A modular approach to simulation modelling offers significant advantages for its application to agricultural and environmental questions, including re-use of model equations in different contexts and ...with different user-interfaces; configuration of model structures that are most appropriate to a given problem; and facilitation of collaboration between modelling teams. This paper describes the Common Modelling Protocol (CMP), a generic, open and platform-independent framework for modular simulation modelling that is in widespread use. The CMP is distinguished from existing simulation frameworks by taking an explicitly hierarchical view of the biophysical system being simulated and by representing continuous and discontinuous processes equally naturally. Modules of model logic are represented in the CMP by entities known as “components”. Each component may possess “properties” that convey the value of the quantities in its equations and “event handlers” that compute model logic. Low-level information-transfers in the CMP are carried out by means of a message-passing system. Co-ordinated sequences of messages carry out tasks such as initialization, exchange of variable values and the control of computation order. Extensible Markup Language (XML) is used in the protocol for tasks such as denoting data types, submitting simulations for execution and describing components to user-interface software. Examples are presented showing how the CMP can be used to couple modules developed by different teams and to configure a complex model structure. The choices and trade-offs encountered when building a framework for modular simulation are analyzed, using the CMP and other simulation frameworks as examples. The kinds of scientific issues that arise when the CMP is used to realize collaboration between modelling groups are discussed.
Lower serum concentrations of the osteoblast-derived protein, osteocalcin, have been associated with poorer glycemic control, insulin resistance and atherosclerosis, and with the development of type ...2 diabetes (T2DM).
This study compares concentrations of two physiological forms of osteocalcin, carboxylated (cOCN) and uncarboxylated (unOCN), between participants with T2DM (n = 20) and age-, gender- and body mass index (BMI)-matched participants without T2DM (n = 40) among patients with coronary artery disease (CAD), and it explores relationships between osteocalcin concentrations and cardiovascular risk factors.
Concentrations of unOCN (2.71 ± 1.86 vs. 4.70 ± 2.03 ng/mL; t = −3.635, p = 0.001) and cOCN (8.70 ± 2.27 vs. 10.77 ± 3.69 ng/mL; t = −2.30, p = 0.025) were lower in participants with T2DM. In participants without T2DM, concentrations of cOCN were associated with fitness (VO2Peak rho = 0.317, p = 0.047) and lower body fat (rho = −0.324, p = 0.041). In participants with T2DM, lower unOCN was associated with HbA1c (rho = −0.516, p = 0.020). Higher body mass was associated with higher unOCN (rho = 0.423, p = 0.009) in participants without T2DM, but with lower concentrations of both unOCN (rho = −0.590, p = 0.006) and cOCN (rho = −0.632, p = 0.003) in participants with T2DM.
In patients with CAD, lower osteocalcin concentrations were related to type 2 diabetes, and to adverse fitness, metabolic and obesity profiles.
Post-stroke cognitive impairment has a high prevalence in stroke patients and is associated with poor short and long term outcomes, including a negative impact on functional recovery. There is ...evidence that post-stroke impairment is the direct result of stroke induced neurological injury. Gray matter atrophy has been implicated in the development of post-stroke cognitive impairment and is the result of a series of neurochemical processes that are activated by ischemia. Lithium, traditionally used as a mood stabilizer, has been recognized in the last 10 years for its robust neuroprotective and neurotrophic effects against diverse insults, such as ischemia, both in vitro and in vivo. This has generated several preclinical and clinical studies of lithium treatment for managing neurodegenerative diseases and cerebral ischemia. Evidence suggests that lithium may protect against the cerebral atrophy and neuronal degeneration induced by the neurochemical processes and pathways known to regulate cell death and atrophy after an ischemic event. Lithium-mediated neurotroprotective and neurotrophic effects involve mechanisms highly relevant to the post-stroke population including the increased expression of brain-derived neurotrophic factor (BDNF) and Bcl-2, and inhibition of GSK-3β. Lithium-induced increases in human gray matter have been reported and occur within a time frame consistent with the known effects of lithium through increased expression of BDNF, Bcl-2 and GSK-3β inhibition. This article reviews the evidence to support the use of lithium to reduce neuronal damage post-stroke through 1) mechanisms of excitotoxicity and post-ischemic inflammation; and 2) neurotrophic signaling cascades. Lithium's relevant actions in preclinical and clinical studies will be reviewed and presented to support the neuroprotective and neurotrophic effects of lithium as well as other clinical considerations in using lithium in the post-ischemic stroke population.
OBJECTIVETo evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with ...Charcot-Marie-Tooth disease type 1A (CMT1A).
METHODSPatients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models.
RESULTSBaseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4–87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99–1.97, p < 0.0001, for baseline CMTES-R score 0–9).
CONCLUSIONThe CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A.
CLINICALTRIALS.GOV IDENTIFIERNCT01193075.
To assess the medial plantar nerve action potential (NAP) and skin biopsy in the evaluation of suspected distal sensory neuropathies (SN) with normal routine nerve conduction studies (NCS).
A total ...of 110 consecutive patients with suspected distal SN and normal routine NCS underwent medial plantar NAP testing and punch skin biopsy. Patients were clinically stratified as having pure small fiber sensory neuropathy (SFSN), or distal SN with large fiber involvement (SN-LFI).
A total of 56 patients were classified as SN-LFI and 54 SFSN. The medial plantar NAP, a measure of large fiber function, was abnormal in 31.8% of patients, more frequently in SN-LFI than SFSN. Distal leg epidermal nerve fiber (ENF) density, a measure of small fibers, was reduced in 47.3% of biopsies, with isolated ENF morphologic changes in 29.1% and normal findings in 23.6%. Biopsy abnormalities were more severe and prevalent in SN-LFI than in SFSN. In patients with a normal medial plantar NAP, distal leg biopsy showed reduced ENF density in 34.7%, and isolated morphologic changes in a further 37% of cases.
The medial plantar nerve action potential and skin biopsy are complementary in evaluation of distal SN with normal routine NCS. Small sensory nerve fibers are affected early in SN, and more severely so when large fiber involvement is apparent clinically.
Objective Studies have shown the Clock Drawing Test (CDT) to be useful as a screening test between normal, elderly populations and those diagnosed with dementia. However, the results of studies which ...have looked at the utility of the CDT to help differentiate Alzheimer's dementia (AD) and other dementias have been conflicting. The purpose of this study was to explore the utility of the CDT in discriminating between patients with AD and other dementias. Method A review was conducted using MEDLINE, PsycINFO and Embase. Search terms included clock drawing or CLOX and dementia or Parkinson's Disease or Alzheimer's Disease or Dementia with Lewy Bodies (DLB) or Vascular Dementia (VaD) or Semantic Dementia. Results 20 studies were selected. In most of the studies included, no significant differences were found in CDT scores between AD and VaD, DLB, and Parkinson's disease dementia (PDD) patients. Frontotemporal dementia (FTD) patients consistently scored higher in the CDT than AD patients. Qualitative analyses of the type of errors seem to suggest a difference between AD and the other types of dementias. Conclusions Overall, the CDT score may be useful in distinguishing between AD and FTD patients, but shows limited value in differentiating between AD and VaD, DLB and PDD. Qualitative analysis of the type of CDT errors may be a useful adjunct in the differential diagnosis of the types of dementias.
Objective
Experimental therapies under development for Friedreich’s Ataxia (FRDA) require validated biomarkers. In‐vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify ...Meissner’s corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross‐sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA.
Methods
Sixteen individuals with FRDA and 16 age‐ and gender‐matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds.
Results
MC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich’s Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset.
Interpretation
MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.
Arterial transit time is the time needed for blood to travel from large arteries to capillaries, as estimated from arterial spin-labeling MR imaging. The purpose of this study was to determine ...whether vascular risk factors and cognitive performance are related to regional differences in cerebral arterial transit time in patients with coronary artery disease who are at risk for cognitive decline.
Arterial transit time was estimated from multiple postlabel delay pseudocontinuous arterial spin-labeling images obtained from 29 men with coronary artery disease. Tests of memory, attention, processing speed, and executive function were administered. Principal component analysis was used to create separate models of cognition and vascular risk, which were related to brain regions through voxelwise analyses of arterial transit time maps.
Principal component analysis identified 2 components of vascular risk: 1) "pressor" (age, systolic blood pressure, and pulse pressure) and 2) "obesity" (body fat percentage and body mass index). Obesity was inversely related to arterial transit time in the posterior cingulate, precuneus, lateral occipital cortices, middle temporal gyrus, and frontal pole (P corrected < .05), whereas pressor was not significant. Cognitive scores were factored into a single component. Poor performance was inversely related to precuneus arterial transit time (P corrected < .05). The average arterial transit time in regions identified by obesity was associated with poorer cognitive function (r(2) = 0.21, t = -2.65, P = .01).
Altered cerebral hemodynamics, notably in nodal structures of the default mode network, may be one way that vascular risk factors impact cognition in patients with coronary artery disease.
PDF
