Statistical inference for the optimal approximating model

In the setting of high-dimensional linear models with Gaussian noise, we investigate the possibility of confidence statements connected to model selection. Although there exist numerous procedures for adaptive (point) estimation, the construction of adaptive confidence regions is severely limited (cf. Li in Ann Stat 17:1001–1008, 1989). The present paper sheds new light on this gap. We develop exact and adaptive confidence regions for the best approximating model in terms of risk. One of our constructions is based on a multiscale procedure and a particular coupling argument. Utilizing exponential inequalities for noncentral χ2-distributions, we show that the risk and quadratic loss of all models within our confidence region are uniformly bounded by the minimal risk times a factor close to one.

The optimal lead insertion depth for esophageal ECG recordings with respect to atrial signal quality

BACKGROUND Diagnosing supraventricular arrhythmias by conventional long-term ECG can be cumbersome because of poor p-waves. Esophageal long-term electrocardiography (eECG) has an excellent sensitivity for atrial signals and may overcome this limitation. However, the optimal lead insertion depth (OLID) is not known. METHODS We registered eECGs at different lead insertion depths in 27 patients and analyzed 199,716 atrial complexes with respect to signal amplitude and slope. Correlation and regression analyses were used to find a criterion for OLID. RESULTS Atrial signal amplitudes and slopes significantly depend on lead insertion depth. OLID correlates with body height (rSpearman=0.71) and can be estimated by OLID [cm]=0.25*body height[cm]-7cm. At this insertion depth, we recorded the largest esophageal atrial signal amplitudes (1.27±0.86mV), which were much larger compared to conventional surface lead II (0.19±0.10mV, p<0.0001). CONCLUSION The OLID depends on body height and can be calculated by a simple regression formula.

A novel technique, dynamic intraligamentary stabilization creates optimal conditions for primary ACL healing: A preliminary biomechanical study

BACKGROUND Anterior cruciate ligament (ACL) rupture is a common lesion. Current treatment emphasizes arthroscopic ACL reconstruction via a graft, although this approach is associated with potential drawbacks. A new method of dynamic intraligamentary stabilization (DIS) was subjected to biomechanical analysis to determine whether it provides the necessary knee stability for optimal ACL healing. METHODS Six human knees from cadavers were harvested. The patellar tendon, joint capsule and all muscular attachments to the tibia and femur were removed, leaving the collateral and the cruciate ligaments intact. The knees were stabilized and the ACL kinematics analyzed. Anterior-posterior (AP) stability measurements evaluated the knees in the following conditions: (i) intact ACL, (ii) ACL rupture, (iii) ACL rupture with primary stabilization, (iv) primary stabilization after 50 motion cycles, (v) ACL rupture with DIS, and (vi) DIS after 50 motion cycles. RESULTS After primary suture stabilization, average AP laxity was 3.2mm, which increased to an average of 11.26mm after 50 movement cycles. With primary ACL stabilization using DIS, however, average laxity values were consistently lower than those of the intact ligament, increasing from an initial AP laxity of 3.00mm to just 3.2mm after 50 movement cycles. CONCLUSIONS Dynamic intraligamentary stabilization established and maintained close contact between the two ends of the ruptured ACL, thus ensuring optimal conditions for potential healing after primary reconstruction. The present ex vivo findings show that the DIS technique is able to restore AP stability of the knee.

Optimal sequence timing of CT angiography and perfusion CT in patients with stroke

OBJECTIVE Standard stroke CT protocols start with non-enhanced CT followed by perfusion-CT (PCT) and end with CTA. We aimed to evaluate the influence of the sequence of PCT and CTA on quantitative perfusion parameters, venous contrast enhancement and examination time to save critical time in the therapeutic window in stroke patients. METHODS AND MATERIALS Stroke CT data sets of 85 patients, 47 patients with CTA before PCT (group A) and 38 with CTA after PCT (group B) were retrospectively analyzed by two experienced neuroradiologists. Parameter maps of cerebral blood flow, cerebral blood volume, time to peak and mean transit time and contrast enhancements (arterial and venous) were compared. RESULTS Both readers rated contrast of brain-supplying arteries to be equal in both groups (p=0.55 (intracranial) and p=0.73 (extracranial)) although the extent of venous superimposition of the ICA was rated higher in group B (p=0.04). Quantitative perfusion parameters did not significantly differ between the groups (all p>0.18), while the extent of venous superimposition of the ICA was rated higher in group B (p=0.04). The time to complete the diagnostic CT examination was significantly shorter for group A (p<0.01). CONCLUSION Performing CTA directly after NECT has no significant effect on PCT parameters and avoids venous preloading in CTA, while examination times were significantly shorter.

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation

The phosphatidylinositol 3-kinase (PI3K) pathway, through its major effector node AKT, is critical for the promotion of cell growth, division, motility and apoptosis evasion. This signaling axis is therefore commonly targeted in the form of mutations and amplifications in a myriad of malignancies. Glycogen synthase kinase 3 (GSK3) was first discovered as the kinase responsible for phosphorylating and inhibiting the activity of glycogen synthase, ultimately antagonizing the storage of glucose as glycogen. Its activity counteracts the effects of insulin in glucose metabolism and AKT has long been recognized as one of the key molecules capable of phosphorylating GSK3 and inhibiting its activity. However, here we demonstrate that GSK3 is required for optimal phosphorylation and activation of AKT in different malignant cell lines, and that this effect is independent of the type of growth factor stimulation and can happen even in basal states. Both GSK3 alpha and GSK3 beta isoforms are necessary for AKT to become fully active, displaying a redundant role in the setting. We also demonstrate that this effect of GSK3 on AKT phosphorylation and full activation is dependent on its kinase activity, since highly specific inhibitors targeting GSK3 catalytic activity also promote a reduction in phosphorylated AKT. Analysis of reverse phase protein array screening of MDA-MB-231 breast cancer cells treated with RNA interference targeting GSK3 unexpectedly revealed an increase in levels of phosphorylated MAPK14 (p38). Treatment with the selective p38 inhibitor SB 202190 rescued AKT activation in that cell line, corroborating the importance of unbiased proteomic analysis in exposing cross-talks between signaling networks and demonstrating a critical role for p38 in the regulation of AKT phosphorylation.

Numerical solution of optimal control problems with constant control delays

We investigate a class of optimal control problems that exhibit constant exogenously given delays in the control in the equation of motion of the differential states. Therefore, we formulate an exemplary optimal control problem with one stock and one control variable and review some analytic properties of an optimal solution. However, analytical considerations are quite limited in case of delayed optimal control problems. In order to overcome these limits, we reformulate the problem and apply direct numerical methods to calculate approximate solutions that give a better understanding of this class of optimization problems. In particular, we present two possibilities to reformulate the delayed optimal control problem into an instantaneous optimal control problem and show how these can be solved numerically with a stateof- the-art direct method by applying Bock’s direct multiple shooting algorithm. We further demonstrate the strength of our approach by two economic examples.

Optimal compliance with emission constraints: dynamic characteristics and the choice of technique

The paper analyzes how to comply with an emission constraint, which restricts the use of an established energy technique, given the two options to save energy and to invest in two alternative energy techniques. These techniques differ in their deterioration rates and the investment lags of the corresponding capital stocks. Thus, the paper takes a medium-term perspective on climate change mitigation, where the time horizon is too short for technological change to occur, but long enough for capital stocks to accumulate and deteriorate. It is shown that, in general, only one of the two alternative techniques prevails in the stationary state, although, both techniques might be utilized during the transition phase. Hence, while in a static economy only one technique is efficient, this is not necessarily true in a dynamic economy.

Optimal dose levels in screening chest CT for unimpaired detection and volumetry of lung nodules, with and without computer assisted detection at minimal patient radiation

OBJECTIVES The aim of this phantom study was to minimize the radiation dose by finding the best combination of low tube current and low voltage that would result in accurate volume measurements when compared to standard CT imaging without significantly decreasing the sensitivity of detecting lung nodules both with and without the assistance of CAD. METHODS An anthropomorphic chest phantom containing artificial solid and ground glass nodules (GGNs, 5-12 mm) was examined with a 64-row multi-detector CT scanner with three tube currents of 100, 50 and 25 mAs in combination with three tube voltages of 120, 100 and 80 kVp. This resulted in eight different protocols that were then compared to standard CT sensitivity (100 mAs/120 kVp). For each protocol, at least 127 different nodules were scanned in 21-25 phantoms. The nodules were analyzed in two separate sessions by three independent, blinded radiologists and computer-aided detection (CAD) software. RESULTS The mean sensitivity of the radiologists for identifying solid lung nodules on a standard CT was 89.7% ± 4.9%. The sensitivity was not significantly impaired when the tube and current voltage were lowered at the same time, except at the lowest exposure level of 25 mAs/80 kVp [80.6% ± 4.3% (p = 0.031)]. Compared to the standard CT, the sensitivity for detecting GGNs was significantly lower at all dose levels when the voltage was 80 kVp; this result was independent of the tube current. The CAD significantly increased the radiologists' sensitivity for detecting solid nodules at all dose levels (5-11%). No significant volume measurement errors (VMEs) were documented for the radiologists or the CAD software at any dose level. CONCLUSIONS Our results suggest a CT protocol with 25 mAs and 100 kVp is optimal for detecting solid and ground glass nodules in lung cancer screening. The use of CAD software is highly recommended at all dose levels.

Evaluating the optimal timing of surgical antimicrobial prophylaxis: study protocol for a randomized controlled trial

BACKGROUND Surgical site infections are the most common hospital-acquired infections among surgical patients. The administration of surgical antimicrobial prophylaxis reduces the risk of surgical site infections . The optimal timing of this procedure is still a matter of debate. While most studies suggest that it should be given as close to the incision time as possible, others conclude that this may be too late for optimal prevention of surgical site infections. A large observational study suggests that surgical antimicrobial prophylaxis should be administered 74 to 30 minutes before surgery. The aim of this article is to report the design and protocol of a randomized controlled trial investigating the optimal timing of surgical antimicrobial prophylaxis.Methods/design: In this bi-center randomized controlled trial conducted at two tertiary referral centers in Switzerland, we plan to include 5,000 patients undergoing general, oncologic, vascular and orthopedic trauma procedures. Patients are randomized in a 1:1 ratio into two groups: one receiving surgical antimicrobial prophylaxis in the anesthesia room (75 to 30 minutes before incision) and the other receiving surgical antimicrobial prophylaxis in the operating room (less than 30 minutes before incision). We expect a significantly lower rate of surgical site infections with surgical antimicrobial prophylaxis administered more than 30 minutes before the scheduled incision. The primary outcome is the occurrence of surgical site infections during a 30-day follow-up period (one year with an implant in place). When assuming a 5 surgical site infection risk with administration of surgical antimicrobial prophylaxis in the operating room, the planned sample size has an 80% power to detect a relative risk reduction for surgical site infections of 33% when administering surgical antimicrobial prophylaxis in the anesthesia room (with a two-sided type I error of 5%). We expect the study to be completed within three years. DISCUSSION The results of this randomized controlled trial will have an important impact on current international guidelines for infection control strategies in the hospital. Moreover, the results of this randomized controlled trial are of significant interest for patient safety and healthcare economics.Trial registration: This trial is registered on ClinicalTrials.gov under the identifier NCT01790529.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease

OBJECTIVE To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.