An insulin infusion advisory system for type 1 diabetes patients based on non-linear model predictive control methods

In this paper, an Insulin Infusion Advisory System (IIAS) for Type 1 diabetes patients, which use insulin pumps for the Continuous Subcutaneous Insulin Infusion (CSII) is presented. The purpose of the system is to estimate the appropriate insulin infusion rates. The system is based on a Non-Linear Model Predictive Controller (NMPC) which uses a hybrid model. The model comprises a Compartmental Model (CM), which simulates the absorption of the glucose to the blood due to meal intakes, and a Neural Network (NN), which simulates the glucose-insulin kinetics. The NN is a Recurrent NN (RNN) trained with the Real Time Recurrent Learning (RTRL) algorithm. The output of the model consists of short term glucose predictions and provides input to the NMPC, in order for the latter to estimate the optimum insulin infusion rates. For the development and the evaluation of the IIAS, data generated from a Mathematical Model (MM) of a Type 1 diabetes patient have been used. The proposed control strategy is evaluated at multiple meal disturbances, various noise levels and additional time delays. The results indicate that the implemented IIAS is capable of handling multiple meals, which correspond to realistic meal profiles, large noise levels and time delays.

Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis

Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type. Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships. Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction ¼ 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P ¼ 0.34) or histologic type (P ¼ 0.26). Conclusions: HRT use modifies the BMI-endometrial cancer risk association. Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30.

Alterations of white matter integrity related to motor activity in schizophrenia

Altered structural connectivity is a key finding in schizophrenia, but the meaning of white matter alterations for behavior is rarely studied. In healthy subjects, motor activity correlated with white matter integrity in motor tracts. To explore the relation of motor activity and fractional anisotropy (FA) in schizophrenia, we investigated 19 schizophrenia patients and 24 healthy control subjects using Diffusion Tensor Imaging (DTI) and actigraphy on the same day. Schizophrenia patients had lower activity levels (AL). In both groups linear relations of AL and FA were detected in several brain regions. Schizophrenia patients had lower FA values in prefrontal and left temporal clusters. Furthermore, using a general linear model, we found linear negative associations of FA and AL underneath the right supplemental motor area (SMA), the right precentral gyrus and posterior cingulum in patients. This effect within the SMA was not seen in controls. This association in schizophrenia patients may contribute to the well known dysfunctions of motor control. Thus, structural disconnectivity could lead to disturbed motor behavior in schizophrenia.

The link between visual exploration and neuronal activity: A multi-modal study combining eye tracking, functional magnetic resonance imaging and transcranial magnetic stimulation

In the present multi-modal study we aimed to investigate the role of visual exploration in relation to the neuronal activity and performance during visuospatial processing. To this end, event related functional magnetic resonance imaging er-fMRI was combined with simultaneous eye tracking recording and transcranial magnetic stimulation (TMS). Two groups of twenty healthy subjects each performed an angle discrimination task with different levels of difficulty during er-fMRI. The number of fixations as a measure of visual exploration effort was chosen to predict blood oxygen level-dependent (BOLD) signal changes using the general linear model (GLM). Without TMS, a positive linear relationship between the visual exploration effort and the BOLD signal was found in a bilateral fronto-parietal cortical network, indicating that these regions reflect the increased number of fixations and the higher brain activity due to higher task demands. Furthermore, the relationship found between the number of fixations and the performance demonstrates the relevance of visual exploration for visuospatial task solving. In the TMS group, offline theta bursts TMS (TBS) was applied over the right posterior parietal cortex (PPC) before the fMRI experiment started. Compared to controls, TBS led to a reduced correlation between visual exploration and BOLD signal change in regions of the fronto-parietal network of the right hemisphere, indicating a disruption of the network. In contrast, an increased correlation was found in regions of the left hemisphere, suggesting an intent to compensate functionality of the disturbed areas. TBS led to fewer fixations and faster response time while keeping accuracy at the same level, indicating that subjects explored more than actually needed.

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.

Regional mRNA expression of key gluconeogenic enzymes in the liver of dairy cows

Liver tissue was collected from eight random dairy cows at a slaughterhouse to test if gene expression of pyruvate carboxylase (PC), mitochondrial phosphoenolpyruvate carboxykinase (PEPCKm) and cytosolic phosphoenolpyruvate carboxykinase (PEPCKc) is different at different locations in the liver. Obtained liver samples were analysed for mRNA expression levels of PC, PEPCKc and PEPCKm and subjected to the MIXED procedure of SAS to test for the sampled locations with cow liver as repeated subject. Additionally, the general linear model procedure (GLM) for analysis of variance was applied to test for significant differences for mRNA abundance of PEPCKm, PEPCKc and bPC between the livers. In conclusion, this study demonstrated that mRNA abundance of PC, PEPCKc and PEPCKm is not different between locations in the liver but may differ between individual cows.

Impact of weather and climate on the incidence of acute coronary syndromes

BACKGROUND: First investigations of the interactions between weather and the incidence of acute myocardial infarctions date back to 1938. The early observation of a higher incidence of myocardial infarctions in the cold season could be confirmed in very different geographical regions and cohorts. While the influence of seasonal variations on the incidence of myocardial infarctions has been extensively documented, the impact of individual meteorological parameters on the disease has so far not been investigated systematically. Hence the present study intended to assess the impact of the essential variables of weather and climate on the incidence of myocardial infarctions. METHODS: The daily incidence of myocardial infarctions was calculated from a national hospitalization survey. The hourly weather and climate data were provided by the database of the national weather forecast. The epidemiological and meteorological data were correlated by multivariate analysis based on a generalized linear model assuming a log-link-function and a Poisson distribution. RESULTS: High ambient pressure, high pressure gradients, and heavy wind activity were associated with an increase in the incidence of the totally 6560 hospitalizations for myocardial infarction irrespective of the geographical region. Snow- and rainfall had inconsistent effects. Temperature, Foehn, and lightning showed no statistically significant impact. CONCLUSIONS: Ambient pressure, pressure gradient, and wind activity had a statistical impact on the incidence of myocardial infarctions in Switzerland from 1990 to 1994. To establish a cause-and-effect relationship more data are needed on the interaction between the pathophysiological mechanisms of the acute coronary syndrome and weather and climate variables.

Increased sensitivity in mapping task demand in visuospatial processing using reaction-time-dependent hemodynamic response predictors in rapid event-related fMRI

Searching for the neural correlates of visuospatial processing using functional magnetic resonance imaging (fMRI) is usually done in an event-related framework of cognitive subtraction, applying a paradigm comprising visuospatial cognitive components and a corresponding control task. Besides methodological caveats of the cognitive subtraction approach, the standard general linear model with fixed hemodynamic response predictors bears the risk of being underspecified. It does not take into account the variability of the blood oxygen level-dependent signal response due to variable task demand and performance on the level of each single trial. This underspecification may result in reduced sensitivity regarding the identification of task-related brain regions. In a rapid event-related fMRI study, we used an extended general linear model including single-trial reaction-time-dependent hemodynamic response predictors for the analysis of an angle discrimination task. In addition to the already known regions in superior and inferior parietal lobule, mapping the reaction-time-dependent hemodynamic response predictor revealed a more specific network including task demand-dependent regions not being detectable using the cognitive subtraction method, such as bilateral caudate nucleus and insula, right inferior frontal gyrus and left precentral gyrus.

Reduced neuronal efficacy in progressive mild cognitive impairment: a prospective fMRI study on visuospatial processing

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimer's disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI.

Cortical and subcortical correlates of electroencephalographic alpha rhythm modulation

Neural correlates of electroencephalographic (EEG) alpha rhythm are poorly understood. Here, we related EEG alpha rhythm in awake humans to blood-oxygen-level-dependent (BOLD) signal change determined by functional magnetic resonance imaging (fMRI). Topographical EEG was recorded simultaneously with fMRI during an open versus closed eyes and an auditory stimulation versus silence condition. EEG was separated into spatial components of maximal temporal independence using independent component analysis. Alpha component amplitudes and stimulus conditions served as general linear model regressors of the fMRI signal time course. In both paradigms, EEG alpha component amplitudes were associated with BOLD signal decreases in occipital areas, but not in thalamus, when a standard BOLD response curve (maximum effect at approximately 6 s) was assumed. The part of the alpha regressor independent of the protocol condition, however, revealed significant positive thalamic and mesencephalic correlations with a mean time delay of approximately 2.5 s between EEG and BOLD signals. The inverse relationship between EEG alpha amplitude and BOLD signals in primary and secondary visual areas suggests that widespread thalamocortical synchronization is associated with decreased brain metabolism. While the temporal relationship of this association is consistent with metabolic changes occurring simultaneously with changes in the alpha rhythm, sites in the medial thalamus and in the anterior midbrain were found to correlate with short time lag. Assuming a canonical hemodynamic response function, this finding is indicative of activity preceding the actual EEG change by some seconds.

Similarities in the Subgingival Microbiota Assessed by a Curet Sampling Method at Sites With Chronic Periodontitis

Background: The goal of this study was to determine whether site-specific differences in the subgingival microbiota could be detected by the checkerboard method in subjects with periodontitis. Methods: Subjects with at least six periodontal pockets with a probing depth (PD) between 5 and 7 mm were enrolled in the study. Subgingival plaque samples were collected with sterile curets by a single-stroke procedure at six selected periodontal sites from 161 subjects (966 subgingival sites). Subgingival bacterial samples were assayed with the checkerboard DNA-DNA hybridization method identifying 37 species. Results: Probing depths of 5, 6, and 7 mm were found at 50% (n = 483), 34% (n = 328), and 16% (n = 155) of sites, respectively. Statistical analysis failed to demonstrate differences in the sum of bacterial counts by tooth type (P = 0.18) or specific location of the sample (P = 0.78). With the exceptions of Campylobacter gracilis (P <0.001) and Actinomyces naeslundii (P <0.001), analysis by general linear model multivariate regression failed to identify subject or sample location factors as explanatory to microbiologic results. A trend of difference in bacterial load by tooth type was found for Prevotella nigrescens (P <0.01). At a cutoff level of >/=1.0 x 10(5), Porphyromonas gingivalis and Tannerella forsythia (previously T. forsythensis) were present at 48.0% to 56.3% and 46.0% to 51.2% of sampled sites, respectively. Conclusions: Given the similarities in the clinical evidence of periodontitis, the presence and levels of 37 species commonly studied in periodontitis are similar, with no differences between molar, premolar, and incisor/cuspid subgingival sites. This may facilitate microbiologic sampling strategies in subjects during periodontal therapy.

Is there good simulation basic training for end-to-side vascular microanastomoses?

BACKGROUND Microvascular anastomosis is the cornerstone of free tissue transfers. Irrespective of the microsurgical technique that one seeks to integrate or improve, the time commitment in the laboratory is significant. After extensive previous training on several animal models, we sought to identify an animal model that circumvents the following issues: ethical rules, cost, time-consuming and expensive anesthesia, and surgical preparation of tissues required to access vessels before performing the microsurgical training, not to mention that laboratories are closed on weekends. METHODS Between January 2012 and April 2012, a total of 91 earthworms were used for 150 microsurgical training exercises to simulate vascular end-to-side microanastomosis. The training sessions were divided into ten periods of 7 days. Each training session included 15 simulations of end-to-side vascular microanastomoses: larger than 1.5 mm (n=5), between 1.0 and 1.5 mm (n=5), and smaller than 1.0 mm (n=5). A linear model with the main variables being the number of weeks (as a numerical covariate) and the size of the animal (as a factor) was used to determine the trend in time of anastomosis over subsequent weeks as well as the differences between the different size groups. RESULTS The linear model shows a significant trend (p<0.001) in time of anastomosis in the course of the training, as well as significant differences (p<0.001) between the groups of animals of different sizes. For microanastomoses larger than 1.5 mm, the mean anastomosis time decreased from 19.3±1.0 to 11.1±0.4 min between the first and last week of training (decrease of 42.5%). For training with smaller diameters, the results showed a decrease in execution time of 43.2% (diameter between 1.0 and 1.5 mm) and 40.9% (diameter<1.0 mm) between the first and last periods. The study demonstrates an improvement in the dexterity and speed of nodes execution. CONCLUSION The earthworm appears to be a reliable experimental model for microsurgical training of end-to-side microanastomoses. Its numerous advantages are discussed here and we predict training on earthworms will significantly grow and develop in the near future. LEVEL OF EVIDENCE III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Normative MR Cervical Spinal Canal Dimensions

Purpose To provide normal values of the cervical spinal canal and spinal cord dimensions in several planes with respect to spinal level, age, sex, and body height. Materials and Methods This study was approved by the institutional review board; all individuals provided signed informed consent. In a prospective multicenter study, two blinded raters independently examined cervical spine magnetic resonance (MR) images of 140 healthy volunteers who were white. The midsagittal diameters and areas of spinal canal and spinal cord, respectively, were measured at the midvertebral levels of C1, C3, and C6. A multivariate general linear model described the influence of sex, body height, age, and spinal level on the measured values. Results There were differences for sex, spinal level, interaction between sex and level, and body height, while age had significant yet limited influence. Normative ranges for the sagittal diameters and areas of spinal canal and spinal cord were defined at C1, C3, and C6 levels for men and women. In addition to a calculation of normative ranges for a specific sex, spinal level, age, and body height data, data for three different height subgroups at 45 years of age were extracted. These results show a range of the spinal canal dimensions at C1 (from 10.7 to 19.7 mm), C3 (from 9.4 to 17.2 mm), and C6 (from 9.2 to 16.8 mm) levels. Conclusion : The dimensions of the cervical spinal canal and cord in healthy individuals are associated with spinal level, sex, age, and height. © RSNA, 2013 Online supplemental material is available for this article.

The Effect Of Misleading Prior Information On The Subjective Visual Vertical

When tilted sideways participants misperceive the visual vertical assessed by means of a luminous line in otherwise complete dark- ness. A recent modeling approach (De Vrijer et al., 2009) claimed that these typical patterns of errors (known as A- and E-effects) could be explained by as- suming that participants behave in a Bayes optimal manner. In this study, we experimentally manipulate participants’ prior information about body-in-space orientation and measure the effect of this manipulation on the subjective visual vertical (SVV). Specifically, we explore the effects of veridical and misleading instructions about body tilt orientations on the SVV. We used a psychophys- ical 2AFC SVV task at roll tilt angles of 0 degrees, 16 degrees and 4 degrees CW and CCW. Participants were tilted to 4 degrees under different instruction conditions: in one condition, participants received veridical instructions as to their tilt angle, whereas in another condition, participants received the mis- leading instruction that their body position was perfectly upright. Our results indicate systematic differences between the instruction conditions at 4 degrees CW and CCW. Participants did not simply use an ego-centric reference frame in the misleading condition; instead, participants’ estimates of the SVV seem to lie between their head’s Z-axis and the estimate of the SVV as measured in the veridical condition. All participants displayed A-effects at roll tilt an- gles of 16 degrees CW and CCW. We discuss our results in the context of the Bayesian model by De Vrijer et al. (2009), and claim that this pattern of re- sults is consistent with a manipulation of precision of a prior distribution over body-in-space orientations. Furthermore, we introduce a Bayesian Generalized Linear Model for estimating parameters of participants’ psychometric function, which allows us to jointly estimate group level and individual level parameters under all experimental conditions simultaneously, rather than relying on the traditional two-step approach to obtaining group level parameter estimates.

Short-term functional outcome and premorbid adjustment in clinical high-risk patients. Results of the EPOS project

PURPOSE In patients with schizophrenia, premorbid psychosocial adjustment is an important predictor of functional outcome. We studied functional outcome in young clinical high-risk (CHR) patients and how this was predicted by their childhood to adolescence premorbid adjustment. METHODS In all, 245 young help-seeking CHR patients were assessed with the Premorbid Adjustment Scale, the Structured Interview for Prodromal Syndromes (SIPS) and the Schizophrenia Proneness Instrument (SPI-A). The SIPS assesses positive, negative, disorganised, general symptoms, and the Global Assessment of Functioning (GAF), the SPI-A self-experienced basic symptoms; they were carried out at baseline, at 9-month and 18-month follow-up. Transitions to psychosis were identified. In the hierarchical linear model, associations between premorbid adjustment, background data, symptoms, transitions to psychosis and GAF scores were analysed. RESULTS During the 18-month follow-up, GAF scores improved significantly, and the proportion of patients with poor functioning decreased from 74% to 37%. Poor premorbid adjustment, single marital status, poor work status, and symptoms were associated with low baseline GAF scores. Low GAF scores were predicted by poor premorbid adjustment, negative, positive and basic symptoms, and poor baseline work status. The association between premorbid adjustment and follow-up GAF scores remained significant, even when baseline GAF and transition to psychosis were included in the model. CONCLUSION A great majority of help-seeking CHR patients suffer from deficits in their functioning. In CHR patients, premorbid psychosocial adjustment, baseline positive, negative, basic symptoms and poor working/schooling situation predict poor short-term functional outcome. These aspects should be taken into account when acute intervention and long-term rehabilitation for improving outcome in CHR patients are carried out.