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BACKGROUND AND OBJECTIVE: Optimal experimental design theory proposes choosing specific settings in experimental trials in order to maximize the precision of the resulting parameter estimates. In dose response experiments, this corresponds to choosing the optimal dose levels for every available observation, and can be applied both to singular dose-response relationships and to interaction experiments where two substances are given simultaneously at several different mixture ratios ("ray designs"). While the theory of experimental design for this situation is well developed, the mathematical complexity prevents widespread use in practical applications. A simple to use application making the theory accessible to practitioners is thus very desirable. METHODS: Results from established optimal experimental design theory are applied to dose response applications, focusing on log-logistic and Weibull class dose response functions. Suitable optimal design algorithms to solve these problems are implemented into an R-shiny based online application. RESULTS: The application provides an interface to easily calculate D-optimal designs not only for singular dose experiments, but also for interaction trials with several combination rays of substances. Furthermore, the app also allows evaluating the efficiency of existing candidate designs, and finally allows construction of designs which perform robustly under different assumptions in regard to the true parameters.

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PURPOSE: Multi-parametric magnetic resonance imaging (MP-MRI) is currently the most comprehensive work up for non-invasive primary tumor staging of prostate cancer (PCa). Prostate-specific membrane antigen (PSMA)-Positron emission tomography-computed tomography (PET/CT) is presented to be a highly promising new technique for N- and M-staging in recurrent PCa-patients. The actual investigation analyses the potential of (68)Ga-PSMA11-PET/CT to assess the extent of primary prostate cancer by intra-individual comparison to MP-MRI. METHODS: In a retrospective study, ten patients with primary PCa underwent MP-MRI and PSMA-PET/CT for initial staging. All tumors were proven histopathological by biopsy. Image analysis was done in a quantitative (SUVmax) and qualitative (blinded read) fashion based on PI-RADS. The PI-RADS schema was then translated into a 3D-matrix and the euclidian distance of this coordinate system was used to quantify the extend of agreement. RESULTS: Both MP-MRI and PSMA-PET/CT presented a good allocation of the PCa, which was also in concordance to the tumor location validated in eight-segment resolution by biopsy. An Isocontour of 50 % SUVmax in PSMA-PET resulted in visually concordant tumor extension in comparison to MP-MRI (T2w and DWI). For 89.4 % of sections containing a tumor according to MP-MRI, the tumor was also identified in total or near-total agreement (euclidian distance ≤1) by PSMA-PET. Vice versa for 96.8 % of the sections identified as tumor bearing by PSMA-PET the tumor was also found in total or near-total agreement by MP-MRI. CONCLUSIONS: PSMA-PET/CT and MP-MRI correlated well with regard to tumor allocation in patients with a high pre-test probability for large tumors. Further research will be needed to evaluate its value in challenging situation such as prostatitis or after repeated negative biopsies.

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PURPOSE: The goal of our study was to quantify the expression of the somatostatin receptors (SSTR2) using the maximum standardized uptake value (SUVmax) of [(68)Ga]DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) positron emission tomography (PET)-computed tomography (CT) in liver metastases of patients with neuroendocrine tumors (NETs) prior to peptide receptor radiation therapy (PRRT) and compare the initial tumor uptake with the final treatment outcome. PROCEDURES: SSTR2 expression of the 60 liver metastases in 30 NET patients was assessed at baseline and after PRRT by measuring SUVmax, tumor to spleen ratio (T/S ratio), and tumor to liver ratio (T/L ratio). Based on morphological changes and tumor size measured at baseline and follow-up contrast-enhanced CT (after three cycles of PRRT), lesions were divided into two groups by the following: (i) responding (n = 40) and (ii) non-responding (n = 20). RESULTS: Statistically significant differences were observed in the mean SUVmax for non-responding vs. responding lesions at baseline (18.00 ± 3.59 vs. 33.55 ± 4.62, p < 0.05) and for the mean T/S ratio (1.20 ± 0.37 vs. 1.90 ± 0.45, p < 0.05) and the mean T/L ratio (3.15 ± 0.53 vs. 4.97 ± 0.62, p < 0.05). Using the receiver operating characteristic curves, SUVmax was found a better metric than both T/L ratio and T/S ratio (area under the curve (AUC) of SUVmax 0.87; T/L ratio 0.78; T/S ratio 0.73) as a stratification criterion. Using a threshold value of >16.4 for SUVmax, the sensitivity and specificity in predicting responding lesions were 95 and 60 %, respectively. CONCLUSION: We propose a SUVmax cutoff of >16.4 from [(68)Ga]DOTATOC-PET-CT to select patients for PRRT. A T/L ratio >2.2 might present a scanner-independent criterion that enables the translation of our results to other institutions. However, the robustness of this arbitrary unit still needs to be evaluated with different PET scanners.

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PURPOSE: Prostate-specific membrane antigen (PSMA) is a cell surface protein with high expression in prostate carcinoma (PC) cells. Recently, procedures have been developed to label PSMA ligands with (68)Ga, (99m)Tc and (123/124/131)I. Our initial experience with Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)]((68)Ga-PSMA) suggests that this novel tracer can detect PC relapses and metastases with high contrast. The aim of this study was to investigate its biodistribution in normal tissues and tumour lesions. METHODS: A total of 37 patients with PC and rising prostate-specific antigen (PSA) levels were subjected to (68)Ga-PSMA positron emission tomography (PET)/CT. Quantitative assessment of tracer uptake was performed 1 and 3 h post-injection (p.i.) by analysis of mean and maximum standardized uptake values (SUVmean/max) of several organs and 65 tumour lesions. Subsequently, tumour to background ratios were calculated. RESULTS: The PET/CT images showed intense tracer uptake in both kidneys and salivary glands. Moderate uptake was seen in lacrimal glands, liver, spleen and in small and large bowel. Quantitative assessment revealed excellent contrast between tumour lesions and most normal tissues. Of 37 patients, 31 (83.8 %) showed at least one lesion suspicious for cancer at a detection rate of 60 % at PSA <2.2 ng/ml and 100 % at PSA >2.2 ng/ml. Median tumour to background ratios were 18.8 (2.4-158.3) in early images and 28.3 (2.9-224.0) in late images. CONCLUSION: The biodistribution of the novel (68)Ga-PSMA tracer and its ability to detect PC lesions was analysed in 37 patients. Within healthy organs, kidneys and salivary glands demonstrated the highest radiotracer uptake. Lesions suspicious for PC presented with excellent contrast as early as 1 h p.i. with high detection rates even at low PSA levels.

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PURPOSE: Feasibility study to evaluate whether a diagnostic pediatric MRI scan of the brain can be performed without sedation by using BLADE sequences with rotating blade-like k-space covering. MATERIALS AND METHODS: Between 01/09 and 12/10 all children with a planned MRI of the brain were included. After age-dependent preparation of the child the MRI was acquired with a parent closely attending. Pharmacological sedation was only applied when strong motion artifacts occurred. All MRI sequences were independently reviewed by 2 radiologists who ranked image quality on a scale of III (excellent image quality, no motion artefacts), II (motion artefacts but still diagnostic quality), and I (non-diagnostic image quality). RESULTS: 326 children (53 % male, mean age 7.2 ± 4.3 years) were evaluated of whom 247 (76 %) had to be sedated. All infants < 1 year and 84 % of 1-year-old patients, 90 % of 2-year-old, 59 % of 3-year-old, 9 % of 4-year-old children, and 2 % of patients older than 4 years had to be sedated. In total, 2461 MRI sequences (7.6 ± 1.2 per study) including 622 BLADE sequences (25 %) were acquired. Reviewer A rated 2077 sequences (84 %) as III, 318 (13 %) as II, and 66 (3 %) as I, whereas reviewer B rated 2119 sequences (86 %) as III, 308 (13 %) as II, and 34 (1 %) as I. Inter-observer agreement was good to excellent (normal/weighted kappa value for BLADE sequences: 0.88/0.56, for all sequences: 0.92/0.71). CONCLUSION: Age-adjusted preparation and implementation of a pediatric cranial MRI may reduce the need for sedation. BLADE sequences abate motion artefacts thus enabling acquisition of diagnostic images even in young children. In patients older than 3 years, performance of MRI scans without sedation should be considered.

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BACKGROUND: Efficacy testing of drugs in seasonal allergic rhinitis (SAR) is often disturbed by seasonal variations of environmental allergens, and assessment of onset and duration of action is hardly possible under natural conditions. Allergen provocation in an environmental challenge chamber (ECC) can be of added value in this respect. However, the specificity, sensitivity, and reproducibility of outcome measures under both settings are unclear. OBJECTIVE: The aim of this study was to investigate and compare the diagnostic value (specificity, sensitivity, and reproducibility) of clinical end-points and biomarkers both following allergen provocation in an ECC and under natural conditions. METHODS: Sixty adult patients with SAR to grass and 60 healthy subjects were exposed twice to grass pollen in an ECC and observed twice during the pollen season. Symptoms, nasal flow, as well as exhaled and nasal nitric oxide (NO) were investigated. RESULTS: The total nasal symptom score (TNSS) in the ECC had the best reproducibility (intraclass correlation coefficient ICC=0.86) and sensitivity/specificity [area under receiver operating characteristic curve (AUC)=0.99] of all measures. Symptoms in season also had good sensitivity/specificity but were far less reproducible. Nasal flow in the ECC had good sensitivity/specificity but reproducibility was limited. NO measurements showed good reproducibility but sensitivity/specificity were limited, except for exhaled NO in season (AUC=0.75). CONCLUSION: The high reproducibility and sensitivity/specificity in the ECC suggests that TNSS is a valuable outcome measure. While exhaled NO can be considered to monitor airway inflammation, nasal NO appears to be unspecific.

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BACKGROUND: Ultraviolet (UV) A1 and narrowband (NB)-UVB have been reported to be effective treatments for atopic eczema (AE). OBJECTIVES: We aimed to compare the efficacy of medium-dose UVA1 and NB-UVB mono-phototherapy in patients with AE. METHODS: A randomized double-blind controlled crossover trial (ClinicalTrials.gov Identifier: NCT00419406) was conducted in which patients with AE received a 6-week course of both medium-dose UVA1 and NB-UVB. Clinical efficacy was assessed using the Six Area, Six Sign, Atopic Dermatitis (SASSAD) score and a visual analogue scale for pruritus. Assessment of health-related quality of life was performed using the Skindex-29. Total immunoglobulin E (IgE) and eosinophilic cationic protein (ECP) were evaluated at baseline and after each phototherapy course. RESULTS: Twenty-eight patients who completed both UVA1 and NB-UVB phototherapy courses on an intention-to-treat basis were analysed according to the crossover design. Both interventions were associated with significant clinical improvement but there was no significant difference between treatments with respect to the mean +/- SD relative reduction (RR) of the clinical scores (SASSAD, 43.7 +/- 31.4% vs. 39.4 +/- 24.1%, P = 0.5; pruritus score, 16 +/- 61.8% vs. 25.2 +/- 30.5%, P = 0.5, respectively). There was no significant difference in the mean +/- SD RR of the Skindex-29 after UVA1 and NB-UVB phototherapy (12.7 +/- 18.8% vs. 16.5 +/- 17.6%, P = 0.1). Changes in the total IgE and ECP levels following UVA1 and NB-UVB did not differ significantly (P = 0.3 and P = 0.9, respectively). CONCLUSIONS: A 6-week course of NB-UVB and UVA1 phototherapy of AE resulted in significant clinical improvement. With regard to efficacy and tolerability, both phototherapeutic modalities may be considered comparably good.

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BACKGROUND: In established risk score models the collection and documentation of clinical data is time-consuming, causes labor-related costs, and is dependent on the examiner. MATERIAL AND METHODS: Based on low-cost laboratory parameters that are routinely measured at admission to the intensive care unit, a new score was developed (n = 271, study sample) and validated in an independent group of patients (n = 283, validation sample). Parameters were selected by a stepwise logistic regression analysis. This new score was compared to established risk models (APACHE II, SAPS II). RESULTS: Mean age was 61.3 +/- 1.2 years (study sample) and 63.1 +/- 1.1 years (validation sample), respectively. In-hospital mortality was 24.7% (67/271, study sample) and 23.3% (66/283, validation sample). The following parameters were used to build the new score called Dense Laboratory Whole Blood Applied Risk Estimation (DELAWARE): alanine aminotransferase, C-reactive protein, cholesterol, creatine kinase MB, leukocytes, potassium, thrombocytes, triglycerides, and age. The areas under the curves were 0.853/0.813 (study sample/validation sample). In the study sample DELAWARE correlated with APACHE II (r = 0.586) and SAPS II (r = 0.614; p < 0.001), respectively. CONCLUSIONS: A general admission risk score for surgical intensive care patients solely based on quality controlled low-cost routine laboratory parameters is feasible.

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The c-Jun N-terminal kinases (JNKs) are considered as novel targets for therapy of inflammatory bowel diseases (IBD). However, the relevant JNK isoforms have to be elucidated. Here, we analyze the individual contribution of the JNK1 and JNK2 isoforms in a dextran sulfate sodium (DSS) model of experimental colitis. JNK1 and JNK2 knockout mice (JNK1 ko, JNK2 ko) and their wild-type controls (WT1, WT2) received three cycles of DSS treatment, each consisting of 1.7% DSS for 5 days, followed by 5 days with water. Animals were daily evaluated by a disease activity index (DAI) comprising measurement of body weight, estimation of stool consistency, and test for occult blood/gross rectal bleeding. After 30 days all animals were sacrificed, and the inflamed intestine was histologically evaluated by a crypt damage score. Unexpectedly, neither JNK1 ko nor JNK2 ko prevented mice from developing a chronic colitis when compared to wild-type controls WT1 and WT2, respectively. On the contrary, DAI and mortality were aggravated in JNK2 ko compared to WT2. DAI and mortality did not differ between JNK1 ko and WT1, but the histological crypt damage score was significantly enhanced in the cecum of JNK1 ko mice. Genetic deletion of JNK2 worsens the disease outcome in an experimental model of murine colitis. We hypothesize that the functional deletion of the otherwise proapoptotic JNK2 prolongs the activity of proinflammatory immune cells with deterioration of disease activity.

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OBJECTIVE: To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure disease severity and progression. METHODS: A 13-item scale was designed to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory. Two independent patient cohorts were evaluated in a two-step validation procedure. RESULTS: Application of SPRS requires less than 15 minutes and does not require any special equipment, so it is suitable for an outpatient setting. Interrater agreement of SPRS was high (intraclass correlation coefficient = 0.99). Reliability was further supported by high internal consistency (Cronbach alpha = 0.91). SPRS values were almost normally distributed without apparent floor or ceiling effect. Construct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative Ataxia Rating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity). CONCLUSION: The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity.

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The presence of erythroblasts is an accurate predictor of a poor prognosis. This study investigates whether this should be taken into account when assessing patients with burn injuries as traditional protocols may underestimate the level of risk.

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We studied 105 patients who received a total hip arthroplasty between June 1985 and August 2001 using freehand positioning of the acetabular cup. Using pelvic CT scan and the hip-plan module of SurgiGATE-System (Medivision, Oberdorf, Switzerland), we measured the angles of inclination and anteversion of the cup. Mean inclination angle was 45.8 degrees +/-10.1 degrees (range: 23.0-71.5 degrees ) and mean anteversion angle was 27.3 degrees +/-15.0 degrees (range: -23.5 degrees to 59.0 degrees ). We compared the results to the "safe" position as defined by Lewinnek et al. and found that only 27/105 cups were implanted within the limits of the safe position. We conclude that a safe position as defined by Lewinnek et al. [13] was only achieved in a minority of the cups that were implanted freehand.

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AIM: The purpose of the current study was to determine the accuracy of free hand and computer-assisted (CAS) cup placement. MATERIAL AND METHODS: Between June 1985 and August 2001, 105 free-hand and from March to November 1999 80 total hip arthroplasties under computer assistance were implanted in the above mentioned centers. To determine the accuracy of the cups, the inclination and anteversion angles were measured. In all cases the cup position was measured with a CT-investigation of the pelvis. Statistical analysis was performed with the F-test. RESULTS: With regard to the inclination and anteversion angles the variability of the cup position was significantly higher in the group of free hand implanted cups. In the CAS group we could not find any "extreme" positions. CONCLUSION: Using computer-assisted surgery a significantly higher reproducible cup position can be obtained. Long time survey may present a lowering of the rate of early and late complications caused by better prostheses alignment in the follow up.

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BACKGROUND: Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double-blind placebo-controlled study in children with grass pollen allergy using high dose allergen extracts. METHODS: A total of 161 children with seasonal rhinoconjunctivitis of which, 68 had also asthma symptoms were enrolled in a multicenter double-blind placebo-controlled study for 1 year and treated on a daily basis with sublingually applied allergen drops. After 1 year all children were given treatment for another 2 years in an open-controlled setting. Symptom scores and medication were assessed during the pollen seasons with structured interviews. Applied allergen dosage, compliance, and side effects were documented by daily diary cards. Primary endpoint was a clinical index (CI) combining symptom scores with medication index. Titrated skin prick tests (SPT) and specific antibody measurements were performed each year. RESULTS: Combining symptom with medication scores to CI was highly reliable (reliability coefficient = 0.89, standard error = 9.6%). Allergen-specific IgE- and IgG-subclass antibodies increased significantly in patients treated with SLIT indicating an activation of the immune response induced by the locally applied grass pollen extract. SPT reactivity did not change during therapy. After 1 year of SLIT in the original design we observed no significant difference in the CI between treatment and placebo analyzing all patients included in the study per intention to treat and per protocol. However, subgroup analysis in a repeated measures model revealed that patients with SLIT and severe symptoms before the beginning of treatment (CI > mean/ > 1.51) showed a significant improvement of clinical symptoms after 3 years. CONCLUSION: In this study SLIT was accompanied by a significant placebo effect. Efficacy of treatment could only be seen in children with severe clinical symptoms and this became clinically marked after 3 years of therapy.

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We suggest a quantitatively correct procedure for reducing the spatial degrees of freedom of the space-dependent rate equations of a multimode laser that describe the dynamics of the population inversion of the active medium and the mode intensities of the standing waves in the laser cavity. The key idea of that reduction is to take advantage of the small value of the parameter that defines the ratio between the population inversion decay rate and the cavity decay rate. We generalize the reduction procedure for the case of an intracavity frequency doubled laser. Frequency conversion performed by an optically nonlinear crystal placed inside the laser cavity may cause a pronounced instability in the laser performance, leading to chaotic oscillations of the output intensity. Based on the reduced equations, we analyze the dynamical properties of the system as well as the problem of stabilizing the steady state. The numerical analysis is performed considering the specific system of a Nd:YAG (neodymium-doped yttrium aluminum garnet) laser with an intracavity KTP (potassium titanyl phosphate) crystal.

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We predict theoretically that it is possible to stabilize the steady state in multimode, intracavity doubled, diode pumped Nd:YAG (neodymium-doped yttrium aluminum garnet) lasers using two output signals, namely, the sum intensities of the infrared laser modes polarized in two different orthogonal directions (X and Y) and one feedback input parameter, the pump rate. The stabilization is possible for arbitrarily large numbers of modes polarized in the X and Y direction. Different strategies of stabilization based on proportional feedback, derivative control, and their combination are discussed. The analytical and numerical results of the linear control theory are illustrated with numerical simulations of the underlying nonlinear differential equations. We show that one can maintain the stable steady state of the laser output for an arbitrarily large pump rate by taking advantage of a tracking procedure.