131–138, 2005)

The ultimate goal of this study is to develop a simple dynamic river water quality model that can be applicable in a data limited situation and is compatible with typical activated sludge models, so that the model can be used in integrated modelling of wastewater and river water quality in the future. A simplified river water quality model was formulated based on a conceptual hydraulic sub-model and simplification of an existing river water quality model. The simplified water quality was derived from the River Water Quality Model No. 1, which is one of the most comprehensive basic river water quality models available in literature. The applicability of the simplified model in data limited situations was investigated using a case study of inorganic nitrogen (nitrate and ammonia) in the Crocodile River (South Africa). The model was calibrated and validated on the basis of independent data collected for four years (1987-1990). The results show that the model can adequately describe the seasonal dynamics of inorganic nitrogen in the Crocodile River. The sensitivity of the model output to the model inputs was also analysed, and the results indicate that the model is most sensitive to the microbial biomass (nitrifier) followed by hydraulic parameters. The relation of river flow versus concentration of inorganic nitrogen in the downstream section of the river was also examined in order to identify the main source and critical time for nitrate pollution.

A simple procedure is described for the determination of the 1,2-propanediol (propylene glycol) content of cream formulations containing the antiviral drug Acyclovir. Analysis of a solvent extract by gas chromatography coupled to an infra-red spectrometer enables the target analyte to be positively identified and an estimate of its concentration to be made. This application utilises the newer Tracer cryogenic deposition interface for gas chromatography and infra-red spectroscopy. This offers an alternative and complementary analytical strategy to gas chromatography coupled to mass spectrometry.

Serum cortisol concentrations and testosterone:cortisol concentration ratios of eight prepubescent elite male gymnasts (mean age 10 years 11 months) and 11 controls (mean age 11 years 1 month) were examined during 5 consecutive training days. During this period, the gymnasts trained 3 h each day with moderate intensity mobility, strength and skill exercises while the controls were relatively sedentary. Blood samples were taken from all the boys in both groups before (1630 hours) and 30 min after (2000 hours) training on 4 days. Serum cortisol concentrations of the gymnasts were not significantly different from those of the controls throughout the experiment. Serum cortisol concentrations of both groups were significantly larger (P < 0.05) at 1630 hours than at 2000 hours, indicating that cortisol secretion followed the typical adult circadian change, seemingly unaltered by training. However, there was a significant decrease (P < 0.05) in the testosterone:cortisol ratio of the gymnasts when compared with controls from day 1 to day 3. After a rest on day 4 the testosterone: cortisol ratio of the gymnasts significantly increased (P < 0.05) but the ratio of the control group also increased indicating that there may have been some day-to-day change by factor(s) other than training. The most obvious factor which may have accounted for the unresponsiveness of serum cortisol concentration to the gymnastics training was that the exercise intensity was too low. However, several days of the training seemed to reduce the anabolic to catabolic balance but further experiments are needed to confirm this finding.

We study the relation between short-time vibrational modes and long-time relaxational dynamics in a kinetically constrained lattice gas with harmonic interactions between neighbouring particles. We find a correlation between the location of the low (high) frequency vibrational modes and regions of high (low) propensity for motion. This is similar to what was observed in continuous force systems, but our interpretation is different: in our case relaxation is due to localised excitations which propagate through the system; these localised excitations act as background disorder for the elastic network, giving rise to anomalous vibrational modes. Our results show that a correlation between spatially extended low frequency modes and high propensity regions does not imply that relaxational dynamics originates in extended soft modes. We consider other measures of elastic heterogeneity, such as non-affine displacement fields and mode localisation lengths, and discuss implications of our results to interpretations of dynamic heterogeneity more generally., Comment: 5 pages, 5 figures

Inland salt lakes are widely distributed in southern Africa: they are particularly common in South Africa, but many occur in Namibia and Botswana. All are shallow, and most are ephemeral with salinities that are not very high (mostly < 50 g l−1). Fringing zones of halophytes or submerged macrophytes are neither well-developed nor taxonomically diverse. The Cyanobacteria, especially Nodularia spumigena, often dominate the phytoplankton. The fauna of the Makgadikgadi area (northeast Botswana) is diverse and is similar to that of East African salt lakes. The aquatic fauna of salt water south of the Makgadikgadi Basin, on the other hand, is extremely depauperate, has no well-defined assemblage confined to saline waters, and appears mostly to comprise tolerant freshwater forms. Lovenula falcifera and Metadiaptomus transvaalensis (diaptomid copepods), Moina micrura (Cladocera) and Brachionus plicatilis (Rotifera) are frequently encountered zooplankton species, a few species of insects (Anisops sp., beetles, chironomids and ephydrids) are the principal non-planktonic macroinvertebrates. Artemia ‘salina’ is occasionally present, but may be an introduced form. The avifauna, in contrast to the aquatic macroinvertebrate fauna, is rich, with the greater and lesser flamingo often common.

We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimer’s disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimer’s Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimer’s Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials.