Background:In patients on oral anticoagulation with warfarin, genetic variations of the cytochrome P 450 - CYP2C9 have recently been associated with very low warfarin requirements. Patients needing low doses had an increased risk for bleeding complications. In Germany, phenprocoumon (having a similar metabolic pathway) is the most commonly employed vitamin K antagonist. Treatment is usually monitored by general practitioners (GPs).Objectives:To determine if CYP2C9 variant alleles can serve as risk markers in general practice patients anticoagulated with phenprocoumon. Methods: All adult anticoagulated patients in 12 teaching general practices and one university outpatient clinic were to be recruited. 185 patients agreed to having blood samples drawn during routine anticoagulation controls and testing for CYP2C9 mutations. Subjects answered a questionnaire concerning bleeding complications, drug intolerance, and personal and family medical history. Phenprocoumon dosages required for stable anticoagulation were retrieved. Odds ratios (OR) with 95% confidence intervals (CI) were calculated based on 2-way cross-tabulations and multivariate logistic regression models, t-tests used where appropriate.Results:Bleeding complications were reported by 19% of the patients. 2.2% had suffered life-threatening bleeding. CYP2C9 variants were carried by 26.3% of 179 patients tested (17.9% *1/*2, 7.8% *1/*3, 0.6% *2/*3). While presence of a *2 allele was not associated with an increased risk (OR 0.35, CI 0.10 1.24), carriers of the rare *3 alleles had a higher risk of bleeding (OR 3.10, CI 1.02 9.40). With regard to bleeding, carrying CYP2C9 *3 was highly specific (94%), though sensitivity was low at 17%; post-test probability of bleeding was 40%.Conclusions:CYP2C9 *3 variants are associated with an increased bleeding risk in patients anticoagulated with phenprocoumon. Screening can identify patients with a high risk for bleeding. Appropriate clinical consequences (restricted indication for anticoagulation, careful induction, adjustment of target INR, closer monitoring or self-testing of INR) as well as the cost effectiveness of screening for variant CYP2C9 with regard to patient outcomes should be subject of further research.
From previous thermal and photoinduced charge-transfer reactions in duplex DNA there is accumulative evidence for an attenuation parameter β of the distance dependence in the range 0.6−0.8 Å-1, with the exception of one specific system exhibiting β = 1.5 Å-1 which is reinvestigated in this paper. Femtosecond to nanosecond time-resolved pump−probe spectroscopy has been used to follow photoinduced charge-shift dynamics in DNA duplexes containing a covalently appended, protonated 9-alkylamino-6-chloro-2-methoxyacridine chromophore. This acridine derivative (X+) resides in the DNA duplex at a specific abasic site, which is highly defined as reflected in the monoexponentiality of the kinetics. In the presence of only neighboring A:T base pairs, no charge transfer occurs within the excited-state lifetime (18 ns) of the chromophore. However, the presence of a guanine nucleobase as either a nearest neighbor or with one interspersed A:T base pair does result in fluorescence quenching. In the case of nearest neighbors, the intermediate radical state X• is formed within 4 ps and decays on the 30 ps time scale. Placing one A:T base pair between the X+ and guanine slows down the forward transfer rate by 3 orders of magnitude, corresponding to an apparent β value of >2.0 Å-1. This dramatic decrease in the rate is due to a change in charge-transfer mechanism from a (nearly) activationless to a thermally activated regime in which the forward transfer is slower than the back transfer and the X• state is no longer observed. These observations indicate that the distance dependence of charge injection in the X+-labeled DNA duplex is not solely caused by a decrease in electronic couplings but also by a concomitant increase of the activation energy with increasing distance. This increase in activation energy may result from the loss of driving force due to excited-state relaxation competing with charge transfer, or reflect distance-dependent changes in the energetics, predominantly of the low-frequency reorganization energy in this charge-shift reaction, on purely electrostatic grounds. To test the hypothesis of distance-dependent activation energy, guanine has been replaced by 7-deazaguanine, its easier-to-oxidize purine analogue. In these duplexes, a similar change of charge-transfer mechanism is found. However, consistent with an a priori larger driving force this change occurs at a larger donor−acceptor separation than in the X+-guanine systems. Independent of the detailed contributions to the distance-dependent activation energy, this phenomenon illustrates the complex nature of experimental β values.
It is estimated that there are currently over 3 million patients receiving dialysis treatment worldwide. With effective pre-dialysis counselling, a majority of patients choose the home-based therapy peritoneal dialysis (PD) but only approximately 11% of prevalent dialysis patients use this modality. Connection-assist devices can overcome the challenges posed by decreased manual dexterity and/or visual acuity, and can allow more patients to be treated with home-based therapies. As part of the CE marking authorization, a connection device has been evaluated for safety and ease of use in a usability study.Fifteen patients and nine carers volunteered in this study, ranging from 23 to 86 years in age and from 0.3 to 24 years in experience in the PD therapy. The operating cycle consisted of eight tasks, each having several handling steps. The data analysis focused on the task effectiveness and the subjects' subjective feedback from the NASA task load index (N-TLX) questionnaire and semi-structured interviews.Of 1248 handling steps performed in total, 38 use errors were observed and discussed with the subjects. This equates to 97% of all handling steps being performed safely and easily. In all six dimensions of the N-TLX, more than 50 percent of subjects rated the task load 50 points or less on the scale. Regarding the handling of the device, 13 of 15 of the patients and 8 of 9 of the carers gave positive feedback.Safety and ease of use was demonstrated by evaluating task effectiveness (97% SU), interviews and N-TLX. Additionally the study provided valuable individual user feedback, which will inform the final design of the system for PD. The majority of patients and carers gave positive feedback regarding use and handling of this connection device. Innovative connection devices in general promise to reduce the barriers to using this home-based dialysis treatment.
In the energy industry, a time of dynamic innovation and uncertainties drives R&D incumbents to extend their technology screening process to the early technology lifecycle. Many early breakthrough technology innovations stem from academia and are developed by academic spin-offs. In these situations an incumbent’s future technology organization (FTO), focused on open innovation, needs to expand its evaluation and development capabilities towards R&D alliances with academic technology spin-offs. In the light of the open innovation and real option frameworks this study analyzes R&D projects using the real options analysis (ROA) and discusses the critical decision of whether to develop technology internally or externally. It explores R&D alliances between academic spin-offs and a large power industry player and investigates the concept and role of a FTO in the open innovation process. A model will be introduced to operationalize the FTO concept and practically evaluate the risk of open innovation with R&D alliances for breakthrough technologies. Contrary to the common view that risks increase when open innovation is applied along with external development of a breakthrough technology in R&D alliances, the present study shows that the risks and uncertainties can be mitigated and controlled when applying ROA and the FTO model.
