Hierarchical network structure as the source of hierarchical dynamics (power-law frequency spectra) in living and non-living systems: How state-trait continua (body plans, personalities) emerge from first principles in biophysics.

Living systems are hierarchical control systems that display a small world network structure. In such structures, many smaller clusters are nested within fewer larger ones, producing a fractal-like structure with a 'power-law' cluster size distribution (a mereology). Just like their structure, the dynamics of living systems shows fractal-like qualities: the timeseries of inner message passing and overt behavior contain high frequencies or 'states' (treble) that are nested within lower frequencies or 'traits' (bass), producing a power-law frequency spectrum that is known as a 'state-trait continuum' in the behavioral sciences. Here, we argue that the power-law dynamics of living systems results from their power-law network structure: organisms 'vertically encode' the deep spatiotemporal structure of their (anticipated) environments, to the effect that many small clusters near the base of the hierarchy produce high frequency signal changes and fewer larger clusters at its top produce ultra-low frequencies. Such ultra-low frequencies exert a tonic regulatory pressure that produces morphological as well as behavioral traits (i.e., body plans and personalities). Nested-modular structure causes higher frequencies to be embedded within lower frequencies, producing a power-law state-trait continuum. At the heart of such dynamics lies the need for efficient energy dissipation through networks of coupled oscillators, which also governs the dynamics of non-living systems (e.q., earthquakes, stock market fluctuations). Since hierarchical structure produces hierarchical dynamics, the development and collapse of hierarchical structure (e.g., during maturation and disease) should leave specific traces in system dynamics (shifts in lower frequencies, i.e. morphological and behavioral traits) that may serve as early warning signs to system failure. The applications of this idea range from (bio)physics and phylogenesis to ontogenesis and clinical medicine.

PO-07 - Excluding pulmonary embolism in cancer patients using the Wells rule and age-adjusted D-dimer testing: an individual patient data meta-analysis.

INTRODUCTION: Among patients with clinically suspected pulmonary embolism (PE), imaging and anticoagulant treatment can be safely withheld in approximately one-third of patients based on the combination of a "PE unlikely" Wells score and a D-dimer below the age-adjusted threshold. The clinical utility of this diagnostic approach in cancer patients is less clear. AIM: To evaluate the efficiency and failure rate of the original and simplified Wells rules in combination with age-adjusted D-dimer testing in patients with active cancer. MATERIALS AND METHODS: Individual patient data were used from 6 large prospective studies in which the diagnostic management of PE was guided by the original Wells rule and D-dimer testing. Study physicians classified patients as having active cancer if they had new, recurrent, or progressive cancer (excluding basal-cell or squamous-cell skin carcinoma), or cancer requiring treatment in the last 6 months. We evaluated the dichotomous Wells rule and its simplified version (Table). The efficiency of the algorithm was defined as the proportion of patients with a "PE unlikely" Wells score and a negative age-adjusted D-dimer, defined by a D-dimer below the threshold of a patient's age times 10 µg/L in patients aged ≥51 years. A diagnostic failure was defined as a patient with a "PE unlikely" Wells score and negative age-adjusted D-dimer who had symptomatic venous thromboembolism during 3 months follow-up. A one-stage random effects meta-analysis was performed to estimate the efficiency and failure. RESULTS: The dataset comprised 938 patients with active cancer with a mean age of 63 years. The most frequent cancer types were breast (13%), gastrointestinal tract (11%), and lung (8%). The type of cancer was not specified in 42%. The pooled PE prevalence was 29% (95% CI 25-32). PE could be excluded in 122 patients based on a "PE unlikely" Wells score and a negative age-adjusted D-dimer (efficiency 13%; 95% CI 11-15). Two of 122 patients were diagnosed with non-fatal symptomatic venous thromboembolism during follow-up (failure rate 1.5%; 95% CI 0.13-14.8). The simplified Wells score in combination with a negative age-adjusted D-dimer had an efficiency of 3.9% (95% CI 2.0-7.6) and a failure rate of 2.4% (95% CI 0.3-15). CONCLUSIONS: Among cancer patients with clinically suspected PE, imaging and anticoagulant treatment can be withheld in 1 out of every 8 patients by the original Wells rule and age-adjusted D-dimer testing. The simplified Wells rule was neither efficient nor safe in this population.

[Network clusters of symptoms as elementary syndromes of psychopathology: implications for clinical practice]. / Netwerkclusters van symptomen als elementaire syndromen in de psychopathologie: consequenties voor de klinische praktijk.

BACKGROUND: In a recent publication we reported the existence of around 11 (to 15) 'elementary syndromes' that may combine in various ways, rather like 'building blocks', to explain the wide range of psychiatric symptoms. 'Bridge symptoms' seem to be responsible both for combining large sets of symptoms into elementary syndromes and for combining the various elementary syndromes to form one globally connected network structure. AIM: To discuss the implication of these findings for clinical practice. METHOD: We performed a network analysis of symptom scores. RESULTS: Elementary syndromes provide a massive simplification of the description of psychiatric disease. Instead of the more than 300 categories in DSM-5, we now need to consider only a handful of elementary syndromes and personality domains. This modular representation of psychiatric illnesses allows us to make a complete, systematic and efficient assessment of patients and a systematic review of treatment options. Clinicians, patients, managerial staff and insurance companies can verify whether symptom reduction is taking place in the most important domains of psychopathology. Unlike classic multidimensional methods of disease description, network models of psychopathology can be used to explain comorbidity patterns, predict the clinical course of psychopathology and to designate primary targets for therapeutic interventions. CONCLUSION: A network view on psychopathology could significantly improve everyday clinical practice.

Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1†year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study.

AIM: To assess whether in early (rheumatoid) arthritis (RA) patients, metacarpal bone mineral density (BMD) loss after 4 months predicts radiological progression after 1 year of antirheumatic treatment. METHODS: Metacarpal BMD was measured 4 monthly during the first year by digital X-ray radiogrammetry (DXR-BMD) in patients participating in the IMPROVED study, a clinical trial in 610 patients with recent onset RA (2010 criteria) or undifferentiated arthritis, treated according to a remission (disease activity score<1.6) steered strategy. With Sharp/van der Heijde progression ≥0.5 points after 1 year (yes/no) as dependent variable, univariate and multivariate logistic regression analyses were performed. RESULTS: Of 428 patients with DXR-BMD results and progression scores available, 28 (7%) had radiological progression after 1 year. Independent predictors for radiological progression were presence of baseline erosions (OR (95% CI) 6.5 (1.7 to 25)) and early DXR-BMD loss (OR (95% CI) 1.5 (1.1 to 2.0)). In 366 (86%) patients without baseline erosions, early DXR-BMD loss was the only independent predictor of progression (OR (95% CI) 2.0 (1.4 to 2.9)). CONCLUSIONS: In early RA patients, metacarpal BMD loss after 4 months of treatment is an independent predictor of radiological progression after 1 year. In patients without baseline erosions, early metacarpal BMD loss is the main predictor of radiological progression.

A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study.

OBJECTIVES: To assess which treatment strategy is most effective in inducing remission in early (rheumatoid) arthritis. METHODS: 610 patients with early rheumatoid arthritis (RA 2010 criteria) or undifferentiated arthritis (UA) started treatment with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (Disease Activity Score <1.6 after 4 months) tapered prednisone to zero and those with persistent remission after 8 months, tapered and stopped MTX. Patients not in early remission were randomised to receive either MTX plus hydroxychloroquine plus sulfasalazine plus low-dose prednisone (arm 1) or to MTX plus adalimumab (ADA) (arm 2). If remission was present after 8 months both arms tapered to MTX monotherapy; if not, arm 1 changed to MTX plus ADA and arm 2 increased the dose of ADA. Remission rates and functional and radiological outcomes were compared between arms and between patients with RA and those with UA. RESULTS: 375/610 (61%) patients achieved early remission. After 1 year 68% of those were in remission and 32% in drug-free remission. Of the randomised patients, 25% in arm 1 and 41% in arm 2 achieved remission at year 1 (p<0.01). Outcomes were comparable between patients with RA and those with UA. CONCLUSIONS: Initial MTX and prednisone resulted in early remission in 61% of patients with early (rheumatoid) arthritis. Of those, 68% were in remission and 32% were in drug-free remission after 1 year. In patients not in early remission, earlier introduction of ADA resulted in more remission at year 1 than first treating with disease-modifying antirheumatic drug combination therapy plus prednisone.

Determinants of absence of osteoarthritis in old age.

OBJECTIVE: To investigate factors associated with absence of osteoarthritis (OA). METHODS: In 82 well-functioning 90-year-old participants from a cross-sectional birth cohort, radiographs of hands, hips, and knees were acquired and scored according to the Kellgren and Lawrence (K-L) method for determining OA. A score of ≥ 2 was considered as OA. 'Free from OA' was defined as no hip or knee OA and less than three hand joints with OA. Logistic regression analyses were used to investigate associations with absence of OA. RESULTS: Absence of hip, knee, and hand OA was seen in 63, 51, and 29% of participants, respectively. Joints on the left and right side of the body were equally affected. Sixteen per cent of 90-year old participants were 'free from OA'. Absence of knee OA was associated with being male. A family history of finger nodes was negatively associated with absence of hip and hand OA. Body mass index (BMI) was negatively associated with 'free from OA', and also with absence of hip and knee OA. A history of heavy occupational work was associated with 'free from OA' [odds ratio (OR) 7.2, 95% confidence interval (CI) 1.3-39.9] and with absence of hand OA in particular (OR 2.7, 95% CI 1.0-7.1). CONCLUSIONS: In 90-year-olds, absence of OA is associated with male sex, a normal BMI, absence of familial predisposition for OA, and, contrary to our expectation, heavy work. Further research in protective genetic factors is needed.

Low innate production of interleukin-1beta and interleukin-6 is associated with the absence of osteoarthritis in old age.

OBJECTIVE: We investigated whether innate differences in cytokine response were associated with the absence of osteoarthritis (OA) in old age. DESIGN: In 82 participants from a cross-sectional birth cohort, radiographs of hands, hips and knees were taken at the age of 90 years. OA was defined as a Kellgren-Lawrence score of at least two. "Free from OA" was defined at patient level as absence of hip and knee OA, and presence of OA in maximally two hand joints. The innate cytokine response was determined in whole-blood samples upon stimulation with lipopolysaccharide. Logistic regression analyses were used to investigate associations between absence of OA in relation to tertiles of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-1 receptor antagonist (RA) and IL-10. Adjustments were made for gender and body mass index. RESULTS: Sixteen percent of the participants were "free from OA". Subjects in the lowest tertile of Il-1beta production had a 11-fold increased chance to be free of OA [odds ratio (OR) 11.3, confidence intervals (CI) 95% 1.1-115.9], subjects in the lowest tertile of IL-6 production had an almost 7-fold increased chance to be free of OA (OR 6.7, 95% CI 1.1-41.2). Absence of hand OA was associated with low innate production of IL-6 and IL-1RA, absence of hip OA was associated with low innate IL-1beta production. No associations were found for TNF-alpha and IL-10. CONCLUSIONS: Low innate capacity to produce the pro-inflammatory cytokines IL-1beta and IL-6 is associated with the absence of OA in old age.

Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis.

INTRODUCTION: The Wells clinical decision rule (CDR) and D-dimer tests can be used to exclude pulmonary embolism (PE). We performed a meta-analysis to determine the negative predictive value (NPV) of an "unlikely" CDR (

Amnestic mild cognitive impairment: structural MR imaging findings predictive of conversion to Alzheimer disease.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is considered by many to be a prodromal phase of Alzheimer disease (AD). We used voxel-based morphometry (VBM) to find out whether structural differences on MR imaging could offer insight into the development of clinical AD in patients with amnestic MCI at 3-year follow-up. MATERIALS AND METHODS: Twenty-four amnestic patients with MCI were included. After 3 years, 46% had progressed to AD (n = 11; age, 72.7 +/- 4.8 years; women/men, 8/3). For 13 patients (age, 72.4 +/- 8.6 years; women/men, 10/3), the diagnosis remained MCI. Baseline MR imaging at 1.5T included a coronal heavily T1-weighted 3D gradient-echo sequence. Localized gray matter differences were assessed with VBM. RESULTS: The converters had less gray matter volume in medial (including the hippocampus) and lateral temporal lobe, parietal lobe, and lateral temporal lobe structures. After correction for age, sex, total gray matter volume, and neuropsychological evaluation, left-sided atrophy remained statistically significant. Specifically, converters had more left parietal atrophy (angular gyrus and inferior parietal lobule) and left lateral temporal lobe atrophy (superior and middle temporal gyrus) than stable patients with MCI. CONCLUSION: By studying 2 MCI populations, converters versus nonconverters, we found atrophy beyond the medial temporal lobe to be characteristic of patients with MCI who will progress to dementia. Atrophy of structures such as the left lateral temporal lobe and left parietal cortex may independently predict conversion.

Not all age-related white matter hyperintensities are the same: a magnetization transfer imaging study.

PURPOSE: Our aim was to assess whether presumed histologic heterogeneity of age-related white matter hyperintensities (WMH) is reflected in quantitative magnetization transfer imaging measures. MATERIALS AND METHODS: From a group of patients participating in a double-blind placebo-controlled multicenter study on the effect of pravastatin (PROSPER), we selected 56 subjects with WMH. WMH were classified as periventricular WMH (PVWMH) and deep WMH (DWMH). PVWMH were subclassified as irregular or smooth, depending on the aspect of their border. Signal intensity of WMH on T1-weighted images was scored as iso- or hypointense. The mean magnetization transfer ratio (MTR) value of different types of WMH was assessed and compared. As a control group, we selected 19 subjects with no or limited WMH. RESULTS: Mean (SE) MTR of PVWMH (frontal, 31.2% [0.2%]; occipital, 32.2% [0.2%]) was lower than that of DWMH (33.7% [0.5%]). The mean MTR of frontal PVWMH (31.2% [0.2%]) was lower than that of occipital PVWMH (32.2% [0.2%]). Compared with occipital PVWMH, frontal PVWMH more often had a smooth lining (72% frontal versus 8% occipital) and an area with low signal intensity on T1-weighted images (76% frontal versus 35% occipital). MTR did not differ between smooth (31.1% [0.3%]) and irregular (31.6% [0.5%]) PVWMH. CONCLUSION: Age-related WMH are heterogeneous, despite their similar appearance on T2-weighted images. By taking into account heterogeneity of age-related WMH, both in terms of etiology and in terms of severity of tissue destruction, one may obtain better understanding on the causes and consequences of these lesions.

C-reactive protein and D-dimer with clinical probability score in the exclusion of pulmonary embolism.

This study evaluated the diagnostic value of C-reactive protein (CRP) combined with a clinical decision rule in the exclusion of pulmonary embolism (PE) and compared this with D-dimer. In 363 consecutive outpatients CRP and D-dimer test were performed and clinical probability of PE was assessed. Patients with D-dimer levels<500 microg/l and clinical probability indicating 'PE unlikely' were followed for 3 months. Ventilation-perfusion scan or spiral computerized tomography was performed in patients with D-dimer levels>or=500 microg/l or clinical probability indicating 'PE likely'. The CRP had a sensitivity of 95.7% [95% confidence interval (CI): 90-100] and negative predictive value (NPV) of 98.4% (96-100). CRP<5 mg/l with clinical probability score indicating 'PE unlikely' (n=108, 30%), had a sensitivity of 96.7% (90-100), a specificity of 43.0% (37-49) and NPV of 99.1% (97-100). D-dimer<500 microg/l with clinical probability score indicating 'PE unlikely' (n=170, 51%), had a sensitivity of 96.7% (90-100), a specificity of 67.9% (62-74) and NPV of 99.4% (98-100). Based on retrospective data it was concluded that a standard CRP test can potentially be used to safely exclude PE, either as a sole test or combined with clinical probability assessment. Prospective studies are needed to confirm these findings.

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Interindividual differences of medial temporal lobe activation during encoding in an elderly population studied by fMRI.

Functional MRI (fMRI) is used to study medial temporal lobe (MTL) activation during encoding of new information into memory. In most studies, fMRI data of different subjects are averaged in standard coordinate space. However, interindividual differences in activation can be extensive, reflecting functional heterogeneity. Further, anatomical differences in brain structure cause additional variance and loss of registration accuracy. Such differences in structural and functional MTL characteristics may interfere with the efficiency of averaging data across subjects, and may become more significant with aging and dementia. The current study concerns the analysis of individual differences in MTL activation associated with episodic encoding.Twenty-nine healthy elderly men between 60 and 70 years old performed a simple face encoding task during fMRI scanning. Individual data were analyzed in native space, and compared to the group average in standard space (Talairach and Tournoux).MTL volumes between subjects varied between 6.34 and 11.27 cm(3), and had considerable variation when mapped to standard space. Eighteen of the 29 subjects showed MTL activity and activation patterns varied both in location and size (ranging from 0.11 to 1.78 cm(3)), with the strongest activation in the left posterior part of the MTL. In standard space, no region was significantly activated on a group level at a comparable alpha level. We conclude that while the majority of elderly subjects show MTL activation during episodic encoding of faces, there is considerable structural and functional variability between subjects. Group analysis in standard space may not be appropriate for studies of a complex structure such as the MTL, particularly not in aging and dementia.

Loss of frontal fMRI activation in early frontotemporal dementia compared to early AD.

OBJECTIVE: To compare frontal cortex activation in patients with early frontotemporal dementia (FTD) with that in patients with early AD. METHODS: Seven patients with FTD and seven patients with AD were studied (Clinical Dementia Rating: four patients with FTD 0.5, three patients with FTD 1, all patients with AD 1; mean Mini-Mental State Examination score: FTD 28.0 +/- 2.1, AD 23.1 +/- 2.7). Cerebral atrophy on MRI was mild, with no differences between FTD and AD. A parametric working memory task was applied to assess frontal activation as a function of working memory load. RESULTS: The activated working memory network in FTD and AD included frontal and parietal lobe and thalamus. In frontal and parietal cortex, brain activation was significantly decreased in FTD. Frontal regions in patients with FTD showed less linear activation increase with working memory load than in AD. Possibly as a compensation mechanism, the cerebellum showed a stronger increasing response in FTD. CONCLUSIONS: These data on regional functional loss in the frontal cortex in early FTD suggest that fMRI can identify FTD when results on structural MRI are normal.