In utero haematopoietic stem cell transplantation. Experiences in mice, sheep and humans

Early prenatal diagnosis and in utero therapy of certain fetal diseases have the potential to reduce fetal morbidity and mortality. The intrauterine transplantation of stem cells provides in some instances a therapeutic option before definitive organ failure occurs. Clinical experiences show that certain diseases, such as immune deficiencies or inborn errors of metabolism, can be successfully treated using stem cells derived from bone marrow. However, a remaining problem is the low level of engraftment that can be achieved. Efforts are made in animal models to optimise the graft and study the recipient's microenvironment to increase long-term engraftment levels. Our experiments in mice show similar early homing of allogeneic and xenogeneic stem cells and reasonable early engraftment of allogeneic murine fetal liver cells (17.1% donor cells in peripheral blood 4 weeks after transplantation), whereas xenogeneic HSC are rapidly diminished due to missing self-renewal and low differentiation capacities in the host's microenvironment. Allogeneic murine fetal liver cells have very good long-term engraftment (49.9% donor cells in peripheral blood 16 weeks after transplantation). Compared to the rodents, the sheep model has the advantage of body size and gestation comparable to the human fetus. Here, ultrasound-guided injection techniques significantly decreased fetal loss rates. In contrast to the murine in utero model, the repopulation capacities of allogeneic ovine fetal liver cells are lower (0.112% donor cells in peripheral blood 3 weeks after transplantation). The effect of MHC on engraftment levels seems to be marginal, since no differences could be observed between autologous and allogeneic transplantation (0.117% donor cells vs 0.112% donor cells in peripheral blood 1 to 2 weeks after transplantation). Further research is needed to study optimal timing and graft composition as well as immunological aspects of in utero transplantation.

Regulation of human (adrenal) androgen biosynthesis-New insights from novel throughput technology studies

Androgens are precursors for sex steroids and are predominantly produced in the human gonads and the adrenal cortex. They are important for intrauterine and postnatal sexual development and human reproduction. Although human androgen biosynthesis has been extensively studied in the past, exact mechanisms underlying the regulation of androgen production in health and disease remain vague. Here, the knowledge on human androgen biosynthesis and regulation is reviewed with a special focus on human adrenal androgen production and the hyperandrogenic disorder of polycystic ovary syndrome (PCOS). Since human androgen regulation is highly specific without a good animal model, most studies are performed on patients harboring inborn errors of androgen biosynthesis, on human biomaterials and human (tumor) cell models. In the past, most studies used a candidate gene approach while newer studies use high throughput technologies to identify novel regulators of androgen biosynthesis. Using genome wide association studies on cohorts of patients, novel PCOS candidate genes have been recently described. Variant 2 of the DENND1A gene was found overexpressed in PCOS theca cells and confirmed to enhance androgen production. Transcriptome profiling of dissected adrenal zones established a role for BMP4 in androgen synthesis. Similarly, transcriptome analysis of human adrenal NCI-H295 cells identified novel regulators of androgen production. Kinase p38α (MAPK14) was found to phosphorylate CYP17 for enhanced 17,20 lyase activity and RARB and ANGPTL1 were detected in novel networks regulating androgens. The discovery of novel players for androgen biosynthesis is of clinical significance as it provides targets for diagnostic and therapeutic use.

Why do humans make antisaccade errors?

Antisaccade errors are attributed to failure to inhibit the habitual prosaccade. We investigated whether the amount of information about the required response the patient has before the trial begins also contributes to error rate. Participants performed antisaccades in five conditions. The traditional design had two goals on the left and right horizontal meridians. In the second condition, stimulus-goal confusability between trials was eliminated by displacing one goal upward. In the third, hemifield uncertainty was eliminated by placing both goals in the same hemifield. In the fourth, goal uncertainty was eliminated by having only one goal, but interspersed with no-go trials. The fifth condition eliminated all uncertainty by having the same goal on every trial. Antisaccade error rate increased by 2% with each additional source of uncertainty, with the main effect being hemifield information, and a trend for stimulus-goal confusability. A control experiment for the effects of increasing angular separation between targets without changing these types of prior response information showed no effects on latency or error rate. We conclude that other factors besides prosaccade inhibition contribute to antisaccade error rates in traditional designs, possibly by modulating the strength of goal activation.

Oncology nurses' perceptions about involving patients in the prevention of chemotherapy administration errors

To explore oncology nurses' perceptions and experiences with patient involvement in chemotherapy error prevention.

Impact of random and systematic recall errors and selection bias in case--control studies on mobile phone use and brain tumors in adolescents (CEFALO study)

Whether the use of mobile phones is a risk factor for brain tumors in adolescents is currently being studied. Case--control studies investigating this possible relationship are prone to recall error and selection bias. We assessed the potential impact of random and systematic recall error and selection bias on odds ratios (ORs) by performing simulations based on real data from an ongoing case--control study of mobile phones and brain tumor risk in children and adolescents (CEFALO study). Simulations were conducted for two mobile phone exposure categories: regular and heavy use. Our choice of levels of recall error was guided by a validation study that compared objective network operator data with the self-reported amount of mobile phone use in CEFALO. In our validation study, cases overestimated their number of calls by 9% on average and controls by 34%. Cases also overestimated their duration of calls by 52% on average and controls by 163%. The participation rates in CEFALO were 83% for cases and 71% for controls. In a variety of scenarios, the combined impact of recall error and selection bias on the estimated ORs was complex. These simulations are useful for the interpretation of previous case-control studies on brain tumor and mobile phone use in adults as well as for the interpretation of future studies on adolescents.

Frequency of and predictors for patient-reported medical and medication errors in Switzerland

OBJECTIVES: To analyse the frequency of and identify risk factors for patient-reported medical errors in Switzerland. The joint effect of risk factors on error-reporting probability was modelled for hypothetical patients. METHODS: A representative population sample of Swiss citizens (n = 1306) was surveyed as part of the Commonwealth Fund’s 2010 lnternational Survey of the General Public’s Views of their Health Care System’s Performance in Eleven Countries. Data on personal background, utilisation of health care, coordination of care problems and reported errors were assessed. Logistic regression analysis was conducted to identify risk factors for patients’ reports of medical mistakes and medication errors. RESULTS: 11.4% of participants reported at least one error in their care in the previous two years (8% medical errors, 5.3% medication errors). Poor coordination of care experiences was frequent. 7.8% experienced that test results or medical records were not available, 17.2% received conflicting information from care providers and 11.5% reported that tests were ordered although they had been done before. Age (OR = 0.98, p = 0.014), poor health (OR = 2.95, p = 0.007), utilisation of emergency care (OR = 2.45, p = 0.003), inpatient-stay (OR = 2.31, p = 0.010) and poor care coordination (OR = 5.43, p <0.001) are important predictors for reporting error. For high utilisers of care that unify multiple risk factors the probability that errors are reported rises up to p = 0.8. CONCLUSIONS: Patient safety remains a major challenge for the Swiss health care system. Despite the health related and economic burden associated with it, the widespread experience of medical error in some subpopulations also has the potential to erode trust in the health care system as a whole.

Impact of measurement errors on the determination of the linear modulus of human meniscal attachments

For the development of meniscal substitutes and related finite element models it is necessary to know the mechanical properties of the meniscus and its attachments. Measurement errors can falsify the determination of material properties. Therefore the impact of metrological and geometrical measurement errors on the determination of the linear modulus of human meniscal attachments was investigated. After total differentiation the error of the force (+0.10%), attachment deformation (−0.16%), and fibre length (+0.11%) measurements almost annulled each other. The error of the cross-sectional area determination ranged from 0.00%, gathered from histological slides, up to 14.22%, obtained from digital calliper measurements. Hence, total measurement error ranged from +0.05% to −14.17%, predominantly affected by the cross-sectional area determination error. Further investigations revealed that the entire cross-section was significantly larger compared to the load-carrying collagen fibre area. This overestimation of the cross-section area led to an underestimation of the linear modulus of up to −36.7%. Additionally, the cross-sections of the collagen-fibre area of the attachments significantly varied up to +90% along their longitudinal axis. The resultant ratio between the collagen fibre area and the histologically determined cross-sectional area ranged between 0.61 for the posterolateral and 0.69 for the posteromedial ligament. The linear modulus of human meniscal attachments can be significantly underestimated due to the use of different methods and locations of cross-sectional area determination. Hence, it is suggested to assess the load carrying collagen fibre area histologically, or, alternatively, to use the correction factors proposed in this study.

Medication errors in a swiss cardiovascular surgery department: a cross-sectional study based on a novel medication error report method

The purpose of this study was (1) to determine frequency and type of medication errors (MEs), (2) to assess the number of MEs prevented by registered nurses, (3) to assess the consequences of ME for patients, and (4) to compare the number of MEs reported by a newly developed medication error self-reporting tool to the number reported by the traditional incident reporting system. We conducted a cross-sectional study on ME in the Cardiovascular Surgery Department of Bern University Hospital in Switzerland. Eligible registered nurses (n = 119) involving in the medication process were included. Data on ME were collected using an investigator-developed medication error self reporting tool (MESRT) that asked about the occurrence and characteristics of ME. Registered nurses were instructed to complete a MESRT at the end of each shift even if there was no ME. All MESRTs were completed anonymously. During the one-month study period, a total of 987 MESRTs were returned. Of the 987 completed MESRTs, 288 (29%) indicated that there had been an ME. Registered nurses reported preventing 49 (5%) MEs. Overall, eight (2.8%) MEs had patient consequences. The high response rate suggests that this new method may be a very effective approach to detect, report, and describe ME in hospitals.

Dosimetric impact of geometric errors due to respiratory motion prediction on dynamic multileaf collimator-based four-dimensional radiation delivery

The synchronization of dynamic multileaf collimator (DMLC) response with respiratory motion is critical to ensure the accuracy of DMLC-based four dimensional (4D) radiation delivery. In practice, however, a finite time delay (response time) between the acquisition of tumor position and multileaf collimator response necessitates predictive models of respiratory tumor motion to synchronize radiation delivery. Predicting a complex process such as respiratory motion introduces geometric errors, which have been reported in several publications. However, the dosimetric effect of such errors on 4D radiation delivery has not yet been investigated. Thus, our aim in this work was to quantify the dosimetric effects of geometric error due to prediction under several different conditions. Conformal and intensity modulated radiation therapy (IMRT) plans for a lung patient were generated for anterior-posterior/posterior-anterior (AP/PA) beam arrangements at 6 and 18 MV energies to provide planned dose distributions. Respiratory motion data was obtained from 60 diaphragm-motion fluoroscopy recordings from five patients. A linear adaptive filter was employed to predict the tumor position. The geometric error of prediction was defined as the absolute difference between predicted and actual positions at each diaphragm position. Distributions of geometric error of prediction were obtained for all of the respiratory motion data. Planned dose distributions were then convolved with distributions for the geometric error of prediction to obtain convolved dose distributions. The dosimetric effect of such geometric errors was determined as a function of several variables: response time (0-0.6 s), beam energy (6/18 MV), treatment delivery (3D/4D), treatment type (conformal/IMRT), beam direction (AP/PA), and breathing training type (free breathing/audio instruction/visual feedback). Dose difference and distance-to-agreement analysis was employed to quantify results. Based on our data, the dosimetric impact of prediction (a) increased with response time, (b) was larger for 3D radiation therapy as compared with 4D radiation therapy, (c) was relatively insensitive to change in beam energy and beam direction, (d) was greater for IMRT distributions as compared with conformal distributions, (e) was smaller than the dosimetric impact of latency, and (f) was greatest for respiration motion with audio instructions, followed by visual feedback and free breathing. Geometric errors of prediction that occur during 4D radiation delivery introduce dosimetric errors that are dependent on several factors, such as response time, treatment-delivery type, and beam energy. Even for relatively small response times of 0.6 s into the future, dosimetric errors due to prediction could approach delivery errors when respiratory motion is not accounted for at all. To reduce the dosimetric impact, better predictive models and/or shorter response times are required.