Multi-Model Data Fusion to Improve an Early Warning System for Hypo-/Hyperglycemic Events

Correct predictions of future blood glucose levels in individuals with Type 1 Diabetes (T1D) can be used to provide early warning of upcoming hypo-/hyperglycemic events and thus to improve the patient's safety. To increase prediction accuracy and efficiency, various approaches have been proposed which combine multiple predictors to produce superior results compared to single predictors. Three methods for model fusion are presented and comparatively assessed. Data from 23 T1D subjects under sensor-augmented pump (SAP) therapy were used in two adaptive data-driven models (an autoregressive model with output correction - cARX, and a recurrent neural network - RNN). Data fusion techniques based on i) Dempster-Shafer Evidential Theory (DST), ii) Genetic Algorithms (GA), and iii) Genetic Programming (GP) were used to merge the complimentary performances of the prediction models. The fused output is used in a warning algorithm to issue alarms of upcoming hypo-/hyperglycemic events. The fusion schemes showed improved performance with lower root mean square errors, lower time lags, and higher correlation. In the warning algorithm, median daily false alarms (DFA) of 0.25%, and 100% correct alarms (CA) were obtained for both event types. The detection times (DT) before occurrence of events were 13.0 and 12.1 min respectively for hypo-/hyperglycemic events. Compared to the cARX and RNN models, and a linear fusion of the two, the proposed fusion schemes represents a significant improvement.

Predictors of early mortality after acute ischaemic stroke.

BACKGROUND The study set out to identify clinical, laboratory and radiological predictors of early mortality after an acute ischaemic stroke (AIS) and to analyse medical and neurological complications that caused death. METHODS A total of 479 consecutive patients (mean age 63+/-14 years) with AIS underwent stroke examination and treatment. Examination included clinical evaluation, laboratory tests, and brain CT and/or MRI. Follow-up data at 30 days were available for 467 patients (93%) who were included in the present analysis. RESULTS The median National Institute of Health Stroke Study (NIHSS) score on admission was 6. A total of 62 patients (13%) died within 30 days. The cause of death was the initial event in 43 (69%), pneumonia in 12 (19%), intracerebral haemorrhage in 9 (15%), recurrent stroke in 6 (10%), myocardial infarction in 2 (3%), and cancer in 1 (2%) of the patients. In univariate comparisons, advanced age (p<0.001), hypertension (p=0.013), coronary disease (p=0.001), NIHSS score (p<0.001), undetermined stroke etiology (p=0.031), relevant co-morbidities (p=0.008), hyperglycemia (p<0.001), atrial fibrillation (p<0.001), early CT signs of ischemia (p<0.001), dense artery sign (p<0.001), proximal vessel occlusion (p<0.001), and thrombolysis (p=0.008) were associated with early mortality. In multivariate analysis, advanced age (HR=1.12; 95% CI 1.05-1.19; p<0.001) and high NIHSS score on admission (HR=1.15, 95% CI 1.05-1.25; p=0.002) were independent predictors of early mortality. CONCLUSIONS We report 13% mortality at 30 days after AIS. More than two thirds of the deaths are related to the initial stroke. Advanced age and high NIHSS score are the only independent predictors of early mortality in this series.

The association between early hemodynamic variables and outcome in normothermic comatose patients following cardiac arrest

Currently, few data exist on the association between post-cardiac arrest hemodynamic function and outcome. In this explorative, retrospective analysis, the association between hemodynamic variables during the first 24 h after intensive care unit admission and functional outcome at day 28 was evaluated in 153 normothermic comatose patients following a cardiac arrest.

Early repolarization, left ventricular diastolic function, and left atrial size in professional soccer players

Recent data have suggested a relation among long-term endurance sport practice, left atrial remodeling, and atrial fibrillation. We investigated the influence of an increased vagal tone, represented by the early repolarization (ER) pattern, on diastolic function and left atrial size in professional soccer players. Fifty-four consecutive athletes underwent electrocardiography, echocardiography, and exercise testing as part of their preparticipation screening. Athletes were divided into 2 groups according to presence or absence of an ER pattern, defined as a ST-segment elevation at the J-point (STE) > or =0.1 mm in 2 leads. For linear comparisons average STE was calculated. Mean age was 24 +/- 4 years. Twenty-five athletes (46%) showed an ER pattern. Athletes with an ER pattern had a significant lower heart rate (54 +/- 9 vs 62 +/- 11 beats/min, p = 0.024), an increased E/e' ratio (6.1 +/- 1.2 vs 5.1 +/- 1.0, p = 0.002), and larger volumes of the left atrium (25.6 +/- 7.3 vs 21.8 +/- 5.0 ml/m(2), p = 0.031) compared to athletes without an ER pattern. There were no significant differences concerning maximum workload, left ventricular dimensions, and systolic function. Univariate regression analysis revealed significant correlations among age, STE, and left atrial volume. In a stepwise multivariate regression analysis age, STE and e' contributed independently to left atrial size (r = 0.659, p <0.001). In conclusion, athletes with an ER pattern had an increased E/e' ratio, reflecting a higher left atrial filling pressure, contributing to left atrial remodeling over time.

Application of the specular and diffuse reflection analysis for in vitro diagnostics of dental erosion: correlation with enamel softening, roughness, and calcium release

We present assembly and application of an optical reflectometer for the analysis of dental erosion. The erosive procedure involved acid-induced softening and initial substance loss phases, which are considered to be difficult for visual diagnosis in a clinic. Change of the specular reflection signal showed the highest sensitivity for the detection of the early softening phase of erosion among tested methods. The exponential decrease of the specular reflection intensity with erosive duration was compared to the increase of enamel roughness. Surface roughness was measured by optical analysis, and the observed tendency was correlated with scanning electron microscopy images of eroded enamel. A high correlation between specular reflection intensity and measurement of enamel softening (r(2) ? -0.86) as well as calcium release (r(2) ? -0.86) was found during erosion progression. Measurement of diffuse reflection revealed higher tooth-to-tooth deviation in contrast to the analysis of specular reflection intensity and lower correlation with other applied methods (r(2) = 0.42-0.48). The proposed optical method allows simple and fast surface analysis and could be used for further optimization and construction of the first noncontact and cost-effective diagnostic tool for early erosion assessment in vivo.

Circulation dynamics and its influence on European and Mediterranean January-April climate over the past half millennium: results and insights from instrumental data, documentary evidence and coupled climate models

We use long instrumental temperature series together with available field reconstructions of sea-level pressure (SLP) and three-dimensional climate model simulations to analyze relations between temperature anomalies and atmospheric circulation patterns over much of Europe and the Mediterranean for the late winter/early spring (January–April, JFMA) season. A Canonical Correlation Analysis (CCA) investigates interannual to interdecadal covariability between a new gridded SLP field reconstruction and seven long instrumental temperature series covering the past 250 years. We then present and discuss prominent atmospheric circulation patterns related to anomalous warm and cold JFMA conditions within different European areas spanning the period 1760–2007. Next, using a data assimilation technique, we link gridded SLP data with a climate model (EC-Bilt-Clio) for a better dynamical understanding of the relationship between large scale circulation and European climate. We thus present an alternative approach to reconstruct climate for the pre-instrumental period based on the assimilated model simulations. Furthermore, we present an independent method to extend the dynamic circulation analysis for anomalously cold European JFMA conditions back to the sixteenth century. To this end, we use documentary records that are spatially representative for the long instrumental records and derive, through modern analogs, large-scale SLP, surface temperature and precipitation fields. The skill of the analog method is tested in the virtual world of two three-dimensional climate simulations (ECHO-G and HadCM3). This endeavor offers new possibilities to both constrain climate model into a reconstruction mode (through the assimilation approach) and to better asses documentary data in a quantitative way.

Impact of Bone Harvesting Techniques on Cell Viability and the Release of Growth Factors of Autografts

Background: Autogenous bone grafts obtained by different harvesting techniques behave differently during the process of graft consolidation; the underlying reasons are however not fully understood. One theory is that harvesting techniques have an impact on the number and activity of the transplanted cells which contribute to the process of graft consolidation. Materials and Methods: To test this assumption, porcine bone grafts were harvested with four different surgical procedures: bone mill, piezosurgery, bone drilling (bone slurry), and bone scraper. After determining cell viability, the release of molecules affecting bone formation and resorption was assessed by reverse transcription polymerase chain reaction and immunoassay. The mitogenic and osteogenic activity of the conditioned media was evaluated in a bioassay with isolated bone cells. Results: Cell viability and the release of molecules affecting bone formation were higher in samples harvested by bone mill and bone scraper when compared with samples prepared by bone drilling and piezosurgery. The harvesting procedure also affected gene expression, for example, bone mill and bone scraper samples revealed significantly higher expression of growth factors such as bone morphogenetic protein-2 and vascular endothelial growth factor compared with the two other modalities. Receptor activator of nuclear factor kappa B ligand expression was lowest in bone scraper samples. Conclusion: These data can provide a scientific basis to better understand the impact of harvesting techniques on the number and activity of transplanted cells, which might contribute to the therapeutic outcome of the augmentation procedure.

Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study

Intravenous (IV) Δ9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5 mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis.

Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma

Background Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. Objectives We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). Search methods We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. Selection criteria Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. Data collection and analysis Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. Main results Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Authors' conclusions Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma.

Improved sensitivity of an interferon-gamma release assay (T-SPOT.TB™) in combination with tuberculin skin test for the diagnosis of latent tuberculosis in the presence of HIV co-infection

Background Interferon-gamma release assays (IGRA) are more specific than the tuberculin skin test (TST) for the diagnosis of Mycobacterium tuberculosis infection. Data on sensitivity are controversial in HIV infection. Methods IGRA (T-SPOT.TB) was performed using lymphocytes stored within 6 months before culture-confirmed tuberculosis was diagnosed in HIV-infected individuals in the Swiss HIV Cohort Study. Results 64 individuals (69% males, 45% of non-white ethnicity, median age 35 years (interquartile range [IQR] 31-42), 28% with prior AIDS) were analysed. Median CD4 cell count was 223 cells/μl (IQR 103-339), HIV-RNA was 4.7 log10 copies/mL (IQR 4.3-5.2). T-SPOT.TB resulted positive in 25 patients (39%), negative in 18 (28%) and indeterminate in 21 (33%), corresponding to a sensitivity of 39% (95% CI 27-51%) if all test results were considered, and 58% (95% CI 43-74%) if indeterminate results were excluded. Sensitivity of IGRA was independent of CD4 cell count (p = 0.698). Among 44 individuals with available TST, 22 (50%) had a positive TST. Agreement between TST and IGRA was 57% (kappa = 0.14, p = 0.177), and in 34% (10/29) both tests were positive. Combining TST and IGRA (at least one test positive) resulted in an improved sensitivity of 67% (95% CI 52-81%). In multivariate analysis, older age was associated with negative results of TST and T-SPOT.TB (OR 3.07, 95% CI 1,22-7.74, p = 0.017, per 10 years older). Conclusions T-SPOT.TB and TST have similar sensitivity to detect latent TB in HIV-infected individuals. Combining TST and IGRA may help clinicians to better select HIV-infected individuals with latent tuberculosis who qualify for preventive treatment.

Effects of drilling and stress release on hydraulic properties and porewater chemistry of crystalline rocks

The experimental verification of matrix diffusion in crystalline rocks largely relies on indirect methods performed in the laboratory. Such methods are prone to perturbations of the rock samples by collection and preparation and therefore the laboratory-derived transport properties and fluid composition might not represent in situ conditions. We investigated the effects induced by the drilling process and natural rock stress release by mass balance considerations and sensitivity analysis of analytical out-diffusion data obtained from originally saturated, large-sized drillcore material from two locations drilled using traced drilling fluid. For in situ stress-released drillcores of quartz-monzodiorite composition from the Aspo HRL, Sweden, tracer mass balance considerations and 1D and 2D diffusion modelling consistently indicated a contamination of <1% of the original pore water. This chemically disturbed zone extends to a maximum of 0.1 mm into the drillcore (61.8 mm x 180.1 mm) corresponding to about 0.66% of the total pore volume (0.77 vol.%). In contrast, the combined effects of stress release and the drilling process, which have influenced granodioritic drillcore material from 560 m below surface at Forsmark. Sweden, resulted in a maximum contamination of the derived porewater Cl(-) concentration of about 8%. The mechanically disturbed zone with modified diffusion properties covers the outermost similar to 6 mm of the drillcore (50 mm x 189 mm), whereas the chemically disturbed zone extends to a maximum of 0.3 mm based on mass balance considerations, and to 0.15 mm to 0.2 mm into the drillcore based on fitting the observed tracer data. This corresponds to a maximum of 2.4% of the total pore volume (0.62 vol.%) being affected by the drilling-fluid contamination. The proportion of rock volume affected initially by drilling fluid or subsequently with experiment water during the laboratory diffusion and re-saturation experiments depends on the size of the drillcore material and will become larger the smaller the sample used for the experiment. The results are further in support of matrix diffusion taking place in the undisturbed matrix of crystalline rocks at least in the cm range.

Best combination of pre-stimulation and latency period duration before cluster attachment for efficient oxytocin release and milk ejection in cows with low to high udder-filling levels

Experiments were designed to investigate the suitability of a combination of a short manual teat stimulation with a short latency period before teat cup attachment to induce and maintain oxytocin release and milk ejection without interruption. In Experiment 1, seven dairy cows in mid lactation were manually pre-stimulated for 15, 30 or 45 s, followed by either 30 s or 45 s of latency period. It was shown that all treatments induced a similar release of oxytocin without interruption until the end of milking. In particular, the latency period of up to 45 s did not cause a transient decrease of oxytocin concentration. In Experiment 2, milking characteristics were recorded in seven cows each in early, mid, and late lactation, respectively. Because the course of milk ejection depends mainly on the degree of udder filling, individual milkings were classified based on the actual degree of udder filling which differs between lactational stages but also between morning and evening milkings. All animals underwent twelve different udder preparation treatments, i.e. 15, 30, or 45 s of pre-stimulation followed by latency periods of 0, 30, 45, or 60 s. Milking characteristics were recorded. Total milk yield, main milking time and average milk flow rate did not differ between treatments if the degree of udder filling at the start of milking was >40% of the maximum storage capacity. However, if the udder filling was <40%, main milking time was decreased with the duration of a latency period up to 45 s, independent of duration of pre-stimulation. Average milk flow at an udder filling of <40% was highest after a pre-stimulation of 45 s followed by a latency period of another 45 s. In contrast, average milk flow reached its lowest values at a pre-stimulation of 15 s without additional latency period. However, average milk flow after a 15-s pre-stimulation increased with increasing latency period. In conclusion, a very short pre-stimulation when followed by a latency period up to 45 s before teat cup attachment remains a suitable alternative for continuous stimulation to induce milk ejection.

Effect of the prolactin-release inhibitor quinagolide on lactating dairy cows

In most mammals, prolactin (PRL) is essential for maintaining lactation, and yet the short-term suppression of PRL during established lactation by bromocriptine has produced inconsistent effects on milk yield in cows and goats. To assess the effect of the long-term inhibition of PRL release in lactating dairy cows, 5 Holstein cows in early lactation received daily intramuscular injections of 1mg of the PRL-release inhibitor quinagolide for 9 wk. Four control cows received the vehicle (water) only. During the last week of the treatments, one udder half was milked once a day (1x) and the other twice a day (2x). Blood samples were harvested at milking in wk -1, 1, 4, and 8. The daily injections of quinagolide reduced milking-induced PRL release but not the basal PRL concentration. Quinagolide induced a faster decline in milk production, which was about 5.3 kg/d lower in the quinagolide-treated cows during the last 4 wk of treatment. During wk 9, the inhibition of milk production by quinagolide was maintained in the udder half that was milked 2x but not in the half milked 1x. Milk production was significantly correlated with the quantity of PRL released at milking. Quinagolide did not affect the release of oxytocin at milking. Serum concentration of insulin-like growth factor-1 was not affected by treatment or correlated with milk production. Serum concentrations of leptin and the calciotropic hormone stanniocalcin were not affected by the treatment. In conclusion, the chronic administration of the PRL-release inhibitor quinagolide decreases milk production in dairy cows. The effect is likely the result of the reduced release of milking-induced PRL and is modulated at the level of the gland by milking frequency.

Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells

It is increasingly recognised that chronically activated glia contribute to the pathology of various neurodegenerative diseases, including glaucoma. One means by which this can occur is through the release of neurotoxic, proinflammatory factors. In the current study, we therefore investigated the spatio-temporal patterns of expression of three such cytokines, IL-1β, TNFα and IL-6, in a validated rat model of experimental glaucoma. First, only weak evidence was found for increased expression of IL-1β and TNFα following induction of ocular hypertension. Second, and much more striking, was that robust evidence was uncovered showing IL-6 to be synthesised by injured retinal ganglion cells following elevation of intraocular pressure and transported in an orthograde fashion along the nerve, accumulating at sites of axonal disruption in the optic nerve head. Verification that IL-6 represents a novel marker of disrupted axonal transport in this model was obtained by performing double labelling immunofluorescence with recognised markers of fast axonal transport. The stimulus for IL-6 synthesis and axonal transport during experimental glaucoma arose from axonal injury rather than ocular hypertension, as the response was identical after optic nerve crush and bilateral occlusion of the carotid arteries, each of which is independent of elevated intraocular pressure. Moreover, the response of IL-6 was not a generalised feature of the gp130 family of cytokines, as it was not mimicked by another family member, ciliary neurotrophic factor. Finally, further study suggested that IL-6 may be an early part of the endogenous regenerative response as the cytokine colocalised with growth-associated membrane phosphoprotein-43 in some putative regenerating axons, and potently stimulated neuritogenesis in retinal ganglion cells in culture, an effect that was additive to that of ciliary neurotrophic factor. These data comprise clear evidence that IL-6 is actively involved in the attempt of injured retinal ganglion cells to regenerate their axons.