Introduction
Developing cross‐validated multi‐biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge.
Methods
We ...applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid‐PET and fluorodeoxyglucose positron‐emission tomography (FDG‐PET) to predict rates of cognitive decline. Prediction models were trained in autosomal‐dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross‐validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model‐based risk enrichment was estimated.
Results
A model combining all biomarker modalities and established in ADAD predicted the 4‐year rate of decline in global cognition (R2 = 24%) and memory (R2 = 25%) in sporadic AD. Model‐based risk‐enrichment reduced the sample size required for detecting simulated intervention effects by 50%–75%.
Discussion
Our independently validated machine‐learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD.
Dysphagia is a common and frequently undetected complication of many neurological disorders and of sarcopoenia in ageing persons. Spontaneous swallowing frequency (SSF) has been mooted as a possible ...tool to classify dysphagia risk. We conducted a review of the literature to describe SSF in both the healthy population and in disease-specific populations, in order to consider its utility as a screening tool to identify dysphagia. We searched Medline, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials databases. Metadata were extracted, collated and analysed to give quantitative insight. Three hundred and twelve articles were retrieved, with 19 meeting inclusion and quality criteria. Heterogeneity between studies was high (I2 = 99%). Mean SSF in healthy younger sub-groups was 0.98/min CI: 0.67; 1.42. In the Parkinson’s sub-group, mean SSF was 0.59/min 0.40; 0.87. Mean SSF in healthy older, higher risk and dysphagic populations were similar (0.21/min 0.09; 0.52, 0.26/min 0.10; 0.72 and 0.30/min 0.16; 0.54, respectively). SSF is a novel, non-invasive clinical variable which warrants further exploration as to its potential to identify persons at risk of dysphagia. Larger, well-conducted studies are needed to develop objective, standardised methods for detecting SSF, and develop normative values in healthy populations.
Since the 1940s, the anadromous allis shad, Alosa alosa (L.), has suffered population declines throughout its distribution range in Europe. In context of EU‐LIFE projects for the reintroduction of ...the allis shad in the Rhine system, a comprehensive study was started in 2012 to investigate infectious diseases occurring in allis shad. In course of the study, 217 mature and young‐of‐the‐year allis shad originating from the wild population from the Gironde–Garonne–Dordogne system (GGD‐system) and the Rhine system as well as 38 allis shad from the breeding population were examined by use of bacteriological and histological methods. In 2012 and 2014, an endocarditis valvularis thromboticans caused by a coccoid bacterium was detected in 16% and 25% of mature allis shad originating from the GGD‐system. Results of microbiologic examinations, including biochemical characteristics, matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) and 16S rRNA gene sequence analysis, revealed Lactococcus lactis as causative agent of this infection. This is the first report of an endocarditis valvularis and parietalis thromboticans caused by Lactococcus lactis in fish. Possible sources of infection as well as the impact for the reintroduction programme are discussed.
There is an urgent need to improve the understanding of neuroinflammation in Alzheimer’s disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume ...and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.
•Neuroinflammation biomarker study on cerebrospinal fluid of DELCODE and F.ACE cohorts•Synchronous pre-dementia elevation of inflammatory, tau, and neurodegeneration markers•Among these, sTyro3 and sAXL positively relate to MRI structure and cognition•Could TAM signaling be protective during pre-dementia neuroinflammation?
In the DELCODE and F.ACE cohorts, Brosseron, Maass, Kleineidam, et al. find that inflammatory CSF biomarkers rise in pre-dementia stages alongside tau and neurodegeneration markers. Within this pattern, soluble TAM receptors sTyro3 and sAXL positively relate to MRI structure and cognition, potentially as proxies of immune regulatory protective mechanisms.
The response to freeze-thaw stress was examined for two co-occurring evergreen species, Malosma laurina and Rhus ovata. Laboratory and field experiments on adults and seedlings were made in the ...spring and winter in 1996 and again on adults in 2003 and 2004. Laboratory and field results indicated that the stem xylem for adults of M. laurina and R. ovata were similarly susceptible to freezing-induced cavitation (percentage loss of conductivity = 92 ± 2.6% for R. ovata and 90 ± 4.2% for M. laurina at ≤ -6°C). In contrast, leaves of M. laurina were more susceptible to freezing injury than leaves of R. ovata. Among seedlings in the field, leaves of M. laurina exhibited freezing injury at -4°C and total shoot mortality at - 7.2°C, whereas co-occurring seedlings of R. ovata were uninjured. Surprisingly, R. ovata tolerates high levels of freezing-induced xylem embolism in the field, an apparently rare condition among evergreen plants. Rhus ovata avoids desiccation when xylem embolism is high by exhibiting low minimum leaf conductance compared to M. laurina. These results suggest a link between minimum leaf conductance and stem hydraulics as a mechanism permitting the persistence of an evergreen leaf habit in freezing environments.
1 A Bayesian approach was used to fit a conceptual transpiration model to half-hourly transpiration rates for a sugar maple (Acer saccharum) stand collected over a 5-month period and ...probabilistically estimate its parameter and prediction uncertainties. The model used the Penman-Monteith equation with the Jarvis model for canopy conductance. This deterministic model was extended by adding a normally distributed error term. This extension enabled using Markov chain Monte Carlo simulations to sample the posterior parameter distributions. The residuals revealed approximate conformance to the assumption of normally distributed errors. However, minor systematic structures in the residuals at fine timescales suggested model changes that would potentially improve the modeling of transpiration. Results also indicated considerable uncertainties in the parameter and transpiration estimates. This simple methodology of uncertainty analysis would facilitate the deductive step during the development cycle of deterministic conceptual models by accounting for these uncertainties while drawing inferences from data.
Objective
Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the ...physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non‐invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE‐ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non‐demented older adults.
Methods
Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid β1‐42 and p‐Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow‐up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed‐effects model for each tract.
Results
AD pathology, APOE‐ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE‐ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect.
Interpretation
Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.
Abstract The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a ...collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (⩾50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded ( n = 141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma ( n = 323) or squamous cell carcinoma ( n = 596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma ( p = 0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA–IIB ( p < 0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis ( p = 0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables ( p = 0.037 and p = 0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA–IIB.
Read the Commentaries on this Feature Paper: Extinction debt at different spatial scales; Setting conservation priorities when what you see is not what you get
Response from the authors: From ...ecological pessimism to conservation chance: reviving living dead in changing landscapes
Cities are expanding rapidly worldwide. Modern cities are expected to carry heavy extinction debts owing to their recent and drastic fragmentation histories. Therefore, detecting extinction debt and identifying species threatened by it in recently created cities are necessary to prevent future biodiversity losses. Here, we studied the relationship between the life‐history traits of butterfly species and the extent of their extinction debts using two different methodological approaches in Tokyo, central Japan. First, we compared the effects of current and past landscape parameters on current species richness using generalized linear models. Second, we predicted species richness in unstable (i.e. high loss) habitats using a model developed for stable (i.e. low loss) habitats. The difference between predicted and observed species richness was used to estimate the extinction debt (the number of species expected to go extinct). We classified butterfly species as seasonal specialists or generalists and as habitat specialists or generalists based on their life‐history traits. With both methods, we found significant extinction debts only for specialist species. Mapping the potential extinction debts within our study area indicated that currently large patches had relatively low extinction debts, whereas small patches often had high extinction debts. These results suggested that improving patch area, connectivity and especially quality, would have more significant impacts in small patches than in large ones. Extinction debt is an important concept for setting conservation priorities in highly fragmented landscapes, especially in urban areas.
Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. ...Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.
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