Effectively Selecting a Target Population for a Future Comparative Study

When comparing a new treatment with a control in a randomized clinical study, the treatment effect is generally assessed by evaluating a summary measure over a specific study population. The success of the trial heavily depends on the choice of such a population. In this paper, we show a systematic, effective way to identify a promising population, for which the new treatment is expected to have a desired benefit, using the data from a current study involving similar comparator treatments. Specifically, with the existing data we first create a parametric scoring system using multiple covariates to estimate subject-specific treatment differences. Using this system, we specify a desired level of treatment difference and create a subgroup of patients, defined as those whose estimated scores exceed this threshold. An empirically calibrated group-specific treatment difference curve across a range of threshold values is constructed. The population of patients with any desired level of treatment benefit can then be identified accordingly. To avoid any ``self-serving'' bias, we utilize a cross-training-evaluation method for implementing the above two-step procedure. Lastly, we show how to select the best scoring system among all competing models. The proposals are illustrated with the data from two clinical trials in treating AIDS and cardiovascular diseases. Note that if we are not interested in designing a new study for comparing similar treatments, the new procedure can also be quite useful for the management of future patients who would receive nontrivial benefits to compensate for the risk or cost of the new treatment.

Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not

Simple collagen-related peptides (CRPs) containing a repeat Gly-Pro-Hyp sequence are highly potent platelet agonists. Like collagen, they must exhibit tertiary (triple-helical) and quaternary (polymeric) structure to activate platelets. Platelet signaling events induced by the peptides are the same as most of those induced by collagen. The peptides do not recognize the alpha 2 beta 1 integrin. To identify the signaling receptor involved, we have evaluated the response to the CRP, Gly-Lys-Hyp(Gly-Pro-Hyp)10-Gly-Lys-Hyp-Gly of platelets with defined functional deficiencies. These studies exclude a primary recognition role for CD36, von Willebrand factor (vWF), or glycoprotein (GP) IIb/IIIa. Thus, both CD36 and vWF-deficient platelets exhibited normal aggregation, normal fibrinogen binding, and normal expression of CD62 and CD63, measured by flow cytometry, in response to the peptide, and there was normal expression of CD62 and CD63 on thrombasthenic platelets. In contrast, GPVI-deficient platelets were totally unresponsive to the peptide, indicating that this receptor recognizes the Gly-Pro-Hyp sequence in collagen. GPVI-deficient platelets showed some fibrinogen binding in response to collagen but failed to aggregate and to express CD62 and CD63. Collagen, but not CRP-XL, contains binding sites for alpha 2 beta 1. Therefore, it is possible that collagen still induces some signaling via alpha 2 beta 1, leading to activation of GPIIb/IIIa. Our findings are consistent with a two-site, two-step model of collagen interaction with platelets involving recognition of specific sequences in collagen by an adhesive receptor such as alpha 2 beta 1 to arrest platelets under flow and subsequent recognition of another specific collagen sequence by an activatory receptor, namely GPVI.

Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation

Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.

ATP modeling of internal transformer faults for relay performance testing

Transformers are very important elements of any power system. Unfortunately, they are subjected to through-faults and abnormal operating conditions which can affect not only the transformer itself but also other equipment connected to the transformer. Thus, it is essential to provide sufficient protection for transformers as well as the best possible selectivity and sensitivity of the protection. Nowadays microprocessor-based relays are widely used to protect power equipment. Current differential and voltage protection strategies are used in transformer protection applications and provide fast and sensitive multi-level protection and monitoring. The elements responsible for detecting turn-to-turn and turn-to-ground faults are the negative-sequence percentage differential element and restricted earth-fault (REF) element, respectively. During severe internal faults current transformers can saturate and slow down the speed of relay operation which affects the degree of equipment damage. The scope of this work is to develop a modeling methodology to perform simulations and laboratory tests for internal faults such as turn-to-turn and turn-to-ground for two step-down power transformers with capacity ratings of 11.2 MVA and 290 MVA. The simulated current waveforms are injected to a microprocessor relay to check its sensitivity for these internal faults. Saturation of current transformers is also studied in this work. All simulations are performed with the Alternative Transients Program (ATP) utilizing the internal fault model for three-phase two-winding transformers. The tested microprocessor relay is the SEL-487E current differential and voltage protection relay. The results showed that the ATP internal fault model can be used for testing microprocessor relays for any percentage of turns involved in an internal fault. An interesting observation from the experiments was that the SEL-487E relay is more sensitive to turn-to-turn faults than advertized for the transformers studied. The sensitivity of the restricted earth-fault element was confirmed. CT saturation cases showed that low accuracy CTs can be saturated with a high percentage of turn-to-turn faults, where the CT burden will affect the extent of saturation. Recommendations for future work include more accurate simulation of internal faults, transformer energization inrush, and other scenarios involving core saturation, using the newest version of the internal fault model. The SEL-487E relay or other microprocessor relays should again be tested for performance. Also, application of a grounding bank to the delta-connected side of a transformer will increase the zone of protection and relay performance can be tested for internal ground faults on both sides of a transformer.

Highly Efficient Non-palladium Catalyzed Controlled Synthesis and X-ray Analysis of Functionalized 1,2-Diaryl-, 1,2,3-Triaryl- and 1,2,3,4-Tetraarylbenzene

A general, two-step highly efficient synthesis of 1,2-diaryl-, 1,2,3-triaryl- and 1,2,3,4-tetraarylbenzenes from simple stitching of alpha-oxo-ketene-S,S-acetals and active methylene compounds via a ‘lactone intermediate’ is described. This procedure offers easy access to highly functionalized arylated-benzenes containing sterically demanding groups in good to excellent yields. The novelty of the procedure lies in the fabrication of aromatic compounds with desired conformational flexibility along the molecular axis in a transition metal-free environment through easily accessible precursors. The crystal analysis of these arylated-benzene scaffolds showed that the peripheral aryl rings are arranged in propeller-like fashion with respect to the central benzene rings. Examination of the crystal packing in the structure of a 1,2,3,4-tetraarylbenzene 12c revealed a “N…pi interaction” between molecules related by a two-fold screw axis running in a direction. It is interesting that the repeat of the array of N…pi interaction around the axis of the 1,2,3,4-tetraarylbenzene 12c enforces the molecules in a helical pattern.

How well do radiographic absorptiometry and quantitative ultrasound predict osteoporosis at spine or hip? A cost-effectiveness analysis

Dual energy X-ray absorptiometry (DXA) is widely accepted as the reference method for diagnosis and monitoring of osteoporosis and for assessment of fracture risk, especially at hip. However, axial-DXA is not suitable for mass screening, because it is usually confined to specialized centers. We propose a two-step diagnostic approach to postmenopausal osteoporosis: the first step, using an inexpensive, widely available screening technique, aims at risk stratification in postmenopausal women; the second step, DXA of spine and hip is applied only to potentially osteoporotic women preselected on the basis of the screening measurement. In a group of 110 healthy postmenopausal woman, the capability of various peripheral bone measurement techniques to predict osteoporosis at spine and/or hip (T-score < -2.5SD using DXA) was tested using receiver operating characteristic (ROC) curves: radiographic absorptiometry of phalanges (RA), ultrasonometry at calcaneus (QUS. CALC), tibia (SOS.TIB), and phalanges (SOS.PHAL). Thirty-three women had osteoporosis at spine and/or hip with DXA. Areas under the ROC curves were 0.84 for RA, 0.83 for QUS.CALC, 0.77 for SOS.PHAL (p < 0.04 vs RA) and 0.74 for SOS.TIB (p < 0.02 vs RA and p = 0.05 vs QUS.CALC). For levels of sensitivity of 90%, the respective specificities were 67% (RA), 64% (QUS.CALC), 48% (SOS.PHAL), and 39% (SOS.TIB). In a cost-effective two-step, the price of the first step should not exceed 54% (RA), 51% (QUS.CALC), 42% (SOS.PHAL), and 25% (SOS.TIB). In conclusion, RA, QUS.CALC, SOS.PHAL, and SOS.TIB may be useful to preselect postmenopausal women in whom axial DXA is indicated to confirm/exclude osteoporosis at spine or hip.

Intelligente Werkzeugtechnik- Harmonisieren der Temperatureinflüsse

Der Schlüssel zu Produktivität und Qualität in zahlreichen abformenden Prozessen ist eine optimale Temperierung, die bedingt, dass die Kühl- und Heißkanäle der Oberfläche angepasst sind. Eine Hauptrolle um Durchlaufzeiten und Werkzeugkosten zu senken und die Qualität zu steigern spielt die wirtschaftliche Erwärmung und Kühlung der Teile. Konventionelle Arten der Temperierung können diesen Anforderungen nicht gerecht werden. Der vorliegende Beitrag beschäftigt sich mit zwei neuen Prozesskombinationen: a) Intelligente Werkzeugtechnik mit erfolgreicher industrieller Anwendung, hauptsächlich für Spritz- und Druckgusswerkzeuge. b) Neue Prozessketten für Formen mit geöffnetem Formstück oder RTM (englisch: Resin Transfer Moulding) mit Verwendung der inkrementellen Blechumformung

Intelligente Werkzeugtechnik - Harmonisieren der Temperatureinflüsse

Der Schlüssel zu Produktivität und Qualität in zahlreichen abformenden Prozessen ist eine optimale Temperierung, die bedingt, dass die Kühl- und Heißkanäle der Oberfläche angepasst sind. Eine Hauptrolle um Durchlaufzeiten und Werkzeugkosten zu senken und die Qualität zu steigern spielt die wirtschaftliche Erwärmung und Kühlung der Teile. Konventionelle Arten der Temperierung können diesen Anforderungen nicht gerecht werden. Der vorliegende Beitrag beschäftigt sich mit zwei neuen Prozesskombinationen: a) Intelligente Werkzeugtechnik mit erfolgreicher industrieller Anwendung, hauptsächlich für Spritz- und Druckgusswerkzeuge. b) Neue Prozessketten für Formen mit geöffnetem Formstück oder RTM (englisch: Resin Transfer Moulding) mit Verwendung der inkrementellen Blechumformung.

Double arterial perfusion strategy for extensive thoracic aortic surgery to avoid lower body hypothermic circulatory arrest

OBJECTIVE To analyse our results of using a double arterial perfusion strategy to avoid lower body hypothermic circulatory arrest after extensive thoracic aortic surgery. METHODS We analysed the intra- and perioperative courses of 10 patients (median age 58 years, median logistic EuroSCORE 14.6) who underwent extensive thoracic aortic surgery with a double arterial perfusion strategy. The main goal of double arterial perfusion is to separate myocardial and supra-aortic from systemic perfusion. Aortic repair starts at the most distal level of the descending aorta, followed by reinsertion of the supra-aortic vessels, and ends with completion of the proximal anastomosis or by any kind of root repair as needed. RESULTS Seven of 10 patients had prior surgery of the thoracic aorta. Indications for surgery were post-dissection aneurysm in 4 patients, true aneurysm in 3, anastomotic aneurysms in 2 and Type B aortic dissection with pseudo-coarctation in 1. Surgical access was performed through median sternotomy with left hemi-clamshell extension in all cases. There was no in-hospital mortality, but perioperative neurological symptoms occurred in 2 patients. These 2 patients developed delayed stroke (after awaking) after an initial uneventful clinical course, and in 1 of them, neurological symptoms resolved completely during follow-up. The median follow-up was 7 (±13) months. There was no death and no need for additional redo surgery during this observational period. CONCLUSIONS Extensive surgery of the thoracic aorta using a double arterial perfusion technique in order to avoid lower body hypothermic circulatory arrest is an attractive option. Further refinements of this technique may enable the safe and effective simultaneous multisegmental treatment of thoracic aortic pathology in patients who would otherwise have to undergo a two-step surgical approach.

Hybrid aortic arch repair

The successes of thoracic endovascular aortic repair (TEVAR) have spurned new approaches to addressing thoracic aortic pathologies. These hybrid techniques offer an alternative in patients with multi-segmental thoracic aortic pathologies which would have otherwise required a two-step arch replacement and open descending arch repair. The following article offers a clinical insight to the available hybrid approaches, such as rerouting of supra-aortic vessels. Unique complications to endovascular repairs, and technical risks and issues, are also presented along with management options and strategies to minimize such concerns.

The effect of aerobic exercise on intrahepatocellular and intramyocellular lipids in healthy subjects

BACKGROUND Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass). AIM To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy. METHODS Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO(2max)) using ¹H-MR-spectroscopy. RESULTS Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO(2max), 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (-22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity. CONCLUSIONS IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions. TRIAL REGISTRATION ClinicalTrial.gov NCT00491582.

Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals

Objectives: Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals. Materials and methods: The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated. Results: A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13–69%] and a 42% (95% CI: 17–68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8–38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL. Conclusion: ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.

Immediate shear bond strengths of a composite, a compomer and a glass ionomer to a ceramic substrate.

PURPOSE To determine the best-performing combination of three core buildup materials and three bonding materials based on their bond strength to ceramic blocks in vitro. MATERIALS AND METHODS The materials used for core buildup were a composite (Tetric EvoCeram), a compomer (Compoglass F), and a glass-ionomer cement (Ketac Fil Plus), and for bonding, a three-step etch-and-rinse adhesive (Syntac), a two-step etch-and-rinse adhesive (ExciTE), and a single-step system (RelyX Unicem). Bond strength to ceramic blocks was determined by shear bond strength testing. Fracture behavior was evaluated by scanning electron microscopy. RESULTS The highest adhesive values between buildup and ceramic were obtained using the materials Compoglass F and Syntac, followed by Compoglass F and ExciTE. Among the two other core buildups, Tetric EvoCeram performed better than Ketac Fil Plus, which was independent of the bonding materials. Adhesive fractures were characteristically observed with Syntac and ExciTE, and cohesive fractures were characteristically observed with RelyX Unicem. CONCLUSION These data show that compomers bonded with a multistep adhesive system achieved statistically significantly higher shear bond strength than composites and glass-ionomer cements. Within the limitations inherent to this in vitro study, the use of compomers for core buildup can be recommended.

Bonding of simplified adhesive systems to caries-affected dentin of primary teeth.

PURPOSE To evaluate the bonding of simplified adhesive systems to sound and caries-affected dentin of primary teeth with microtensile (µTBS) and nanoleakage (NL) tests. MATERIALS AND METHODS Occlusal cavities were prepared in 36 sound second primary molars. Half of the specimens were submitted to pH cycling to simulate caries-affected dentin. Teeth were randomly restored with one of three materials: the etch-and-rinse adhesive system Adper Single Bond 2 (SB), the two-step self-etching adhesive system Adper SE Plus (SE), and the one-step self-etching adhesive system Adper Easy One (EASY). After storage for 24 h, specimens with cross-sectional areas of 0.8 mm2 were prepared for microtensile testing (1 mm/min). One stick from each tooth was immersed in silver nitrate solution (24 h) and allowed to develop for 8 h in order to score the nano leakage with SEM. The fracture pattern was evaluated using a stereomicroscope (400X). The µTBS means were analyzed by two-way ANOVA and Tukey's post-hoc test. For NL, the Kruskal- Wallis and Mann-Whitney tests were used (α < 0.05). RESULTS SB (35.5 ± 3.5) showed the highest µTBS value to sound dentin, followed by EASY (26.3 ± 1.9) and SE (18.2 ± 6.5) (p < 0.05). No difference among materials was observed for caries-affected dentin (SB: 17.8 ± 4.2; SE: 13.9 ± 3.2; EASY: 14.4 ± 4.2, p > 0.05). For all groups, adhesive/mixed fracture prevailed. Caries affected dentin promoted silver nitrate uptake into the adhesive interface; however, with SE, the nano leakage was more pronounced than in the other adhesive systems, even in sound dentin. CONCLUSION Caries-affected dentin negatively influences the bond strength and nano leakage of the two-step etch-and-rinse and one-step self-etching adhesive systems tested in primary teeth.

Bovine viral diarrhea (BVD): from biology to control

Bovine viral diarrhea virus (BVDV) is endemic worldwide. Together with classical swine fever and border disease viruses, it belongs to the genus Pestivirus of the family Flaviviridae. Most infections with BVDV take a transient, acute, course. Only rarely BVDV persists in its hosts. Due to the early time point of infection in utero, persistently infected (PI) animals are immunotolerant to the infecting non-cytopathic BVDV. In such animals the virus may mutate to a cytopathic biotype, causing lethal mucosal disease. In BVD-endemic regions, approximately 1% of the animals are PI. Removal of all PI animals leads to extinction of BVD. This approach to BVD eradication has been vindicated in Scandinavia. Following the same principles, regional and country-wide eradication programs are run in different parts of the world. These programs differ in the way PI animals are detected and in the role of vaccines. The Scandinavian two-step method of detecting PI animals is based on (i) the high level of seroprevalence in herds where PI animals are present and (ii) on testing all animals for virus in such herds. However, the high average herd seroprevalence in Switzerland made it impossible to define a reasonable threshold for virus testing. Therefore, all animals were directly tested for virus in the year 2008 and all newborn calves until the end of 2012, when the PI prevalence had dropped to 0.02%. Vaccination remains prohibited. Since 2013, surveillance for BVD is accomplished by serology. As a unique consequence of eradication, over 7500 viral strains are available to us for genetic studies.