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Background and Aims: The purpose of this study was to compare the knowledge and practices of specialist and experienced nonspecialist physical therapists in performing patient education about physical activity with patients with heart failure (HF). Methods: Responses on a nationwide anonymous online survey were used to compare specialist and experienced nonspecialist physical therapists on knowledge and frequency of providing physical activity related education to patients hospitalized with acutely decompensated HF. Responses to survey items were scored on 5‐point scales ranging from "Strongly agree" to "Strongly disagree" or "Always" to "Never." Mann−Whitney U statistics were used to compare specialist and experienced nonspecialist responses and Wilcoxon signed‐ranks tests were used to examine the gap between knowledge and practice. Results: Twenty‐seven specialists and 43 experienced nonspecialists completed the survey. Both groups were similar in age, and experience treating patients hospitalized with acutely decompensated HF. Both groups "strongly agree" that they had the required knowledge and skills to educate patients with HF on the physical activity topics. However, specialists more often than experienced nonspecialists provided education on topics such as how to monitor vital signs during physical activity ("most of the time" vs. "about half of the time") that promoted patient confidence and safety during exercise. Specialists demonstrated a smaller gap between knowledge and frequency of providing patient education than experienced nonspecialists on three of the four patient education topics. Conclusion: Specialist physical therapists treating patients with HF in the inpatient hospital setting provided patient education on physical activity at a level more closely matching their skills and the clinical practice guideline than did experienced nonspecialists. Physical therapy clinical specialists practicing in the inpatient hospital setting may improve patient outcomes and lower costs to the health care system by improving physical activity adherence and thereby may reduce avoidable hospital readmissions. [ABSTRACT FROM AUTHOR]

The marine cyanobacterium Trichodesmium has the remarkable ability to interact with and utilize air-borne dust as a nutrient source. However, dust may adversely affect Trichodesmium through buoyancy loss and exposure to toxic metals. Our study explored the effect of desert dust on buoyancy and mortality of natural Red Sea puff-shaped Trichodesmium thiebautii. Sinking velocities and ability of individual colonies to stay afloat with increasing dust loads were studied in sedimentation chambers. Low dust loads of up to ~400 ng per colony did not impact initial sinking velocity and colonies remained afloat in the chamber. Above this threshold, sinking velocity increased linearly with the colony dust load at a slope matching prediction based on Stoke's law. The potential toxicity of dust was assessed with regards to metal dissolution kinetics, differentiating between rapidly released metals, which may impact surface blooms, and gradually released metals that may impact dustcentering colonies. Incubations with increasing dust concentrations revealed colony death, but the observed lethal dose far exceeded dust concentrations measured in coastal and open ocean systems. Removal of toxic particles as a mechanism to reduce toxicity was explored using SEM-EDX imaging of colonies incubated with Cu-minerals, yet observations did not support this pathway. Combining our current and former experiments, we suggest that in natural settings the nutritional benefits gained by Trichodesmium via dust collection outweigh the risks of buoyancy loss and toxicity. Our data and concepts feed into the growing recognition of the significance of dust for Trichodesmium's ecology and subsequently to ocean productivity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Overlooking the heterogeneity in Alzheimer's disease (AD) may lead to diagnostic delays and failures. Neuroanatomical normative modeling captures individual brain variation and may inform our understanding of individual differences in AD‐related atrophy. METHODS: We applied neuroanatomical normative modeling to magnetic resonance imaging from a real‐world clinical cohort with confirmed AD (n = 86). Regional cortical thickness was compared to a healthy reference cohort (n = 33,072) and the number of outlying regions was summed (total outlier count) and mapped at individual‐ and group‐levels. RESULTS: The superior temporal sulcus contained the highest proportion of outliers (60%). Elsewhere, overlap between patient atrophy patterns was low. Mean total outlier count was higher in patients who were non‐amnestic, at more advanced disease stages, and without depressive symptoms. Amyloid burden was negatively associated with outlier count. DISCUSSION: Brain atrophy in AD is highly heterogeneous and neuroanatomical normative modeling can be used to explore anatomo‐clinical correlations in individual patients. [ABSTRACT FROM AUTHOR]

Background: Gait is a complex everyday activity that depends upon supraspinal activity and a host of cognitive functions such as attention and executive functions. As cognition declines in neurodegenerative diseases, the interaction and competition for neuronal resources during motor‐cognitive dual‐tasking (e.g., walking while talking) might be a sensitive measure of subtle functional impairments in early Alzheimer's disease (AD). Here, we aim to identify gait deficits due to neuronal competition across the AD spectrum. Method: This investigation is part of the ongoing Remote Assessment of Disease and Relapse – Alzheimer's Disease (RADAR‐AD) study. We attached three inertial measurement units (accelerometer and gyroscope) to both feet and one hip to assess dual task effects (DTE) assessing gait performance with/without concurrent serial subtraction‐by‐1 task in four groups: 1) amyloid negative healthy controls (HC, N = 59); and 2) amyloid positive preclinical AD (PreAD, N = 30); 3) prodromal AD (ProAD, N = 51); and 4) mild‐to‐moderate AD dementia (MildAD, N = 44) (Table 1). We furthermore investigated associations of DTE with observer‐reported cognition. Result: Group comparisons showed that dual‐tasking induced lower cadence and increased stance, which were significantly different between HC and ProAD. Several DTE measures of variability differed significantly between PreAD and MildAD, with variability in the path length separating best between PreAD and ProAD (Table 2, Figure 1). DTE measures were associated with observer‐rated divided attention only in the MildAD group. Conclusion: Neuronal competition as assessed with motor‐cognitive dual‐tasking, specifically the DTE variability, might reflect functional deficits already in early AD, and could be a valuable additional measure to detect early impairments not captured by cognitive or motor tests alone. Future studies should implement an adaptive cognitive load to improve sensitivity/specificity in early AD stages and investigate the use of sensor technologies in predicting and monitoring changes in gait and fall prevention in later stages of the disease. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Interventions focused on the home language environment have been shown to improve a number of child language outcomes in the first years of life. However, data on the longer‐term effects of the intervention are still somewhat limited. The current study examines child vocabulary and complex speech outcomes (N = 59) during the year following completion of a parent‐coaching intervention, which was previously found to increase the quantity of parent‐child conversational turns and to improve child language outcomes through 18 months of age. Measures of parental language input, child speech output, and parent‐child conversational turn‐taking were manually coded from naturalistic home recordings (Language Environment Analysis System, LENA) at regular 4‐month intervals when children were 6‐ to 24‐months old. Child language skills were assessed using the MacArthur–Bates Communicative Development Inventory (CDI) at four time‐points following the final intervention session (at 18, 24, 27, and 30 months). Vocabulary size and growth from 18 to 30 months was greater in the intervention group, even after accounting for differences in child language ability during the intervention period. The intervention group also scored higher on measures of speech length and grammatical complexity, and these effects were mediated by 18‐month vocabulary. Intervention was associated with increased parent‐child conversational turn‐taking in home recordings at 14 months, and mediation analysis suggested that 14‐month conversational turn‐taking accounted for intervention‐related differences in subsequent vocabulary. Together, the results suggest enduring, positive effects of parental language intervention and underscore the importance of interactive, conversational language experience during the first 2 years of life. Research Highlights: Parent coaching was provided as part of a home language intervention when children were 6–18 months of age.Naturalistic home language recordings showed increased parent‐child conversational turn‐taking in the intervention group at 14 months of age.Measures of productive vocabulary and complex speech indicated more advanced expressive language skills in the intervention group through 30 months of age, a full year after the final intervention session.Conversational turn‐taking at 14 months predicted subsequent child vocabulary and accounted for differences in vocabulary size across the intervention and control groups. [ABSTRACT FROM AUTHOR]

Thanks to the considerable research which has been undertaken in the last few years to improve our understanding of the biology and mechanism of action of SARS‐CoV‐2, we know how the virus uses its surface spike protein to infect host cells. The transmembrane prosthesis, serine 2 (TMPRSS2) protein, located on the surface of human cells, recognizes the cleavage site in the spike protein, leading to the release of the fusion peptide and entry of the virus into the host cells. Because of its role, TMPRSS2 has been proposed as a drug target to prevent infection by the virus. In this study, we aim to increase our understanding of TMPRSS2 using long scale microsecond atomistic molecular dynamics simulations, focusing on the conformational changes over time. The comparison between simulations conducted on the protein in the native (apo) and inhibited form (holo), has shown that in the holo form the inhibitor stabilizes the catalytic site and induces rearrangements in the extracellular domain of the protein. In turn, it leads to the formation of a new cavity in the vicinity of the ligand binding pocket that is stable in the microsecond time scale. Given the low specificity of known protease inhibitors, these findings suggest a new potential drug target site that can be used to improve TMPRSS2 specific recognition by newly designed inhibitors. [ABSTRACT FROM AUTHOR]

Low iron (Fe) and phosphorus (P) ocean regions are often home to the globally important N2‐fixing cyanobacterium Trichodesmium spp., which are physiologically adapted to Fe/P co‐limitation. Given Trichodesmium's eminent ability to capture particles and the common associations between Fe and P in sediments and aerosols, we hypothesized that mineral bio‐dissolution by Trichodesmium spp. may enable them to co‐acquire Fe and P. We present a new sensitive assay to determine P uptake from particles, utilizing 33P‐labeled ferrihydrite. To validate the method, we examined single natural Trichodesmium thiebautii colonies in a high‐resolution radiotracer ß‐imager, identifying strong colony‐mineral interactions, efficient removal of external 33P‐labeled ferrihydrite, and elevated 33P uptake in the colony core. Next, we determined bulk P uptake rates, comparing natural Red Sea colonies and P‐limited Trichodesmium erythraeum cultures. Uptake rates by natural and cultured Trichodesmium were similar to P release rates from the mineral, suggesting tight coupling between dissolution and uptake. Finally, synthesizing P‐ferrihydrite labeled with either 33P or 55Fe, we probed for Fe/P co‐extraction by common microbial mineral solubilization pathways. Dissolution rates of ferrihydrite were accelerated by exogenous superoxide and strong Fe‐chelator and subsequently enhanced 33P release and uptake by Trichodesmium. Our method and findings can facilitate further Fe/P co‐acquisition studies and highlight the importance of biological mechanisms and microenvironments in controlling bioavailability and nutrient fluxes from particles. [ABSTRACT FROM AUTHOR]

Objectives: Visual rating scales (VRS) are the quantification method closest to the approach used in routine clinical practice to assess brain atrophy. Previous studies have suggested that the medial temporal atrophy (MTA) rating scale is a reliable diagnostic marker for AD, equivalent to volumetric quantification, while others propose a higher diagnostic utility for the Posterior Atrophy (PA) scale in early‐onset AD. Methods: Here, we reviewed 14 studies that assessed the diagnostic accuracy of PA and MTA, we explored the issue of cut‐off heterogeneity, and assessed 9 rating scales in a group of patients with biomarker‐confirmed diagnosis. A neuroradiologist blinded to all clinical information rated the MR images of 39 amyloid‐positive and 38 amyloid‐negative patients using 9 validated VRS assessing multiple brain regions. Automated volumetric analyses were performed on a subset of patients (n = 48) and on a group of cognitively normal individuals (n = 28). Results: No single VRS could differentiate amyloid‐positive from amyloid‐negative patients with other neurodegenerative conditions. 44% of amyloid‐positive patients were deemed to have age‐appropriate levels of MTA. In the amyloid‐positive group, 18% had no abnormal MTA or PA scores. These findings were substantially affected by cut‐off selection. Amyloid‐positive and amyloid‐negative patients had comparable hippocampal and parietal volumes, and MTA but not PA scores correlated with the respective volumetric measures. Interpretation: Consensus guidelines are needed before VRS can be recommended for use in the diagnostic workup of AD. Our data are suggestive of high intragroup variability and non‐superiority of volumetric quantification of atrophy over visual assessment. [ABSTRACT FROM AUTHOR]

Background: RADAR‐AD is a European project in the context of the Innovative Medicine Initiative (IMI) focusing on the earlier identification of patients at risk for developing Alzheimer's Disease (AD) via a panel of remote monitoring technologies (RMTs), including smartphone apps and wearable devices. Method: We examined the ability of 6 RMTs (Altoida, Axivity, Banking app, Fitbit, Physilog, and Mezurio) to distinguish between healthy controls (HC) and disease stages of preclinical (PreAD), prodromal (ProAD), and mild to moderate Alzheimer's disease (MildAD) based on 175 patients (interim analysis). We trained three machine learning classifiers (Logistic Regression, Random Forest, and XGBoost) in a pairwise setting (HC vs. PreAD, HC vs. ProAD, HC vs. MildAD, PreAD vs. ProAD, and ProAD vs. MildAD). Since the interim dataset is still limited, we performed repeated, stratified nested cross‐validation to get a robust performance estimate. Each classifier was trained with the features of the different devices and a set of baseline variables. The latter include a patient's gender, age, years of education, and body mass index (BMI) when physical conditions might play a role (Axivitiy, Fitbit, Physilog). In addition, we checked whether specific patterns of the study groups allowed discrimination of the different study groups based on the baseline variables alone. Therefore, we trained one Logistic Regression model with these variables and compared the performance of the other three models with this baseline. The models trained with the baseline and questionnaire‐based data served as the reference value in our benchmark that represents how well the discrimination of the different groups works with clinical tests. Result: Our preliminary data show that RMTs can identify patients already in a prodromal disease stage (AUC ∼69%, Figure 1). Furthermore, the pairwise combination of data from a banking app and an app monitoring functional cognitive abilities via an augmented reality game slightly increased our model's discriminative ability (Altoida ‐ Banking, Figure 2). The overall best performance was achieved when combining RMTs with the Amsterdam I‐ADL questionnaire. Conclusion: Our results demonstrate the potential of RMTs and the Amsterdam I‐ADL questionnaire for identifying patients in prodromal stage in primary care settings. [ABSTRACT FROM AUTHOR]

Background: Remote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer's disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer's disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia. Method: Four study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida's research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams. Result: Compliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p<0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity). Conclusion: The RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Background: Remote monitoring technologies (RMTs), such as smartphone apps, smartwatches, and in‐home sensors, are rapidly changing the way functional and cognitive performance is measured in Alzheimer's disease (AD) patients. Here, we present results from the European RADAR‐AD study on the use of multimodal data streams for the identification of functional deficits across all syndromic stages of AD. Method: Four study groups (Healthy controls (HC), preclinical AD (pre. AD), prodromal AD (pro. AD), and mild AD) were included in this cross‐sectional study. The RMT features (gait measures from Timed up and Go (TUG), Dual Task Effect (DTE) using physilog, acoustic features from Speech task in Mezurio, neurocognitive function using Altoida, managing finances with Banking app) with in‐clinic neuropsychological (NP) tests, activities of daily living with Amsterdam IADL and demographics (age, gender, education years) were analyzed for different combinations of the multimodal digital biomarker of disease stage in AD across different pairwise comparisons. The analysis includes data from 175 participants (HC = 67, Pre.AD = 26, Pro.AD = 50, Mild AD = 32) collected for 8 weeks. An extreme gradient boosting (XGBoost) machine learning model was trained to obtain a multimodal biomarker of AD disease stage with repeated cross‐validation (5‐fold with 4 repeats) (Figure 1). This investigation is part of the ongoing RADAR‐AD study. Result: The multimodal combination of RMTs achieved a mean AUC of > 0.60 in all pairwise comparisons with a mean AUC > 0.65 for HC vs (Pre.AD, Pro.AD and Mild) (Figures 2 and 3). The addition of NP tests increases the performance considerably across all pairwise comparisons except HC vs Pre.AD. Conclusion: Our results highlight the advantage of combining RMTs to identify functional deficits in the early stage of AD. In particular, in prodromal and mild AD patients, a combined signal shows much more strength compared to individual tests. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Background: Augmented reality apps merge real world with virtual experiences and can be used to remotely assess complex instrumental activities of daily living (iADL) that are affected early in Alzheimer's disease (AD). Our aim was to compare standard clinical measures with an augmented reality app to assess iADL that are related to memory and spatial navigation in early AD and its feasibility in the home‐setting. Method: We administered an augmented reality app (Altoida Inc., Washington DC, USA) in an on‐going cross‐sectional study (RADAR‐AD: Remote Assessment of Disease and Relapse – Alzheimer's Disease) in three groups: 1) amyloid negative healthy controls (HC, N = 49); and amyloid positive 2) preclinical AD (PreAD, N = 17); and 3) prodromal AD (ProAD, N = 29) (Table 1). Altoida's research algorithm DNS‐MCI (Digital Neuro Signature) produces the outcome of a machine learning model trained to identify cognitively normal individuals from those with cognitive impairment). DNS‐MCI reflects performance in app‐based tasks assessing memory and visuo‐spatial function (placing and finding virtual objects, fire drill simulation) further including attention and motor performance (reaction time, finger tapping, navigational trajectory). At baseline, app‐based tasks were performed in the clinic together with a standard neuropsychological assessment and iADL questionnaires (Figure 1). Participants were furthermore given the option of using Altoida in the home environment. Result: The DNS‐MCI score could significantly distinguish HC and PreAD participants from the ProAD group and was correlated with all neuropsychological tests and iADL questionnaires (Figures 1 and 2). Participants used the app on average 3‐4 times at home (Table 1). Baseline in‐clinic assessments were strongly correlated with at‐home assessments (r = 0.53, p<.001). Conclusion: App‐based augmented reality tasks are applicable in the home setting and successful in capturing cognitive impairment in early AD. Future research should focus on fine graining algorithms to also detect possible subtle impairment in preAD. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

The development of skills related to executive function (EF) in infancy, including their emergence, underlying neural mechanisms, and interconnections to other cognitive skills, is an area of increasing research interest. Here, we report on findings from a multidimensional dataset demonstrating that infants' behavioral performance on a flexible learning task improved across development and that the task performance is highly correlated with both neural structure and neural function. The flexible learning task probed infants' ability to learn two different associations, concurrently, over 16 trials, requiring multiple skills relevant to EF. We examined infants' neural structure by measuring myelin density in the brain, using a novel macromolecular proton fraction (MPF) mapping method. We further examined an important neural function of speech processing by characterizing the mismatch response (MMR) to speech contrasts using magnetoencephalography (MEG). All measurements were performed longitudinally in monolingual English‐learning infants at 7‐ and 11‐months of age. At the group level, 11‐month‐olds, but not 7‐month‐olds, demonstrated evidence of learning both associations in the behavioral task. Myelin density in the prefrontal region at 7 months of age was found to be highly predictive of behavioral task performance at 11 months of age, suggesting that myelination may support the development of these skills. Furthermore, a machine‐learning regression analysis revealed that individual differences in the behavioral task are predicted by concurrent neural speech processing at both ages, suggesting that these skills do not develop in isolation. Together, these cross‐modality results revealed novel insights into EF‐related skills. Highlight: Monolingual infants demonstrated flexible learning on a task requiring executive function skills at 11 months, but not at 7 months.Infants' myelin density at 7 months is highly predictive of their behavioral performance in the flexible learning task at 11 months of age.Individual differences in the flexible learning task performance are also correlated with concurrent neural processing of speech at both ages. [ABSTRACT FROM AUTHOR]

Innate immune signaling pathways are essential mediators of inflammation and repair following myelin injury. Inflammasome activation has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models, although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not completely understood. Herein, we investigated the NLRP3 (NBD‐, LRR‐ and pyrin domain‐containing protein 3) inflammasome and its endogenous regulator microRNA‐223‐3p within the demyelinated CNS in both MS and an animal model of focal demyelination. We observed that NLRP3 inflammasome components and microRNA‐223‐3p were upregulated at sites of myelin injury within activated macrophages and microglia. Both microRNA‐223‐3p and a small‐molecule NLRP3 inhibitor, MCC950, suppressed inflammasome activation in macrophages and microglia in vitro; compared with microglia, macrophages were more prone to inflammasome activation in vitro. Finally, systemic delivery of MCC950 to mice following lysolecithin‐induced demyelination resulted in a significant reduction in axonal injury within demyelinated lesions. In conclusion, we demonstrate that NLRP3 inflammasome activity by macrophages and microglia is a critical component of the inflammatory microenvironment following demyelination and represents a potential therapeutic target for inflammatory‐mediated demyelinating diseases, including MS. Cover Image for this issue: https://doi.org/10.1111/jnc.15422 [ABSTRACT FROM AUTHOR]

Objectives: We sought to define the rate of unexpected death from acute coronary syndrome or arrhythmia in chest pain patients directly discharged from the ED. Methods: Retrospective audit of all chest pain patients at a tertiary ED for 7 years. Medical and post‐mortem records of the deceased were reviewed with independent cardiologist adjudication to determine outcomes. Primary outcome measure was 28‐day unexpected death secondary to acute coronary syndrome or arrhythmia. Results: During the study period, 25 924 patients presented with chest pain, 292 (1.1%, 95% confidence interval [CI] 0.99–1.01%) died within 28 days. Of these, 16 680(64%, 95% CI 63.88–64.12%) were discharged by ED, two (0.01%, 95% CI 0–0.011%) of this group died from the primary outcome. Conclusion: Unexpected death is very uncommon after ED discharge of chest pain patients. [ABSTRACT FROM AUTHOR]

Background: There exists a dearth of evidence on rehabilitation factors that influence prosthetic mobility in people with lower limb amputation (LLA). Examining variables that contribute to prosthetic mobility can inform rehabilitation interventions, providing guidance in developing more comprehensive care for these individuals.Objective: To determine the influence of modifiable and non-modifiable variables related to LLA and their impact on prosthetic mobility, using the International Classification of Functioning, Disability and Health (ICF) model. Secondarily, to determine if personal factors and self-reported balance and mobility are predictive of Component timed-up-and-go (cTUG) performance.Design: Cross-sectional study of a convenience sample.Setting: National conference.Participants: People (N=68) with non-vascular causes of unilateral LLA.Methods: Assessment of anthropometrics, mobility, bilateral hip extensor strength, hip range of motion, single limb balance, and self report measures. Lasso linear regression and extreme gradient boosting analyses were used to determine influence of variables on prosthetic mobility.Main Outcome Measure: Timed performance of the cTUG.Results: The following five variables were found to influence basic prosthetic mobility (P ≤ .05) in people with transtibial amputation: hip extensor strength, hip range of motion, single limb balance, waist circumference, and age. In the transfemoral cohort, number of comorbidities and waist circumference primarily influenced prosthetic mobility. Additionally, 66% of the variance in cTUG total time for the entire sample could be explained by simply regressing on level of amputation, number of comorbidities, age and Activities-specific Balance Confidence scale score, all variables easily collected in a waiting room.Conclusion: Variables that are modifiable with physical therapy intervention including hip extensor strength, hip range of motion, single limb balance, and waist circumference significantly influenced basic prosthetic mobility. These variables can be affected by targeted rehabilitation interventions and lifestyle changes.Level Of Evidence: II. [ABSTRACT FROM AUTHOR]

The Ansaldo A.1 "Balilla" biplane is of great historical interest, because it illustrates the level of development reached by the Italian aircraft industry during the last stages of World War I. To date, the airplane is kept in its original state, and it has never been restored. The aircraft is essentially made of wood and fabric. Wood in particular has been used in a very skilful way, making the airplane lightweight, yet elastic and resistant. In this work, the entire wooden structure of the aircraft was analysed, and the tree species were microscopically identified. Species belonging to six different genera have been identified. We found spruce in the frame, elm in the wing ribs, walnut in the propeller, alder in various plywood layers, rosewood in the outer layer of the decorative plywood, and pine in the tail rudder. The main structure of the aircraft was made of spruce, most likely a Sitka spruce, which was widely used for aircraft construction. The Ansaldo A.1 "Balilla" biplane is an excellent example of the wise use of wood before the revolution upon the boost in synthetic materials and represents an important historical and cultural heritage. [ABSTRACT FROM AUTHOR]

In normal pregnancy, hepatic metabolism adaptation occurs with an increase in lipid biosynthesis. Placental shedding of syncytiotrophoblast‐derived extracellular vesicles (STBEVs) into the maternal circulation constitutes a major signalling mechanism between foetus and mother. We investigated whether STBEVs from normal pregnant women might target liver cells in vitro and induce changes in lipid synthesis. This study was performed at the Nuffield Department of Women's & Reproductive Health, Oxford, UK. STBEVs were obtained by dual‐lobe placental perfusion from 11 normal pregnancies at term. Medium/large and small STBEVs were collected by ultracentrifugation at 10,000g and 150,000g, respectively. STBEVs were analysed by Western blot analysis and flow cytometry for co‐expression of apolipoprotein‐E (apoE) and placental alkaline phosphatase (PLAP). The uptake of STBEVs by liver cells and the effect on lipid metabolism was evaluated using a hepatocarcinoma cell line (HepG2 cells). Data were analysed by one‐way ANOVA and Student's t test. We demonstrated that: (a) STBEVs carry apoE; (b) HepG2 cells take up STBEVs through an apoE‐LDL receptor interaction; (c) STBEV incorporation into HepG2 cells resulted in (i) increased cholesterol release (ELISA); (ii) increased expression of the genes SQLE and FDPS (microarray) involved in cholesterol biosynthesis; (iii) downregulation of the CLOCK gene (microarray and PCR), involved in the circadian negative control of lipid synthesis in liver cells. In conclusion, the placenta may orchestrate the metabolic adaptation of the maternal liver through release of apoE‐positive STBEVs, by increasing lipid synthesis in a circadian‐independent fashion, meeting the nutritional needs of the growing foetus. [ABSTRACT FROM AUTHOR]

The ICH E9 (R1) guidance and the related estimand framework propose to clearly define and separate the clinical question of interest formulated as estimand from the estimation method. With that it becomes important to assess the validity of the estimation method and the assumptions that must be made. When going beyond the intention to treat analyses that can rely on randomization, causal inference is usually used to discuss the validity of estimation methods for the estimand of interest. In pharmacometrics, mixed‐effects models are routinely used to analyze longitudinal clinical trial data; however, they are rarely discussed as a method for causal inference. Here, we evaluate nonlinear mixed‐effects modeling and simulation (NLME M&S) in the context of causal inference as a standardization method for longitudinal data in the presence of confounders. Standardization is a well‐known method in causal inference to correct for confounding by analyzing and combining results from subgroups of patients. We show that nonlinear mixed‐effects modeling is a particular implementation of standardization that conditions on individual parameters described by the random effects of the mixed‐effects model. As an example, we use a simulated clinical trial with within‐subject dose titration. Being interested in the outcome of the hypothetical situation that patients adhere to the planned treatment schedule, we put assumptions in a causal diagram. From the causal diagram, conditional independence assumptions are derived either by conditioning on the individual parameters or on earlier outcomes. With both conditional independencies unbiased estimates can be obtained. [ABSTRACT FROM AUTHOR]

Magnetic resonance spectroscopy (MRS) measures cerebral metabolite concentrations, which can inform our understanding of the neurobiological processes associated with stroke recovery. Here, we investigated whether metabolite concentrations in primary motor and somatosensory cortices (sensorimotor cortex) are impacted by stroke and relate to upper‐extremity motor impairment in 45 individuals with chronic stroke. Cerebral metabolite estimates were adjusted for cerebrospinal fluid and brain tissue composition in the MRS voxel. Upper‐extremity motor impairment was indexed with the Fugl‐Meyer (FM) scale. N‐acetylaspartate (NAA) concentration was reduced bilaterally in stroke participants with right hemisphere lesions (n = 23), relative to right‐handed healthy older adults (n = 15; p =.006). Within the entire stroke sample (n = 45) NAA and glutamate/glutamine (GLX) were lower in the ipsilesional sensorimotor cortex, relative to the contralesional cortex (NAA: p <.001; GLX: p =.003). Lower ipsilesional NAA was related to greater extent of corticospinal tract (CST) injury, quantified by a weighted CST lesion load (p =.006). Cortical NAA and GLX concentrations did not relate to the severity of chronic upper‐extremity impairment (p >.05), including after a sensitivity analysis imputing missing metabolite data for individuals with large cortical lesions (n = 5). Our results suggest that NAA, a marker of neuronal integrity, is sensitive to stroke‐related cortical damage and may provide mechanistic insights into cellular processes of cortical adaptation to stroke. However, cortical MRS metabolites may have limited clinical utility as prospective biomarkers of upper‐extremity outcomes in chronic stroke. [ABSTRACT FROM AUTHOR]

Acute cycling exercise can modulate motor cortical circuitry in the non‐exercised upper‐limb. Within the primary motor cortex, measures of intracortical inhibition are reduced and intracortical facilitation is enhanced following acute exercise. Further, acute cycling exercise decreases interhemispheric inhibition between the motor cortices and lowers cerebellar‐to‐motor cortex inhibition. Yet, investigations into the effects of acute exercise on sensorimotor integration, referring to the transfer of incoming afferent information from the primary somatosensory cortex to motor cortex, are lacking. The current work addresses this gap in knowledge with two experimental sessions. In the first session, we tested the exercise‐induced changes in somatosensory and motor excitability by assessing somatosensory (SEP) and motor evoked potentials (MEPs). In the second session, we explored the effects of acute cycling exercise on short‐ (SAI) and long‐latency afferent inhibition (LAI), and afferent facilitation. In both experimental sessions, neurophysiological measures were obtained from the non‐exercised upper‐limb muscle, tested at two time points pre‐exercise separated by a 25‐min period of rest. Next, a 25‐min bout of moderate‐intensity lower‐limb cycling was performed with measures assessed at two time points post‐exercise. Acute lower‐limb cycling increased LAI, without modulation of SAI or afferent facilitation. Further, there were no exercise‐induced changes to SEP or MEP amplitudes. Together, these results suggest that acute exercise has unique effects on sensorimotor integration, which are not accompanied by concurrent changes in somatosensory or motor cortical excitability. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has impacted spine care around the globe. Much uncertainty remains regarding the immediate and long‐term future of spine care and education in this COVID‐19 era. Study design: Cross‐sectional, international study of spine surgeons. Methods: A multi‐dimensional survey was distributed to spine surgeons around the world. A total of 73 questions were asked regarding demographics, COVID‐19 observations, personal impact, effect on education, adoption of telemedicine, and anticipated challenges moving forward. Multivariate analysis was performed to assess factors related to likelihood of future conference attendance, future online education, and changes in surgical indications. Results: A total of 902 spine surgeons from seven global regions completed the survey. Respondents reported a mean level of overall concern of 3.7 on a scale of one to five. 84.0% reported a decrease in clinical duties, and 67.0% reported a loss in personal income. The 82.5% reported being interested in continuing a high level of online education moving forward. Respondents who personally knew someone who tested positive for COVID‐19 were more likely to be unwilling to attend a medical conference 1 year from now (OR: 0.61, 95% CI: [0.39, 0.95], P =.029). The 20.0% reported they plan to pursue an increased degree of nonoperative measures prior to surgery 1 year from now, and respondents with a spouse at home (OR: 3.55, 95% CI: [1.14, 11.08], P =.029) or who spend a large percentage of their time teaching (OR: 1.45, 95% CI: [1.02, 2.07], P =.040) were more likely to adopt this practice. Conclusions: The COVID‐19 pandemic has had an adverse effect on surgeon teaching, clinical volume, and personal income. In the future, surgeons with family and those personally affected by COVID‐19 may be more willing to alter surgical indications and change education and conference plans. Anticipating these changes may help the spine community appropriately plan for future challenges. [ABSTRACT FROM AUTHOR]

Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology‐encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes. [ABSTRACT FROM AUTHOR]

Ecological restoration is practiced worldwide as a direct response to the degradation and destruction of ecosystems. In addition to its ecological impact it has enormous potential to improve population health, socioeconomic well‐being, and the integrity of diverse national and ethnic cultures. In recognition of the critical role of restoration in ecosystem health, the United Nations (UN) declared 2021–2030 as the Decade on Ecosystem Restoration. We propose six practical strategies to strengthen the effectiveness and amplify the work of ecological restoration to meet the aspirations of the Decade: (1) incorporate holistic actions, including working at effective scale; (2) include traditional ecological knowledge (TEK); (3) collaborate with allied movements and organizations; (4) advance and apply soil microbiome science and technology; (5) provide training and capacity‐building opportunities for communities and practitioners; and (6) study and show the relationships between ecosystem health and human health. We offer these in the hope of identifying possible leverage points and pathways for collaborative action among interdisciplinary groups already committed to act and support the UN Decade on Ecosystem Restoration. Collectively, these six strategies work synergistically to improve human health and also the health of the ecosystems on which we all depend, and can be the basis for a global restorative culture. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Improving glycemic control in older African Americans with diabetes and mild cognitive impairment (MCI) is important as the population ages and becomes more racially diverse. DESIGN: Randomized controlled trial. SETTING: Recruitment from primary care practices of an urban academic medical center. Community‐based treatment delivery. PARTICIPANTS: Older African Americans with MCI, low medication adherence, and poor glycemic control (N = 101). INTERVENTIONS: Occupational therapy (OT) behavioral intervention and diabetes self‐management education. MEASUREMENTS: The primary outcome was a reduction in hemoglobin A1c level of at least 0.5% at 6 months, with maintenance effects assessed at 12 months. RESULTS: At 6 months, 25 of 41 (61.0%) OT participants and 22 of 46 (48.2%) diabetes self‐management education participants had a reduction in hemoglobin A1c level of at least 0.5%. The model‐estimated rates were 58% (95% confidence interval [CI] = 45%‐75%) and 48% (95% CI = 36%‐64%), respectively (relative risk [RR] = 1.21; 95% CI = 0.84‐1.75; P =.31). At 12 months, the respective rates were 21 of 39 (53.8%) OT participants and 24 of 49 (49.0%) diabetes self‐management education participants. The model‐estimated rates were 50% (95% CI = 37%‐68%) and 48% (95% CI = 36%‐64%), respectively (RR = 1.05; 95% CI = 0.70‐1.57; P =.81). CONCLUSION: Both interventions improved glycemic control in older African Americans with MCI and poor glycemic control. This result reinforces the American Diabetes Associationʼs recommendation to assess cognition in older persons with diabetes and demonstrates the potential to improve glycemic control in this high‐risk population. J Am Geriatr Soc 68:1015–1022, 2020 [ABSTRACT FROM AUTHOR]

Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)–associated treatment‐refractory partial‐onset seizures, based on the EXIST‐3 study (NCT01713946) results. As TSC‐associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (Cmin)) after a dose of 6 mg/m2 and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict Cmin in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short‐term and long‐term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range. [ABSTRACT FROM AUTHOR]

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging‐informed clinical trial enrichment tool. Modeling of integrated longitudinal patient‐level data came from open‐access natural history studies in patients diagnosed with aMCI—the Alzheimer's Disease Neuroimaging Initiative (ADNI)‐1 and ADNI‐2—and indicated that a decrease of 1 cm3 with respect to the analysis dataset median baseline intracranial volume‐adjusted HV (ICV‐HV; ~ 5 cm3) is associated with > 50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale–Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV‐HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD).Methods: Thirty-five participants were randomly allocated to a 36-session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [11 C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation-evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS-UPDRS part III, finger tapping, Timed-up-and-go) and nonmotor assessments (Starkstein Apathy Scale, Beck Depression Inventory, reaction time, Positive and Negative Affect Schedule, Trail Making Test [A and B], and Montreal Cognitive Assessment) before and after the interventions.Results: The aerobic group exhibited increased activity in the ventral striatum during functional magnetic resonance imaging in anticipation of 75% probability of reward (P = 0.01). The aerobic group also demonstrated increased repetitive transcranial magnetic stimulation-evoked dopamine release in the caudate nucleus (P = 0.04) and increased baseline nondisplaceable binding potential in the posterior putamen of the less affected repetitive transcranial magnetic stimulation-stimulated hemisphere measured by position emission tomography (P = 0.03).Conclusions: Aerobic exercise alters the responsivity of the ventral striatum, likely related to changes to the mesolimbic dopaminergic pathway, and increases evoked dopamine release in the caudate nucleus. This suggests that the therapeutic benefits of exercise are in part related to corticostriatal plasticity and enhanced dopamine release. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy and is characterized by insulin resistance and decreased circulating glucagon-like peptide-1 (GLP-1). GDM resolves rapidly after delivery implicating the placenta in the disease. This study examines the biological functions that cause this pathology. The placenta releases syncytiotrophoblast-derived extracellular vesicles (STB-EVs) into the maternal circulation, which is enhanced in GDM. Dipeptidyl peptidase IV (DPPIV) is known to play a role in type 2 diabetes by breaking down GLP-1, which in turn regulates glucose-dependent insulin secretion. STB-EVs from control and GDM women were analysed. We show that normal human placenta releases DPPIV-positive STB-EVs and that they are higher in uterine than paired peripheral blood, confirming placental origin. DPPIV-bound STB-EVs from normal perfused placentae are dose dependently inhibited with vildagliptin. DPPIV-bound STB-EVs from perfused placentae are able to breakdown GLP-1 in vitro. STB-EVs from GDM perfused placentae show greater DPPIV activity. Importantly, DPPIV-bound STB-EVs increase eightfold in the circulation of women with GDM. This is the first report of STB-EVs carrying a biologically active molecule that has the potential to regulate maternal insulin secretion. [ABSTRACT FROM AUTHOR]

Six coupled atmosphere–ocean set‐ups of ALADIN and POM limited‐area models are used to simulate five heavy precipitation events over the Adriatic Sea. We evaluate several approaches to applying the one‐ or two‐way atmosphere–ocean coupling (during the forecast of the warm‐up assimilation cycle, during the main forecast, or both) and using static sea‐surface temperature (SST) information in various resolutions: from POM, from MFS (a regional ocean model) or from OSTIA analysis (used also by the global model ECMWF/IFS). The set‐ups are designed in a way that allows for independent evaluation of various SST sources in ALADIN and the strategy of two‐way coupling. SST quality in these set‐ups is verified against satellite observations. The impact on precipitation forecasts is quantified by verification over 900 stations. Results depend on the weather situation, the frequency of the update of SST and the application of two‐way coupling before and during the events. When SST is used statically in ALADIN, operational‐like forecasts using daily SST analysis from OSTIA are more accurate than those using MFS and especially POM; this illustrates the importance of using fresh information from observations. The two‐way coupling outperformed the one‐way coupling in the cases with heavy and localized convection as the dominating process. The skill of the two‐way coupled experiments was similar in situations with large‐scale synoptic forcing. It was found that including the two‐way coupling in the assimilation cycle a few days before the studied weather events impacts the SST forecast but has neutral impact on precipitation scores. Results suggest that ocean data assimilation is necessary in the two‐way coupled system in order to realistically update SST in the system with fresh observations. Five heavy‐precipitation events over the Adriatic Sea are modelled using two‐way coupled regional ocean and numerical weather prediction models. Six modelling set‐ups with various application of SST information, air–sea coupling and data assimilation are evaluated. Two‐way coupling is superior to one‐way coupling, but SST update frequency also plays a major role. [ABSTRACT FROM AUTHOR]

Abstract: Two subspecies of the house mouse, Mus musculus domesticus and Mus musculus musculus, meet in a narrow contact zone across Europe. Mice in the hybrid zone are highly admixed, representing the full range of mixed ancestry from the two subspecies. Given the distinct morphologies of these subspecies, these natural hybrids can be used for genomewide association mapping at sufficiently high resolution to directly infer candidate genes. We focus here on limb bone length differences, which is of special interest for understanding the evolution of developmentally correlated traits. We used 172 first‐generation descendants of wild‐caught mice from the hybrid zone to measure the length of stylopod (humerus/femur), zeugopod (ulna/tibia) and autopod (metacarpal/metatarsal) elements in skeletal CT scans. We find phenotypic covariation between limb elements in the hybrids similar to patterns previously described in Mus musculus domesticus inbred strains, suggesting that the hybrid genotypes do not influence the covariation pattern in a major way. Mapping was performed using 143,592 SNPs and identified several genomic regions associated with length differences in each bone. Bone length was found to be highly polygenic. None of the candidate regions include the canonical genes known to control embryonic limb development. Instead, we are able to identify candidate genes with known roles in osteoblast differentiation and bone structure determination, as well as recently evolved genes of, as yet, unknown function. [ABSTRACT FROM AUTHOR]

Summary: Objective: The present analysis examined the exposure‐response relationship by means of the predose everolimus concentration (Cmin) and the seizure response in patients with tuberous sclerosis complex–associated seizures in the EXIST‐3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin. Methods: A model‐based approach was used to predict patients' daily Cmin. Time‐normalized Cmin (TN‐Cmin) was calculated as the average predicted Cmin in a time interval. TN‐Cmin was used to link exposure to efficacy and safety end points via model‐based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure‐response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event. Results: There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN‐Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN‐Cmin were not associated with statistically significant increases in the risk of stomatitis or infections. Significance: The recommended TDM is to target everolimus Cmin within a range of 5‐7 ng/mL initially and 5‐15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P‐glycoprotein inducers/inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Coal combustion residuals (CCRs) are composed of various constituents, including radioactive materials. The objective of this study was to utilize methodology on radionuclide risk assessment from the Environmental Protection Agency (EPA) to estimate the potential cancer risks associated with residential exposure to CCR‐containing soil. We evaluated potential radionuclide exposure via soil ingestion, inhalation of soil particulates, and external exposure to ionizing radiation using published CCR radioactivity values for 232Th, 228Ra, 238U, and 226Ra from the Appalachia, Illinois, and Powder River coal basins. Mean and upper‐bound cancer risks were estimated individually for each radionuclide, exposure pathway, and coal basin. For each radionuclide at each coal basin, external exposure to ionizing radiation contributed the greatest to the overall risk estimate, followed by incidental ingestion of soil and inhalation of soil particulates. The mean cancer risks by route of exposure were 2.01 × 10−6 (ingestion), 6.80 × 10−9 (inhalation), and 3.66 × 10−5 (external), while the upper bound cancer risks were 3.70 × 10−6 (ingestion), 1.18 × 10−8 (inhalation), and 6.15 × 10−5 (external), using summed radionuclide‐specific data from all locations. The upper bound cancer risk from all routes of exposure was 6.52 × 10−5. These estimated cancer risks were within the EPA's acceptable cancer risk range of 1 × 10−6 to 1 × 10−4. If the CCR radioactivity values used in this analysis are generally representative of CCR waste streams, then our findings suggest that CCRs would not be expected to pose a significant radiological risk to residents living in areas where contact with CCR‐containing soils might occur. [ABSTRACT FROM AUTHOR]

Background: Patterns of atrophy in the brain highly differ between individual Alzheimer's Disease (AD) patients, however, most clinical research focuses on group‐level differences (Verdi et al., 2021). Here we used a novel technique, neuroanatomical normative modelling, to reveal individual patterns of cortical thickness by quantifying deviations from the normative range. We applied a hierarchical Bayesian regression (HBR) normative model (Kia et al., 2021), to amyloid‐positive AD patients who had clinical amyloid PET imaging at the Imperial Memory Clinic (IMC). Patients had either AD dementia or mild cognitive impairment due to AD. We hypothesised that there would be individual differences in patterns of cortical atrophy in these patients. Method: Cortical thickness across 148 regions of interest (ROIs) was generated using FreeSurfer from n=130 (102 AD patients and 28 healthy controls) T1‐weighted MRIs acquired from the IMC. A reference HBR normative model was trained on a separate dataset of n=34,490 healthy individuals to index population variability, which predicted cortical thickness at each ROI using age and sex. This generated cortical thickness z‐scores for each ROI, per patient (z‐score < ‐1.96 = outlier). Result: The patterns of cortical atrophy outliers were highly varied in amyloid‐positive AD patients. For instance, the largest proportion of outliers in a region was 60% within the superior temporal sulci, if atrophy were homogenous we would expect 100% of outliers to be here (Fig.1). This heterogeneity was also seen when comparing how similar outlier patterns were between patients (Fig.2). We also found that the proportions of outliers differ according to disease severity, e.g. the highest percentage of outliers was 70% within superior temporal sulci within the AD dementia subgroup, and 50% in superior temporal sulci in the mild cognitive impairment due to AD subgroup (Fig.3). Conclusion: Amyloid‐positivity results in heterogenous patterns of cortical atrophy. This is more pronounced in AD dementia, though still present in people with mild cognitive impairment due to AD. Neuroanatomical normative maps have the potential to be individualised markers of disease, and with application to longitudinal data could track individual disease progression. [ABSTRACT FROM AUTHOR]

Purpose We developed diffusion tensor spectroscopic imaging (DTSI), based on proton-echo-planar-spectroscopic imaging (PEPSI), and evaluated the feasibility of mapping brain metabolite diffusion in adults and children. Methods PRESS prelocalized DTSI at 3 Tesla (T) was performed using navigator-based correction of movement-related phase errors and cardiac gating with compensation for repetition time (TR) related variability in T1 saturation. Mean diffusivity (MD) and fractional anisotropy (FA) of total N-acetyl-aspartate (tNAA), total creatine (tCr), and total choline (tCho) were measured in eight adults (17-60 years) and 10 children (3-24 months) using bmax = 1734 s/mm2, 1 cc and 4.5 cc voxel sizes, with nominal scan times of 17 min and 8:24 min. Residual movement-related phase encoding ghosting (PEG) was used as a regressor across scans to correct overestimation of MD. Results After correction for PEG, metabolite slice-averaged MD estimated at 20% PEG were lower ( P < 0.042) for adults (0.17/0.20/0.18 × 10−3 mm2/s) than for children (0.26/0.27/0.24 × 10−3 mm2/s). Extrapolated to 0% PEG, the MD estimates decreased further (0.09/0.11/0.11 × 10−3 mm2/s versus 0.15/0.16/0.15 × 10−3 mm2/s). Slice-averaged FA of tNAA ( P = 0.049), tCr ( P = 0.067), and tCho ( P = 0.003) were higher in children. Conclusion This high-speed DTSI approach with PEG regression allows for estimation of metabolite MD and FA with improved tolerance to movement. Our preliminary data suggesting age-related changes support DTSI as a sensitive technique for investigating intracellular markers of biological processes. Magn Reson Med 78:1246-1256, 2017. © 2016 International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are cytotoxic lymphocytes that selectively respond against abnormal cells. Human cytomegalovirus (HCMV) infection causes expansion of NKG2C+CD57+ NK cells in vivo and NKG2C+ NK cells proliferate when cultured with HCMV-infected cells. This raises the possibility of an NK-cell subset selectively responding against a specific pathogen and accruing memory. To test this possibility, we compared proliferation, natural cytotoxicity and interferon-γ (IFN-γ) production of NK cells from HCMV-seropositive and HCMV-seronegative individuals co-cultured with HCMV-infected or uninfected MRC-5 cells. There was no significant difference in proliferation of NK cells from HCMV-seropositive or seronegative individuals against uninfected MRC-5 cells, but significantly more NK cells from the HCMV-seropositive group proliferated in response to HCMV-infected MRC-5 cells. Natural cytotoxicity of NK cells against K562 cells increased following co-culture with HCMV-infected versus uninfected MRC-5 only for the HCMV-seropositive group. After co-culture with HCMV-infected MRC-5 cells, proliferating NK cells from HCMV-seropositive donors selectively produced IFN-γ when re-exposed to HCMV-infected MRC-5 cells. Both NKG2C+ and NKG2C− NK cells proliferated in co-culture with HCMV-infected MRC-5 cells, with the fraction of proliferating NKG2C+ NK cells directly correlating with the circulating NKG2C+ fraction. These data illustrate an at least partly NKG2C-independent human NK-cell memory-type response against HCMV. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to determine whether motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation and measured with conventional bipolar electromyography (EMG) are influenced by crosstalk from non-target muscles.Methods: MEPs were recorded in healthy participants using conventional EMG electrodes placed over the extensor carpi radialis muscle (ECR) and high-density surface EMG (HDsEMG). Fifty MEPs at 120% resting and active motor threshold were recorded. To determine the contribution of ECR to the MEPs, the amplitude distribution across HDsEMG channels was correlated with EMG activity recorded during a wrist extension task.Results: Whereas the conventional EMG identified MEPs from ECR in >90% of the stimulations, HDsEMG revealed that spatial amplitude distribution representative of ECR activation was observed less frequently at rest than while holding a contraction (P < 0.001).Conclusions: MEPs recorded with conventional EMG may contain crosstalk from non-target muscles, especially when the stimulation is applied at rest. Muscle Nerve 55: 828-834, 2017. [ABSTRACT FROM AUTHOR]

Primary motor cortex (M1) excitability is modulated following a single session of cycling exercise. Specifically, short-interval intracortical inhibition and intracortical facilitation are altered following a session of cycling, suggesting that exercise affects the excitability of varied cortical circuits. Yet we do not know whether a session of exercise also impacts the excitability of interhemispheric circuits between, and other intracortical circuits within, M1. Here we present two experiments designed to address this gap in knowledge. In experiment 1, single and paired pulse transcranial magnetic stimulation ( TMS) were used to measure intracortical circuits including, short-interval intracortical facilitation ( SICF) tested at 1.1, 1.5, 2.7, 3.1 and 4.5 ms interstimulus intervals ( ISIs), contralateral silent period ( CSP) and interhemispheric interactions by measuring transcallosal inhibition ( TCI) recorded from the abductor pollicus brevis muscles. All circuits were assessed bilaterally pre and two time points post (immediately, 30 min) moderate intensity lower limb cycling. SICF was enhanced in the left hemisphere after exercise at the 1.5 ms ISI. Also, CSP was shortened and TCI decreased bilaterally after exercise. In Experiment 2, corticospinal and spinal excitability were tested before and after exercise to investigate the locus of the effects found in Experiment 1. Exercise did not impact motor-evoked potential recruitment curves, Hoffman reflex or V-wave amplitudes. These results suggest that a session of exercise decreases intracortical and interhemispheric inhibition and increases facilitation in multiple circuits within M1, without concurrently altering spinal excitability. These findings have implications for developing exercise strategies designed to potentiate M1 plasticity and skill learning in healthy and clinical populations. [ABSTRACT FROM AUTHOR]

The mechanism by which olivine grains became embedded within iron-nickel alloy in pallasite meteorites continues to be a matter of scientific debate. Geochemical and textural observations have failed to fully elucidate the origin and history of the olivine crystals; however, little research attention has been devoted to their crystallographic orientations within the metal matrix. Using electron backscatter diffraction, we have collected crystallographic orientation data for 296 crystals within ∼65 cm2 sample surface from Springwater. Though no global crystallographic preferred orientation exists, very low misorientations are observed among [100] axes of olivine crystals within specific texturally defined domains. Combined with a thorough characterization of large-scale Springwater textures, the definitively nonrandom spatial distribution of olivine orientations provides clues regarding the nature of the olivine's initial formation environment as well as the sequence of events subsequent to metal incorporation. [ABSTRACT FROM AUTHOR]

Androdioecy was first described by Darwin in his seminal work on barnacle diversity; he identified males and hermaphrodites in the same reproductive population. Today, we realize that many androdioecious plants and animals share astonishing similarities, particularly with regard to their evolutionary history and mating system. Notably, these species were ancestrally dioecious, and their mating system has the following characteristics: hermaphrodites self-fertilize frequently, males are more successful in large mating groups, and males have a mating advantage. A male mating advantage makes androdioecy more likely to persist over evolutionary times. Androdioecious barnacles, however, appear to persist as an outlier with a different evolutionary trajectory: they originate from hermaphroditic species. Although sexual systems of androdioecious barnacles are known, no information on the mating system of androdioecious barnacles is available. This study assessed the mating system of the androdioecious barnacle Chelonibia testudinaria. In contrast to other androdioecious species, C. testudinaria does not self-fertilize, males do not have a mating advantage over hermaphrodites, and the average mating group is quite small, averaging only three individuals. Mating success is increased by proximity to the mate and penis length. Taken together, the mating system of C. testudinaria is unusual in comparison with other androdioecious plants and animals, and the lack of a male mating advantage suggests that the mating system alone does not provide an explanation for the maintenance of androdioecy in this species. Instead, we propose that sex-specific life history equalizes male and hermaphroditic overall fitness. [ABSTRACT FROM AUTHOR]

Circulating endothelial cells (CEC) and their progenitors (EPC) are restricted subpopulations of peripheral blood (PB), cord blood (CB), and bone marrow (BM) cells, involved in the endothelial homeostasis maintenance. Both CEC and EPC are thought to represent potential biomarkers in several clinical conditions involving endothelial turnover/remodeling. Although different flow cytometry methods for CEC and EPC characterization have been published so far, none of them have reached consistent conclusions, therefore consensus guidelines with respect to CEC and EPC identification and quantification need to be established. Here, we have carried out an in depth investigation of CEC and EPC phenotypes in healthy PB, CB and BM samples, by optimizing a reliable polychromatic flow cytometry (PFC) panel. Results showed that the brightness of CD34 expression on healthy PB and CB circulating cells represents a key benchmark for the identification of CEC (CD45neg/CD34bright/CD146pos) respect to the hematopoietic stem cell (HSC) compartment (CD45dim/CD34pos/CD146neg). This approach, combined with a dual-platform counting technique, allowed a sharp CEC enumeration in healthy PB ( n = 38), and resulting in consistent CEC counts with previously reported data (median = 11.7 cells/ml). In parallel, by using rigorous PFC conditions, CD34pos/CD45dim/CD133pos/VEGFR2pos EPC were not found in any healthy PB or CB sample, since VEGFR2 expression was never detectable on the surface of CD34pos/CD45dim/CD133pos cells. Notably, the putative EPC phenotype was observed in all analyzed BM samples ( n = 12), and the expression of CD146 and VEGFR2, on BM cells, was not restricted to the CD34bright compartment, but also appeared on the HSC surface. Altogether, our findings suggest that the previously reported EPC antigen profile, defined by the simultaneous expression of VEGFR2 and CD133 on the surface of CD45dim/CD34pos cells, should be carefully re-evaluated and further studies should be conducted to redefine EPC features in order to translate CEC and EPC characterization into clinical practice. © 2015 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

Background: Digital Measures (DMs) derived from mobile devices and smartphone applications have received a strongly increasing attention during the last years, because they could allow for an accurate, quantitative monitoring of disease symptoms, even outside clinics. In addition, DMs may help to diagnose Alzheimer's Disease (AD) in a pre‐symptomatic stage and thus increase the success chances of therapeutic interventions. However, before any use in clinical routine, DMs have to be evaluated carefully by assessing their relationship to established clinical scores and understanding their diagnostic benefit. In this regard the IMI project RADAR‐AD (www.radar‐ad.org) has the ambition to evaluate a broad panel of digital technologies with respect to their potential for early disease diagnosis while focusing on functional activities of daily living. Method: An example of a panel of digital technology RADAR‐AD uses is a smartphone based virtual reality game resulting into an assessment of cognitive impairment. In our work we analyzed connections between digital readouts and cognitive features like MMSE (Mini Mental State Examination) via one of our recently developed Artificial Intelligence (AI) approaches called Variational Autoencoder Modular Bayesian Networks (VAMBN). Going one step further we also tested the possibility to accurately predict MMSE scores from DMs and vice versa via machine learning. Based on this finding we then simulated DMs within the ADNI cohort and re‐ran VAMBN. Result: Application of VAMBN on the data from virtual reality game resulted into a network comprising DMs, MMSE sub‐item scores and demographic features (Figure 1). It thus allowed to disentangle and quantify the relationship between DMs and established clinical scores. The simulation of DM's and application of VAMBN in the ADNI cohort allowed us to further predict connections of DMs with FAQ (Functional Activity Questionnaire) and even molecular mechanisms. Conclusion: Our results indicate that there is a significant dependency between digital readouts and clinical scores such as MMSE and FAQ. Therefore, DM's may have the potential to act as a vital measure in the diagnosis of AD in a pre‐symptomatic stage. Our next steps will focus on evaluating the diagnostic benefit of DMs compared to the questionnaire‐based FAQ. [ABSTRACT FROM AUTHOR]

Five British ale yeast strains were subjected to flavour profiling under brewery fermentation conditions in which all other brewing parameters were kept constant. Significant variation was observed in the timing and quantity of flavour-related chemicals produced. Genetic tests showed no evidence of hybrid origins in any of the strains, including one strain previously reported as a possible hybrid of Saccharomyces cerevisiae and S. bayanus. Variation maintained in historical S. cerevisiae ale yeast collections is highlighted as a potential source of novelty in innovative strain improvement for bioflavour production. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene ( APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. Methods APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. Results Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes ( P = 0.01). Conclusion APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans. [ABSTRACT FROM AUTHOR]

Mutations in FOXP1, located at 3p13, have been reported in patients with global developmental delay (GDD), intellectual disability (ID), and speech defects. Mutations in FOXP2, located at 7q31, are well known to cause developmental speech and language disorders, particularly developmental verbal dyspraxia (DVD). FOXP2 has been shown to work co-operatively with FOXP1 in mouse development. An overlap in FOXP1 and FOXP2 expression, both in the songbird and human fetal brain, has suggested that FOXP1 may also have a role in speech and language disorders. We report on a male child with a 0.19 MB intragenic deletion that is predicted to result in haploinsufficiency of FOXP1. Review of our patient and others reported in the literature reveals an emerging phenotype of GDD/ID with moderate to severe speech delay where expressive speech is most severely affected. DVD appears not to be a distinct feature in this group. Facial features include a broad forehead, downslanting palpebral fissures, a short nose with broad tip, relative or true macrocephaly, a frontal hair upsweep and prominent digit pads. Autistic traits and other behavioral problems are likely to be associated with haploinsufficiency of FOXP1. Congenital malformations may be associated. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

With the aim to evaluate the selectivity in the antitumor action, the cytotoxic activity of chamomile and marigold tea was tested against various malignant cell lines and against healthy immunocompetent peripheral blood mononuclear cells (PBMC). Chemical profiles of chamomile and marigold infusions and decoctions were analyzed by liquid chromatography/mass spectrometry; their total phenolic content and radical scavenging activity were determined, too. Results from present research demonstrate that chamomile and marigold tea exert selective dose-dependent cytotoxic action against target cancer cells. It is noteworthy that cytotoxicity of tea prepared from Calendula officinalis is remarkably higher in comparison to that from Matricaria recutita tea. The cytotoxic effect of chamomile tea is very weak to healthy PBMC, while the effect of marigold tea on PBMC is more pronounced. Marigold tea exerts highly selective antitumor effect especially to melanoma Fem-x cells in comparison to the action to normal healthy PBMC. Chemical analyses show that dominant phenolic compounds in examined infusions and decoctions are flavonoid glycosides and hydroxycinnamic acid derivatives. There are no considerable differences in total phenolic content and antioxidant activity between examined infusions. Antitumor potential of chamomile and marigold tea should be further investigated. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Early-onset schizophrenia (onset before adulthood) is a rare and severe form of the disorder that shows phenotypic and neurobiological continuity with adult-onset schizophrenia. Here, we provide a synthesis of keynote findings in this enriched population to understand better the neurobiology and pathophysiology of early-onset schizophrenia. A synthetic and integrative approach is applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early-onset schizophrenia. Childhood and adolescent-onset schizophrenia is associated with severe clinical course, greater rates of premorbid abnormalities, poor psychosocial functioning and increased severity of brain abnormalities. Early-onset cases show similar neurobiological correlates and phenotypic deficits to adult-onset schizophrenia, but show worse long-term psychopathological outcome. Emerging technological advances have provided important insights into the genomic architecture of early-onset schizophrenia, suggesting that some genetic variations may occur more frequently and at a higher rate in young-onset than adult-onset cases. Clinical, cognitive, genetic and imaging data suggest increased severity in early-onset schizophrenia. Studying younger-onset cases can provide useful insights into the neurobiological mechanisms of schizophrenia and the complexity of gene-environment interactions leading to the emergence of this debilitating disorder. [ABSTRACT FROM AUTHOR]

The infective, microscopic Strongyloides stercoralis larvae in contaminated soil can penetrate human skin with the help of excretory/secretory proteases. These proteases play a critical role in infection and transmigration of the parasite to the intestines. Strongylastacin is similar to astacin (from the digestive gland of the crayfish Astacus astacus), a multi-domain protein with a signal peptide, a pro-enzyme, a catalytic domain containing the zinc binding consensus astacin family signature sequence HEXXHXXGFXHEXXRXDR, and a second conserved zinc binding motif SIMHY at N- terminal region. An EGF-1 like domain and a CUB domain are located at the COOH- terminal. In this study, the excretory/secretory Strongylastacin gene from S. stercoralis infective larval stage was cloned and expressed as a 45 kDa in Escherichia coli. Immunoblot analysis showed the presence of natural IgG antibodies against strongylastacin in six infected and six non-endemic normal sera. These findings were confirmed in an ELISA of 32 S. stercoralis infected and 32 presumed normal human sera; all contained natural anti-strongylastacin IgG antibodies. By contrast, IgE antibodies specific to strongylastacin were present in sera from individuals infected with S. stercoralis but not in uninfected control sera. Moreover, recombinant strongylastacin did not cross-react with IgE antibodies either from patients infected with filaria or patients with tropical pulmonary eosinophilic (TPE) who had increased IgE antibodies. The present authors conclude that strongylastacin, an excretory/secretory antigen, elicits specific IgE antibodies in S. stercoralis infected humans. Non-specific IgG antibodies to strongylastacin are present in both infected and normal humans. Further investigation is needed to understand the role of the host protective response against strongylastacin. [ABSTRACT FROM AUTHOR]

A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke ( CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission ( MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1* B* C haplotype. Owing to the retrospective design of the study, these results require confirmation. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]