Adverse pregnancy outcome in fetuses with early increased nuchal translucency: prospective cohort study.

OBJECTIVES: An increased nuchal translucency (NT) ≥3.5mm is a well-established marker for congenital anomalies and adverse pregnancy outcome between 11 and 14 weeks of gestation. Little is known about its performance as a screening tool before 11 weeks of gestation. We aimed to investigate in a prospective setting whether fetuses with an increased NT before 11 weeks of gestation are at risk for an adverse pregnancy outcome. METHODS: This is a prospective cohort study including pregnant women with a viable fetus with a NT≥2.5mm and a crown-rump-length (CRL) <45mm. All women were referred to our fetal medicine unit (FMU) and scheduled for a follow-up scan where the NT was remeasured after one week when the CRL was >45mm. Two groups were evaluated: cases with a normalized NT(<3.5mm) and cases with a persistently increased NT (≥3.5mm). We monitored the cases until four weeks after delivery. The main outcome was a composite adverse outcome of aneuploidies, other genetic disorders, structural anomalies and pregnancy loss. We performed subgroup analyses of NT thickness at inclusion and normalized or persistently increased NT at follow-up. RESULTS: We included 109 cases of which 35.8% (39/109) had an adverse pregnancy outcome. Of these 64.1% (25/39) were aneuploidies which corresponds to 22.9% (25/109) aneuploidies in total. The subgroups of NT thickness at inclusion of 2.5-3.4, 3.5-4.4 and ≥4.5mm showed abnormal outcomes in 22.0% (9/41), 40.0% (18/45), 52.2% (12/23) respectively. In fetuses with a normalized NT and without ultrasound abnormalities at follow-up scan, the incidence of adverse outcome was 8.5% (5/59), of which 5.1% (3/59) were aneuploidies. CONCLUSION: Fetuses with an early increased NT thickness are at considerable risk of an adverse pregnancy outcome, even if the NT normalizes after 11 weeks. Not all congenital anomalies can be diagnosed with routine first-trimester screening such as non-invasive prenatal testing and/or a first-trimester anomaly scan. Therefore, expectant parents should always be referred to a FMU for detailed ultrasonography. Invasive prenatal testing should be offered if an increased nuchal translucency of ≥2.5mm is observed before 11 weeks of gestation. This article is protected by copyright. All rights reserved.

Eliminating first trimester combined testing: Consequences for early detection of significant fetal anomalies.

OBJECTIVE: To determine whether implementation of cell-free DNA (cfDNA) testing for aneuploidy as a first-tier test and subsequent abolition of first trimester combined testing (FCT) affected the first trimester detection (<14 weeks) of certain fetal anomalies. METHODS: We performed a geographical cohort study in two Fetal Medicine Units between 2011 and 2020, including 705 fetuses with prenatally detected severe brain, abdominal wall and congenital heart defects. Cases were divided into two groups: before (n = 396) and after (n = 309) cfDNA introduction. The primary outcome was the first trimester detection rate (<14 weeks) overall and for non-chromosomal anomalies solely. RESULTS: Overall, gastroschisis, AVSD and HLHS were detected more often in the first trimester in the before group compared to the after group, respectively 54.5% versus 18.5% (p = 0.004), 45.9% versus 26.9% (p = 0.008) and 30% versus 3.4% (p = 0.005). After exclusion of chromosomal anomalies identifiable through cfDNA testing, the detection of AVSD remained higher in the before group (43.3% vs. 9.5%, p = 0.02), leading to a possible earlier gestation at termination. The termination of pregnancy (TOP) rate did not differ among the groups. In the after group, referrals for suspected anomalies following a dating scan between 11 and 14 weeks significantly increased from 17.4% to 29.1% (p < 0.001). CONCLUSION: This study underscores the value of a scan dedicated to fetal anatomy in the first trimester as we observed a decline in the early detection of certain fetal anomalies (detectable in the first trimester) subsequent to the abolition of FCT.

Fetal premature atrial contractions: natural course, risk factors and adverse outcomes.

OBJECTIVE: Fetal premature atrial contractions (PACs) are usually benign, but are associated with congenital heart defects (CHDs) and tachyarrhythmias, which in turn carry a risk of cardiac failure and fetal death. We aimed to explore the frequency of adverse outcomes and to identify risk factors for tachyarrhythmias in pregnancies complicated by fetal PACs. METHODS: Fetuses diagnosed with PACs at two academic centres in Amsterdam between 2007 and 2022 were included in this retrospective cohort study. Cases with congenital anomalies or a prior diagnosis of CHD or other arrhythmias were excluded. M-mode and Doppler tracings were reanalysed and the PACs frequency recorded. We explored the incidence of adverse outcomes defined as: underlying CHDs not identified during the 20 weeks fetal anomaly scan, tachyarrhythmias, other arrhythmias, administration of antiarrhythmic therapy and death. Risk factors for tachyarrhythmias were analysed using odds ratios (OR). RESULTS: In 24% of the referred cases, PACs resolved before confirmation at the fetal medicine unit (FMU). Of the 939 included cases with proven PACs, the total incidence of adverse outcome was 6.8% (64/939). CHDs were diagnosed in 14 cases (1.5%, 95%-CI 0.9-2.5%) of which eight prenatally and six postnatally. Compared to baseline, the incidence of CHD in the presence of fetal PACs was increased (OR 1.8, 95%-CI 1.0-3.3, p=0.034). Tachyarrhythmias occurred prenatally and/or postnatally in 32 cases (3.4%) of which eight (25.0%) showed signs of cardiac failure and in 23 (71.9%) antiarrhythmic therapy was required. None of the tachyarrhythmias led to fetal or neonatal death. Risk factors for a tachyarrhythmia were: PACs with short runs of supraventricular tachycardia (OR 99), blocked PACs (OR 30), PACs in bigeminy (OR 22), frequent PACs (1 per 5-10 beats) (OR 6.9), signs of cardiac failure (OR 14) and the presence of a foramen ovale aneurysm (OR 5.0). CONCLUSIONS: PACs are generally benign and resolve often spontaneously. However, fetuses with irregular heart rate should be referred for advanced ultrasonography, which should focus on the type of PACs and risk classification. When risk factors for tachyarrhythmias are identified, weekly heart rate monitoring is advised until the PACs resolve. In the absence of risk factors, standard obstetric care may be sufficient with additional instructions to report reduced fetal movements. Should tachyarrhythmias or cardiac failure develop, referral back to the FMU is then indicated. This article is protected by copyright. All rights reserved.

Congenital small bowel obstruction: Prenatal detection and outcome.

OBJECTIVE: To evaluate and compare the outcome of fetuses and neonates with congenital small bowel obstructions (SBO), evaluate the screening performance of prenatal ultrasound for SBO and identify possible risk factors for adverse outcomes. METHODS: All cases referred to the Amsterdam University Medical Centers between 2007 and 2021 for a prenatal suspected SBO, supplemented by cases of postnatal diagnosis of SBO, were included. The primary outcome was survival after 24 weeks of gestation until the first year of life. RESULTS: 147 cases of SBO were included with a survival rate of 86.2% (119/138) after 24 weeks of gestation until the first year of age. Additional structural or chromosomal anomalies were found to have an increased risk of adverse outcomes. Intrauterine fetal demise occurred in 10/147 (6.8%) cases and 9/147 (6.1%) cases died during postnatal follow-up. The overall positive predictive value of all prenatally diagnosed cases was 91.5%. Surgical correction was performed in 123/128 (96.0%) of the live-born cases. CONCLUSIONS: Congenital SBO has an overall favorable prognosis, but the outcome is negatively impacted by the possible presence of additional structural or chromosomal anomalies. Fetal monitoring in the early third trimester should be considered, since all cases of Intrauterine fetal demise occurred between 30 and 35 weeks of gestation.

Implications of fetal premature atrial contractions: systematic review.

OBJECTIVE: Fetal heart-rate irregularities occur in 1-2% of pregnancies and are usually caused by premature atrial contractions (PAC). Although PAC are considered benign, they may be associated with cardiac defects and tachyarrhythmia. We aimed to determine the incidence of congenital heart defects (CHDs) and complications in fetuses with PAC. METHODS: This was a systematic review and meta-analysis conducted in accordance with the PRISMA statement for reporting items for systematic reviews and meta-analyses. MEDLINE and EMBASE were searched from 1990 to June 2021 to identify studies on fetuses with PAC. The primary outcome was CHD; secondary outcomes were complications using the endpoints supraventricular tachyarrhythmia (SVT), cardiac failure and intrauterine fetal demise. Meta-analysis of proportions was performed, subdivided into high-risk and low-risk populations based on reason for referral. Pooled incidences with 95% CIs were calculated. RESULTS: Of 2443 unique articles identified, 19 cohort studies including 2260 fetuses were included. The pooled incidence of CHD in fetuses with PAC was 2.8% (95% CI, 1.5-4.1%), when 0.6% is the incidence expected in the general population. The pooled incidence of CHD was 7.2% (95% CI, 3.5-10.9%) in the high-risk population and 0.9% (95% CI, 0.0-2.0%) in the low-risk population. SVT occurred in 1.4% (95% CI, 0.6-3.4%) of fetuses diagnosed with PAC. Cardiac failure was described in 16 fetuses (1.4% (95% CI, 0.5-3.5%)), of which eight were CHD-related. Intrauterine fetal demise occurred in four fetuses (0.9% (95% CI, 0.5-1.7%)) and was related to CHD in two cases. CONCLUSIONS: Our findings suggest that the risk of CHD in fetuses with PAC is 4-5 times higher than that in the general population. CHD was present more frequently in the high-risk population. Consequently, an advanced ultrasound examination to diagnose PAC correctly and exclude CHD is recommended. Complications of PAC are rare but can result in fetal demise, thus weekly fetal heart-rate monitoring remains advisable to enable early detection of SVT and to prevent cardiac failure. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

International consensus: ovarian tissue cryopreservation in young Turner syndrome patients: outcomes of an ethical Delphi study including 55 experts from 16 different countries.

STUDY QUESTION: What is the standpoint of an international expert panel on ovarian tissue cryopreservation (OTC) in young females with Turner syndrome (TS)? SUMMARY ANSWER: The expert panel states that OTC should be offered to young females with TS, but under strict conditions only. WHAT IS KNOWN ALREADY: OTC is already an option for preserving the fertility of young females at risk of iatrogenic primary ovarian insufficiency (POI). Offering OTC to females with a genetic cause of POI could be the next step. One of the most common genetic disorders related to POI is TS. Due to an early depletion of the ovarian reserve, most females with TS are confronted with infertility before reaching adulthood. However, before offering OTC as an experimental fertility preservation option to young females with TS, medical and ethical concerns need to be addressed. STUDY DESIGN, SIZE, DURATION: A three-round ethical Delphi study was conducted to systematically discuss whether the expected benefits exceed the expected negative consequences of OTC in young females with TS. The aim was to reach group consensus and form an international standpoint based on selected key statements. The study took place between February and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Anonymous panel selection was based on expertise in TS, fertility preservation or medical ethics. A mixed panel of 12 gynaecologists, 13 (paediatric) endocrinologists, 10 medical ethicists and 20 patient representatives from 16 different countries gave consent to participate in this international Delphi study. In the first two rounds, experts were asked to rate and rank 38 statements regarding OTC in females with TS. Participants were offered the possibility to adjust their opinions after repetitive feedback. The selection of key statements was based on strict inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 46 participants completed the first Delphi round (response rate 84%). Based on strict selection criteria, six key statements were selected, and 13 statements were discarded. The remaining 19 statements and two additional statements submitted by the expert panel were re-evaluated in the second round by 41 participants (response rate 75%). The analysis of the second survey resulted in the inclusion of two additional key statements. After the approval of these eight key statements, the majority of the expert panel (96%) believed that OTC should be offered to young females with TS, but in a safe and controlled research setting first, with proper counselling and informed consent procedures, before offering this procedure in routine care. The remaining participants (4%) did not object but did not respond despite several reminders. LIMITATIONS, REASONS FOR CAUTION: The anonymous nature of this study may have led to lack of accountability. The selection of experts was based on their willingness to participate. The fact that not all panellists took part in all rounds may have resulted in selection bias. WIDER IMPLICATIONS OF THE FINDINGS: This international standpoint is the first step in the global acceptance of OTC in females with TS. Future collaborative research with a focus on efficacy and safety and long-term follow-up is urgently needed. Furthermore, we recommend an international register for fertility preservation procedures in females with TS. STUDY FUNDING/COMPETING INTEREST(S): Unconditional funding (A16-1395) was received from Merck B.V., The Netherlands. The authors declare that they have no conflict of interest.

Follow-up ultrasound in second-trimester low-positioned anterior and posterior placentae: prospective cohort study.

OBJECTIVES: The majority of cases of placenta previa or a low-lying placenta in the second trimester will have a normal placental position in the third trimester. The aim of this study was to assess the accuracy of the distance between the placenta and the internal os of the cervix (IOD) in the second trimester for the prediction of third-trimester low-positioned placenta, and to define a cut-off value at which all cases of third-trimester low-positioned placenta are identified. METHODS: This was a prospective cohort study including women undergoing a transvaginal ultrasound examination between 18 and 24 weeks' gestation who had a low-positioned placenta, defined as an IOD of < 20 mm. Low-positioned placenta included placenta previa, defined as a placenta covering the internal os of the cervix, and a low-lying placenta, defined as a placenta lying near to (within 20 mm) but not overlying the internal os. All women were re-evaluated in the third trimester. Relative risks for a low-positioned placenta in the third trimester were calculated for women with placenta previa vs a low-lying placenta, posterior vs anterior placenta and positive vs negative history of Cesarean section. Multilevel likelihood ratios for ranges of IOD in the prediction of a low-positioned placenta in the third trimester were calculated separately for anteriorly and posteriorly located placentae. Corresponding receiver-operating-characteristics curves were constructed. RESULTS: In total, 958 women were included in the study. In the second trimester, placentae were more frequently located on the posterior side (62.0%) than on the anterior side (38.0%). In the third trimester, 48/958 (5.0%) placentae persisted as a low-positioned placenta. Women with placenta previa in the second trimester had a higher risk of a low-positioned placenta in the third trimester than did those with a low-lying placenta in the second trimester (37/181 (20.4%) vs 11/777 (1.4%); relative risk (RR), 17.9 (95% CI, 8.9-36.0)). Women with a posterior placenta had a higher risk of a low-positioned placenta in the third trimester than did those with an anterior placenta (38/594 (6.4%) vs 10/364 (2.7%); RR, 2.4 (95% CI, 1.2-4.9)), as did women with a history of Cesarean section compared with those without such a history (14/105 (13.3%) vs 34/853 (4.0%); RR, 3.7 (95% CI, 1.9-7.2)). The cut-off value of IOD in the second trimester to identify all cases of an abnormally located placenta in the third trimester was 15.5 mm for posteriorly located placentae, while for anteriorly located placentae the IOD cut-off was lower, namely -4.5 mm, representing a 4.5-mm overlap of the placental edge over the internal os of the cervix. CONCLUSIONS: With incorporation of a safety margin of 5 mm and ensuring that all women with placenta previa undergo a follow-up scan, we recommend lowering the IOD cut-off value for follow-up in cases of an anterior low-positioned placenta from 20 to 5 mm, which would decrease the number of unnecessary follow-up ultrasound examinations without missing any high-risk women. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Vaginal delivery in women with a low-lying placenta: a systematic review and meta-analysis.

BACKGROUND: Low-lying placentas are positioned close to the internal os of the cervix. The preferred way of delivery within this group is unclear. OBJECTIVES: To review the literature on the success of a vaginal delivery with a low-lying placenta. SEARCH STRATEGY: We searched OVID EMBASE and MEDLINE for studies on vaginal delivery with a low-lying placenta. DATA COLLECTION AND ANALYSES: Data was extracted on successful vaginal delivery and emergency caesarean section due to haemorrhage. We distinguished between different distances between the cervical os and the placenta (internal os distance, IOD); 0-10, 11-20, and >20 mm. A meta-analysis of proportions was made for successful vaginal delivery and emergency caesarean section at every cut-off value. Maternal morbidity (i.e. antepartum blood loss, postpartum haemorrhage and blood transfusion) at different cut-off values was evaluated. MAIN RESULTS: Of the 999 articles retrieved, 10 articles met our inclusion criteria. A vaginal delivery was successful at an IOD of 0-10 mm in 43%, at an IOD of 11-20 mm in 85%, and at an IOD of >20 mm in 82%. A shorter IOD had a higher chance of antepartum haemorrhage, whereas a larger IOD needed postpartum blood transfusion more often. Postpartum haemorrhage did not depend on IOD. CONCLUSION: A low-lying placenta is not a contraindication for a trial of labour, and the morbidity in these women is not increased. However, women with a low-lying placenta have a higher chance of an emergency caesarean section compared with women with a placenta outside the lower uterine segment. Therefore, shared decision-making is mandatory in case of a trial of labour. TWEETABLE ABSTRACT: This systematic review demonstrates the possibility of a vaginal delivery in women with a low-lying placenta within 20 mm of the cervix.

[Ethical decision making in dental care for frail older people]. / Ethische kwesties in de mondzorg voor kwetsbare ouderen.

Vurnerable older people often need intensive preventive and curative oral health care. However, their physical and cognitive decline does not always allow for lege artis implementation of dental treatments. This causes practical problems often with related moral issues. Including these moral issues in planning and implementation will make oral healthcare more effective and will also alleviate moral pressure on oral healthcare providers. Mostly the moral issues relate to every day ethics, which can be solved by all persons involved collectively, in open consultation and with an ethics of care approach. This means aiming at 'doing the right thing in the right way', including all the relevant aspects of the person of the patient and his/her environment. To achieve this, oral health care should be embedded in the overall care process for the elderly and care providers should feel involved with the older person and have reflective skills.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

A generalized functional response for predators that switch between multiple prey species.

We develop a theory for the food intake of a predator that can switch between multiple prey species. The theory addresses empirical observations of prey switching and is based on the behavioural assumption that a predator tends to continue feeding on prey that are similar to the prey it has consumed last, in terms of, e.g., their morphology, defences, location, habitat choice, or behaviour. From a predator's dietary history and the assumed similarity relationship among prey species, we derive a general closed-form multi-species functional response for describing predators switching between multiple prey species. Our theory includes the Holling type II functional response as a special case and makes consistent predictions when populations of equivalent prey are aggregated or split. An analysis of the derived functional response enables us to highlight the following five main findings. (1) Prey switching leads to an approximate power-law relationship between ratios of prey abundance and prey intake, consistent with experimental data. (2) In agreement with empirical observations, the theory predicts an upper limit of 2 for the exponent of such power laws. (3) Our theory predicts deviations from power-law switching at very low and very high prey-abundance ratios. (4) The theory can predict the diet composition of a predator feeding on multiple prey species from diet observations for predators feeding only on pairs of prey species. (5) Predators foraging on more prey species will show less pronounced prey switching than predators foraging on fewer prey species, thus providing a natural explanation for the known difficulties of observing prey switching in the field.

Towards a richer debate on tissue engineering: a consideration on the basis of NEST-ethics.

In their 2007 paper, Swierstra and Rip identify characteristic tropes and patterns of moral argumentation in the debate about the ethics of new and emerging science and technologies (or "NEST-ethics"). Taking their NEST-ethics structure as a starting point, we considered the debate about tissue engineering (TE), and argue what aspects we think ought to be a part of a rich and high-quality debate of TE. The debate surrounding TE seems to be predominantly a debate among experts. When considering the NEST-ethics arguments that deal directly with technology, we can generally conclude that consequentialist arguments are by far the most prominently featured in discussions of TE. In addition, many papers discuss principles, rights and duties relevant to aspects of TE, both in a positive and in a critical sense. Justice arguments are only sporadically made, some "good life" arguments are used, others less so (such as the explicit articulation of perceived limits, or the technology as a technological fix for a social problem). Missing topics in the discussion, at least from the perspective of NEST-ethics, are second "level" arguments-those referring to techno-moral change connected to tissue engineering. Currently, the discussion about tissue engineering mostly focuses on its so-called "hard impacts"-quantifiable risks and benefits of the technology. Its "soft impacts"-effects that cannot easily be quantified, such as changes to experience, habits and perceptions, should receive more attention.

The interplay between susceptibility and vaccine effectiveness control the timing and size of an emerging seasonal influenza wave in England.

Relaxing social distancing measures and reduced level of influenza over the last two seasons may lead to a winter 2022 influenza wave in England. We used an established model for influenza transmission and vaccination to evaluate the rolled out influenza immunisation programme over October to December 2022. Specifically, we explored how the interplay between pre-season population susceptibility and influenza vaccine efficacy control the timing and the size of a possible winter influenza wave. Our findings suggest that susceptibility affects the timing and the height of a potential influenza wave, with higher susceptibility leading to an earlier and larger influenza wave while vaccine efficacy controls the size of the peak of the influenza wave. With pre-season susceptibility higher than pre-COVID-19 levels, under the planned vaccine programme an early influenza epidemic wave is possible, its size dependent on vaccine effectiveness against the circulating strain. If pre-season susceptibility is low and similar to pre-COVID levels, the planned influenza vaccine programme with an effective vaccine could largely suppress a winter 2022 influenza outbreak in England.

Experts' opinions on the benefit of an incidental prenatal diagnosis of sex chromosomal aneuploidy: a qualitative interview survey.

OBJECTIVE: Incidental findings in prenatal diagnostic testing may or may not have clear prognostic significance for the phenotype. We studied experts' opinions of the benefit and disadvantage of an incidental prenatal diagnosis of a sex chromosomal aneuploidy (SCA). METHODS: We interviewed 16 experts in the field of counseling and treatment of people with SCA and asked 13 clinical geneticists and genetic associates about the clinical relevance of an incidental prenatal diagnosis of SCA. RESULTS: Most of the experts and clinical geneticists (87.5% and 76.9%, respectively) stated that an incidental prenatal diagnosis of SCA was a benefit for the child and the parents. They acknowledged the possibility of parental decisions to terminate pregnancy. Expert options in screening, training, and treatment of health, behavior, and fertility problems increase with an early diagnosis of SCA. CONCLUSION: Most experts favored an incidental prenatal diagnosis of SCA despite the complex counseling issues and their acknowledgment of possible parental decisions to terminate pregnancy. They believed the benefits greatly outweigh the disadvantages.

Moral reasoning perspectives of community pharmacists in situations of drug shortages.

BACKGROUND: Drug shortages affect health systems worldwide. Research in community pharmacy has focused on the nature, extent and impact of these shortages on patients and pharmacists. However, pharmacists' moral reasoning in situations of drug shortages has not been addressed. OBJECTIVE: To explore the moral reasoning perspectives of Dutch community pharmacists in situations of drug shortages. METHOD: An electronic survey was developed around three drug shortage scenarios with a varying impact on patient outcomes: a Contraceptive, a Parkinson's and an Osteoporosis scenario. Pharmacists rated the likelihood of nine handling options and rated and ranked 13 considerations that may have played a role therein. The considerations represented three moral reasoning perspectives (MRPs): a business orientation (BO), a rules and regulations (RR), and a professional ethics (PE) MRP. Principle component analysis (PCA) was used to investigate construct validity of the MRPs. MRP rating and MRP ranking scores measured the relative importance of the different MRPs of pharmacists in the three shortages. RESULTS: Results from 267 Pharmacists were obtained. They reported mostly similar handling in the three shortages, except for the likelihood to make agreements with prescribers or other pharmacists and regarding the decision to import a product. The PCA analysis confirmed the three MRPs that accounted for 29% of variance in the data. Both the MRP rating and especially the MRP ranking scores indicated that PE-MRP considerations were most influential on pharmacists' intended handling of the shortages. In the Contraceptive and the Osteoporosis scenarios, the relative importance of a BO-MRP was higher than in the Parkinson's scenario. CONCLUSION: Pharmacists predominantly reason with a PE-MRP when handling drug shortages. However, this perspective can be compromised when the drug shortage is perceived to have a lower impact on patient outcomes and when alternative drugs or therapy are expensive.

Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes.

In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on shifts in gene expression profiling of the liver. Toxicity screening based on animal liver cells cannot be directly extrapolated to humans due to species differences. The aim of this study was to evaluate precision-cut human liver slices as in vitro method for the prediction of human specific toxicity by toxicogenomics. The liver slices contain all cell types of the liver in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process. Previously we showed that toxicogenomic analysis of rat liver slices is highly predictive for rat in vivo toxicity. In this study we investigated the levels of gene expression during incubation up to 24 h with Affymetrix microarray technology. The analysis was focused on a broad spectrum of genes related to stress and toxicity, and on genes encoding for phase-I, -II and -III metabolizing enzymes and transporters. Observed changes in gene expression were associated with cytoskeleton remodeling, extracellular matrix and cell adhesion, but for the ADME-Tox related genes only minor changes were observed. PCA analysis showed that changes in gene expression were not associated with age, sex or source of the human livers. Slices treated with acetaminophen showed patterns of gene expression related to its toxicity. These results indicate that precision-cut human liver slices are relatively stable during 24h of incubation and represent a valuable model for human in vitro hepatotoxicity testing despite the human inter-individual variability.

Parents' perspectives on the unforeseen finding of a fetal sex chromosomal aneuploidy.

OBJECTIVE: To investigate the parental perspectives of being confronted with an unforeseen fetal sex chromosomal aneuploidy (SCA), in light of the fact that this accidental finding is avoidable by rapid aneuploidy detection (RAD). METHODS: Exploratory qualitative interview study. We conducted 16 semi-structured interviews with parents who decided to continue pregnancy after the unforeseen finding of a fetal SCA. RESULTS: The communication of the unforeseen finding of SCA; the informed decision-making process concerning the pregnancy follow-up and the child and its future were the extracted themes. Parents were not prepared to accidental findings in routine prenatal diagnostics. All started an unguided search on the Internet. It is not at all clear whether parents have preference for an RAD test with X and Y probes Parents were satisfied with the post-test professional information they received to make an informed decision, whereas after birth questions still remained to be answered. CONCLUSION: Parents' perspectives may serve as major contributors to research on the question whether or not the X and Y probes should be standard included for purposes of RAD. The fact that RAD has the possibility to avoid accidental findings of SCAs, brings up the question whether any benefits outweigh the potential harms.

Experts' opinions on ethical issues of genetic research into Alzheimer's disease: results of a Delphi study in the Netherlands.

Most publications on the ethical aspects of genetic research into Alzheimer's Disease (AD) concentrate on the differences between the opinions of professionals and non-professionals. Differences in rating of morally relevant issues between groups of professionals have not yet been described. A modified Delphi study in two rounds was held to identify differences between groups of experts (i.e. clinicians, representatives of patient organisations, ethicists and persons with a commercial background). The strongest correlation was found between the opinions of ethicists and representatives of patient organisations (0.67) and between clinicians and ethicists (0.62). Moderate correlation (0.55) was found between the opinions of clinicians and representatives of patient organisations. Persons with a commercial background showed a weak correlation with clinicians (0.41), ethicists (0.35) and representatives of patient organisations (0.30). These differences in rating of morally relevant issues between various professional groups are relevant for clinical practice and dementia care, particularly the different rating of prenatal diagnosis found between clinicians and representatives of patient organisations. Interdisciplinary consultations between various professional groups -including at least researchers, clinicians and ethicists -are recommended to guarantee that all considerations will be incorporated into the debate on ethical issues of genetic research into AD.

Evolutionary consequences of a search image.

Many predators are able to become better at spotting cryptic prey by recognising specific clues, but by concentrating on one prey type they will become worse at spotting other prey types. This phenomenon is known as the formation of a search image for a certain prey by a predator and is related to apostatic selection. Here, we study the evolution of a search image in the predator by formulating and analysing a mathematical model. The predator forages for two prey types and is able to form an independent search image for both prey. The results show that the evolutionary dynamics can be divided into two parts: a fast and a slow part. At first selection pressure will be strong towards a stable ratio of prey, which is the same as the ratio found for the unbeatable prey choice for predators with a Holling type II functional response. Following this, the slow dynamics will keep this ratio constant independent of the trait values, but the predator will slowly evolve towards a stronger search image and ultimately become a specialist predator or slowly evolve towards generalist with a weak search image. In conclusion, the formation of a search image causes the predator to control the prey densities such that the ratio of available prey is kept constant by the predator.