Statistical problems related to excitation threshold and reset value of membrane potentials

Die vorliegende Arbeit ist motiviert durch biologische Fragestellungen bezüglich des Verhaltens von Membranpotentialen in Neuronen. Ein vielfach betrachtetes Modell für spikende Neuronen ist das Folgende. Zwischen den Spikes verhält sich das Membranpotential wie ein Diffusionsprozess X der durch die SDGL dX_t= beta(X_t) dt+ sigma(X_t) dB_t gegeben ist, wobei (B_t) eine Standard-Brown'sche Bewegung bezeichnet. Spikes erklärt man wie folgt. Sobald das Potential X eine gewisse Exzitationsschwelle S überschreitet entsteht ein Spike. Danach wird das Potential wieder auf einen bestimmten Wert x_0 zurückgesetzt. In Anwendungen ist es manchmal möglich, einen Diffusionsprozess X zwischen den Spikes zu beobachten und die Koeffizienten der SDGL beta() und sigma() zu schätzen. Dennoch ist es nötig, die Schwellen x_0 und S zu bestimmen um das Modell festzulegen. Eine Möglichkeit, dieses Problem anzugehen, ist x_0 und S als Parameter eines statistischen Modells aufzufassen und diese zu schätzen. In der vorliegenden Arbeit werden vier verschiedene Fälle diskutiert, in denen wir jeweils annehmen, dass das Membranpotential X zwischen den Spikes eine Brown'sche Bewegung mit Drift, eine geometrische Brown'sche Bewegung, ein Ornstein-Uhlenbeck Prozess oder ein Cox-Ingersoll-Ross Prozess ist. Darüber hinaus beobachten wir die Zeiten zwischen aufeinander folgenden Spikes, die wir als iid Treffzeiten der Schwelle S von X gestartet in x_0 auffassen. Die ersten beiden Fälle ähneln sich sehr und man kann jeweils den Maximum-Likelihood-Schätzer explizit angeben. Darüber hinaus wird, unter Verwendung der LAN-Theorie, die Optimalität dieser Schätzer gezeigt. In den Fällen OU- und CIR-Prozess wählen wir eine Minimum-Distanz-Methode, die auf dem Vergleich von empirischer und wahrer Laplace-Transformation bezüglich einer Hilbertraumnorm beruht. Wir werden beweisen, dass alle Schätzer stark konsistent und asymptotisch normalverteilt sind. Im letzten Kapitel werden wir die Effizienz der Minimum-Distanz-Schätzer anhand simulierter Daten überprüfen. Ferner, werden Anwendungen auf reale Datensätze und deren Resultate ausführlich diskutiert.

Efficient certification of feasibility and objective value of linear programs and its applications

The use of linear programming in various areas has increased with the significant improvement of specialized solvers. Linear programs are used as such to model practical problems, or as subroutines in algorithms such as formal proofs or branch-and-cut frameworks. In many situations a certified answer is needed, for example the guarantee that the linear program is feasible or infeasible, or a provably safe bound on its objective value. Most of the available solvers work with floating-point arithmetic and are thus subject to its shortcomings such as rounding errors or underflow, therefore they can deliver incorrect answers. While adequate for some applications, this is unacceptable for critical applications like flight controlling or nuclear plant management due to the potential catastrophic consequences. We propose a method that gives a certified answer whether a linear program is feasible or infeasible, or returns unknown'. The advantage of our method is that it is reasonably fast and rarely answers unknown'. It works by computing a safe solution that is in some way the best possible in the relative interior of the feasible set. To certify the relative interior, we employ exact arithmetic, whose use is nevertheless limited in general to critical places, allowing us to rnremain computationally efficient. Moreover, when certain conditions are fulfilled, our method is able to deliver a provable bound on the objective value of the linear program. We test our algorithm on typical benchmark sets and obtain higher rates of success compared to previous approaches for this problem, while keeping the running times acceptably small. The computed objective value bounds are in most of the cases very close to the known exact objective values. We prove the usability of the method we developed by additionally employing a variant of it in a different scenario, namely to improve the results of a Satisfiability Modulo Theories solver. Our method is used as a black box in the nodes of a branch-and-bound tree to implement conflict learning based on the certificate of infeasibility for linear programs consisting of subsets of linear constraints. The generated conflict clauses are in general small and give good rnprospects for reducing the search space. Compared to other methods we obtain significant improvements in the running time, especially on the large instances.

Comparison of two scoring systems for evaluation of treatment outcome in patients with complete bilateral cleft lip and palate

Objective : To compare two scoring systems: the Huddart/Bodenham system (HB system) and the Bauru-BCLP yardstick (BCLP yardstick), which classify treatment outcome in terms of dental arch relationships in patients with complete bilateral cleft lip and palate (CBCLP). The predictive value of these scoring systems for treatment outcome was also evaluated. Design : Retrospective longitudinal study. Patients : Dental arch relationships of 43 CBCLP patients were evaluated at 6, 9, and 12 years. Setting : Treatment outcome in BCLP patients using two scoring systems. Main Outcome Measures : For each age group, the HB scores were correlated with the BCLP yardstick scores using Spearman's correlation coefficient. The predictive value of the two scoring systems was evaluated by backward regression analysis. Results : Intraobserver Kappa values for the BCLP yardstick scoring for the two observers were .506 and .627, respectively, and the interobserver reliability ranged from .427 and .581. The intraobserver reliability for the HB system ranged from .92 to .97 and the interobserver reliability from .88 to .96. The BCLP yardstick scores of 6 and 9 years together were predictors for the outcome at 12 years (explained variance 41.3%). Adding the incisor and lateral HB scores in the regression model increased the explained variance to 67%. Conclusions : The BCLP yardstick and the HB system are reliable scoring systems for evaluation of dental arch relationships of CBCLP patients. The HB system categorizes treatment outcome into similar categories as the BCLP yardstick. In case a more sensitive measure of treatment outcome is needed, selectively both scoring systems should be used.

(99m)Tc-DPD-SPECT/CT predicts the outcome of imaging-guided diagnostic anaesthetic injections: A prospective cohort study

We hypothesized that bone SPECT combined with multiplanar reconstructed CT can identify and target the pain-inducing focus in the foot and can be used to successfully guide anaesthetic infiltrations. Therefore we prospectively investigated feasibility and predictive value of bone SPECT/CT for image guided diagnostic infiltrations in patients with chronic foot pain.

Prognostic value of the Geneva prediction rule in patients in whom pulmonary embolism is ruled out

The prognosis of patients in whom pulmonary embolism (PE) is suspected but ruled out is poorly understood. We evaluated whether the initial assessment of clinical probability of PE could help to predict the prognosis for these patients.

Personal neglect-a disorder of body representation?

The cognitive mechanisms underlying personal neglect are not well known. One theory postulates that personal neglect is due to a disorder of contralesional body representation. In the present study, we have investigated whether personal neglect is best explained by impairments in the representation of the contralesional side of the body, in particular, or a dysfunction of the mental representation of the contralesional space in general. For this, 22 patients with right hemisphere cerebral lesions (7 with personal neglect, 15 without personal neglect) and 13 healthy controls have been studied using two experimental tasks measuring representation of the body and extrapersonal space. In the tasks, photographs of left and right hands as well as left and right rear-view mirrors presented from the front and the back had to be judged as left or right. Our results show that patients with personal neglect made more errors when asked to judge stimuli of left hands and left rear-view mirrors than either patients without personal neglect or healthy controls. Furthermore, regression analyses indicated that errors in interpreting left hands were the best predictor of personal neglect, while other variables such as extrapersonal neglect, somatosensory or motor impairments, or deficits in left extrapersonal space representation had no predictive value of personal neglect. These findings suggest that deficient body representation is the major mechanism underlying personal neglect.

Carotid plaque and intima-media thickness and the incidence of ischemic events in patients with atherosclerotic vascular disease

We aimed to evaluate whether carotid intima-media thickness (CIMT) or the presence of plaque can confer additional predictive value of future cardiovascular (CV) ischemic events in patients with pre-existing atherosclerotic vascular disease. We identified 2317 patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry who had atherosclerotic vascular disease and baseline CIMT measurements. The entire range of CIMT was divided into quartiles and the fourth quartile (? 1.5 mm) was defined as carotid plaque. Mean ± standard deviation baseline CIMT was 1.31 ± 0.65 mm. Associated CV ischemic events and vascular-related hospitalizations were evaluated over a 2-year follow-up. There was a positive increase in adjusted hazard ratios (HRs) for all-cause mortality (p = 0.04 for trend) and the quadruple endpoint (CV death, myocardial infarction (MI), stroke, hospitalization for CV events) with increasing quartiles of CIMT (p = 0.0008 for trend), which was mainly driven by the fourth quartile (carotid plaque). HRs for all-cause mortality, CV death, CV death/MI/stroke and the quadruple endpoint comparing the highest (carotid plaque) with the lowest CIMT quartile were 2.09 (95% CI, 1.07-4.10; p = 0.03); 2.49 (1.10-5.67; p = 0.03); 1.71 (1.10-2.67; p = 0.02); and 1.73 (1.31-2.27; p = 0.0001). In conclusion, our analyses suggest that the presence of carotid plaque, rather than the thickness of intima-media, appears to be associated with increased risk of CV morbidity and mortality, but confirmation of these findings in other population and prospective studies is required.

Can molecular markers stratify the diagnostic value of high-grade prostatic intraepithelial neoplasia?

The diagnostic performance of isolated high-grade prostatic intraepithelial neoplasia in prostatic biopsies has recently been questioned, and molecular analysis of high-grade prostatic intraepithelial neoplasia has been proposed for improved prediction of prostate cancer. Here, we retrospectively studied the value of isolated high-grade prostatic intraepithelial neoplasia and the immunohistochemical markers ?-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67 for better risk stratification of high-grade prostatic intraepithelial neoplasia in our local Swiss population. From an initial 165 diagnoses of isolated high-grade prostatic intraepithelial neoplasia, we refuted 61 (37%) after consensus expert review. We used 30 reviewed high-grade prostatic intraepithelial neoplasia cases with simultaneous biopsy prostate cancer as positive controls. Rebiopsies were performed in 66 patients with isolated high-grade prostatic intraepithelial neoplasia, and the median time interval between initial and repeat biopsy was 3 months. Twenty (30%) of the rebiopsies were positive for prostate cancer, and 10 (15%) showed persistent isolated high-grade prostatic intraepithelial neoplasia. Another 2 (3%) of the 66 patients were diagnosed with prostate cancer in a second rebiopsy. Mean prostate-specific antigen serum levels did not significantly differ between the 22 patients with prostate cancer and the 44 without prostate cancer in rebiopsies, and the 30 positive control patients, respectively (median values, 8.1, 7.7, and 8.8 ng/mL). None of the immunohistochemical markers, including ?-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67, revealed a statistically significant association with the risk of prostate cancer in repeat biopsies. Taken together, the 33% risk of being diagnosed with prostate cancer after a diagnosis of high-grade prostatic intraepithelial neoplasia justifies rebiopsy, at least in our not systematically prostate-specific antigen-screened population. There is not enough evidence that immunohistochemical markers can reproducibly stratify the risk of prostate cancer after a diagnosis of isolated high-grade prostatic intraepithelial neoplasia.

Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans.

Predictive ability of a modified Örebro Musculoskeletal Pain Questionnaire in an acute/subacute low back pain working population

The original 'Örebro Musculoskeletal Pain Questionnaire' (original-ÖMPQ) has been shown to have limitations in practicality, factor structure, face and content validity. This study addressed these concerns by modifying its content producing the 'Örebro Musculoskeletal Screening Questionnaire' (ÖMSQ). The ÖMSQ and original-ÖMPQ were tested concurrently in acute/subacute low back pain working populations (pilot n = 44, main n = 106). The ÖMSQ showed improved face and content validity, which broadened potential application, and improved practicality with two-thirds less missing responses. High reliability (0.975, p < 0.05, ICC: 2.1), criterion validity (Spearman's r = 0.97) and internal consistency (α = 0.84) were achieved, as were predictive ability cut-off scores from ROC curves (112-120 ÖMSQ-points), statistically different ÖMSQ scores (p < 0.001) for each outcome trait, and a strong correlation with recovery time (Spearman's, r = 0.71). The six-component factor structure reflected the constructs originally proposed. The ÖMSQ can be substituted for the original-ÖMPQ in this population. Further research will assess its applicability in broader populations.