Quadruplet pregnancy outcome with and without fetal reduction: Danish national cohort study (2008-2018) and comparison with dichorionic twins.

OBJECTIVES: To perform a nationwide study of quadrichorionic quadriamniotic (QCQA) quadruplet pregnancies and to compare the pregnancy outcome in those undergoing fetal reduction with non-reduced quadruplets and dichorionic diamniotic (DCDA) twin pregnancies from the same time period. METHODS: This was a retrospective Danish national register-based study performed using data from the national Danish Fetal Medicine Database, which included all QCQA quadruplets and all non-reduced DCDA twin pregnancies with an estimated due date between 2008 and 2018. The primary outcome measure was a composite of adverse pregnancy outcomes, including pregnancy loss or intrauterine death of one or more fetuses. Secondary outcomes included gestational age at delivery, the number of liveborn children, preterm delivery before 28, 32 and 37 gestational weeks and birth weight. Data on pregnancy complications and baseline characteristics were also recorded. Outcomes were compared between reduced and non-reduced quadruplet pregnancies, and between DCDA pregnancies and quadruplet pregnancies reduced to twins. A systematic literature search was performed to describe and compare previous results with our findings. RESULTS: Included in the study were 33 QCQA quadruplet pregnancies, including three (9.1%) non-reduced pregnancies, 28 (84.8%) that were reduced to twin pregnancy and fewer than three (6.1%) that were reduced to singleton pregnancy, as well as 9563 DCDA twin pregnancies. Overall, the rate of adverse pregnancy outcome was highest in non-reduced quadruplets (66.7%); it was 50% in quadruplets reduced to singletons and 10.7% in quadruplets reduced to twins. The proportion of liveborn infants overall was 91.1% of the total number expected to be liveborn in quadruplet pregnancies reduced to twins. This was statistically significantly different from 97.6% in non-reduced dichorionic twins (P = 0.004), and considerably higher than 58.3% in non-reduced quadruplets. The rates of preterm delivery < 28, < 32 and < 37 weeks were decreased in quadruplets reduced to twins compared with those in non-reduced quadruplet pregnancies. Quadruplets reduced to twins did not achieve equivalent pregnancy outcomes to those of DCDA twins. CONCLUSION: This national study of QCQA quadruplets has shown that multifetal pregnancy reduction improves pregnancy outcome, including a decreased rate of preterm delivery and higher proportion of liveborn children. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Late first-trimester ultrasound findings can alter management after high-risk NIPT result.

OBJECTIVE: To evaluate the impact of detailed late first-trimester ultrasound (LFTU) on the positive predictive value (PPV) of a high-risk non-invasive prenatal test (NIPT) result for various chromosomal abnormalities. METHODS: This was a retrospective study of all cases undergoing invasive prenatal testing from three tertiary providers of obstetric ultrasound over 4 years, each using NIPT as a first-line screening test. Data were collected from pre-NIPT ultrasound, NIPT, LFTU, placental serology and later ultrasound examinations. Prenatal testing for chromosomal abnormalities was performed by microarray, initially using array comparative genomic hybridization and then single nucleotide polymorphism (SNP) array for the last 2 years. Uniparental disomy testing was performed by SNP array during all 4 years. The majority of NIPT tests were analyzed using the Illumina platform, initially confined to the assessment of the common autosomal trisomies, sex chromosome aneuploidies and rare autosomal trisomies (RAT), then extending to genome-wide analysis for the last 2 years. RESULTS: Amniocentesis or chorionic villus sampling (CVS) was performed on 2657 patients, 1352 (51%) of whom had undergone prior NIPT, with 612 (45%) of these returning a high-risk result and meeting the inclusion criteria for the study. LFTU findings significantly affected the PPV of the NIPT result for trisomies 13 (T13), 18 (T18) and 21 (T21), monosomy X (MX) and RAT but not for the other sex chromosomal abnormalities or segmental imbalances (> 7 Mb). Abnormal LFTU increased the PPV close to 100% for T13, T18, T21, MX and RAT. The magnitude of the change in PPV was highest for the most severe chromosomal abnormalities. When LFTU was normal, the incidence of confined placental mosaicism (CPM) was highest in those with a high-risk NIPT result for T13, followed by T18 and T21. After normal LFTU, the PPV for T21, T18, T13 and MX decreased to 68%, 57%, 5% and 25%, respectively. CONCLUSIONS: LFTU after a high-risk NIPT result can alter the PPV for many chromosomal abnormalities, assisting counseling regarding invasive prenatal testing and pregnancy management. The high PPVs of NIPT for T21 and T18 are not sufficiently modified by normal LFTU findings to alter management. These at-risk patients should be offered CVS for earlier diagnosis, particularly given the low rate of CPM associated with these aneuploidies. Patients with a high-risk NIPT result for T13 and normal LFTU findings often wait for amniocentesis or avoid invasive testing altogether given the low PPV and higher rate of CPM in this context. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Influence of fibroids on cell-free DNA screening accuracy.

OBJECTIVE: Cell-free DNA (cfDNA) screening assesses both maternal and placental cfDNA. Fibroids are common and release cfDNA into maternal serum. Genetic abnormality is seen in 50% of fibroids. We aimed to assess the impact of fibroids on the accuracy of genome-wide cfDNA screening. METHODS: This was a prospective cohort study of singleton pregnancies examined at one of two centers in Melbourne and Sydney, Australia, between 1 November 2019 and 31 December 2020. All cases underwent pretest ultrasound examination to confirm an ongoing pregnancy of at least 10 weeks' gestation, and, at this stage, the number and volume of any uterine fibroid were documented. Genome-wide cfDNA screening was performed to detect all copy-number variants (CNV) > 7 megabases. The incidence of a false-positive result was compared between cases with and those without fibroids. RESULTS: Over the 14-month study period, 13 184 patients underwent cfDNA screening, of whom 1017 (7.7%) had fibroids. Fibroids were not identified in any of the 17 participants who had a false-positive result for chromosomes 13, 18, 21, X or Y. Ninety-five (0.7%) cases were screen-positive for subchromosomal aberration (SA), rare autosomal trisomy (RAT) or multiple abnormalities (MA), with 10 of these cases having a fetal genetic abnormality. The incidence of a false-positive RAT, MA or SA result was significantly higher in participants with fibroids (20/1017 (2.0%)) than in those without fibroids (64/12 167 (0.5%)). Women with fibroids were approximately six times as likely to have a false-positive result for SA, and this was associated positively with both fibroid number and volume. CONCLUSIONS: Most women with fibroids do not have an abnormal result on genome-wide cfDNA screening. However, CNVs due to fibroids are associated with false-positive SA findings, although fibroids do not appear to influence cfDNA screening accuracy for the common autosomal trisomies or sex-chromosomal abnormalities. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Health care provider preferences for, and barriers to, cannabis use in cancer care.

Background: Limited research has been conducted about the perspectives of oncology health care providers (hcps) concerning the use of cannabis in cancer care and their potential role in advising patients. We sought to determine the barriers encountered by hcps with respect to medical cannabis and their preferred practices in this area. Methods: An anonymous survey about cannabis was distributed to oncology hcps at the Tom Baker Cancer Centre in Calgary, Alberta. The 45-question survey measured the opinions of hcps about cannabis use and authorization in oncology. Results: Of 103 oncology hcps who participated in the study, 75% were women. By hcp type, the most commonly reported professional groups were oncology nurse (40%), radiation therapist (9%), and pharmacist (6%). Of respondents, 75% reported providing direct care to cancer patients. More than half (69%) had spoken to a patient about cannabis in the preceding month, and 84% believed that they lacked sufficient knowledge about cannabis to make recommendations. Barriers such as monitoring the patient's use of cannabis (54%), prescribing an accurate dose (61%) or strain (53%), and having insufficient research (50%) were most commonly reported. More than half of hcps (53%) would be interested in receiving more information or training about the use of cannabis in oncology. Conclusions: The survey indicated that this group of oncology hcps believed that they lacked sufficient knowledge about cannabis to make recommendations to patients. In addition to that lack of knowledge, a number of notable barriers were reported, and more than half the hcps indicated interest in learning more about cannabis in the future.

Quality assessment of uterine artery Doppler measurement in first-trimester combined screening for pre-eclampsia.

OBJECTIVE: To assess the quality of mean uterine artery (UtA) pulsatility index (PI) measurement in a first-trimester pre-eclampsia screening program. METHODS: Consecutive women with a singleton pregnancy attending first-trimester screening for fetal chromosomal abnormalities also had combined screening for pre-eclampsia based on the Fetal Medicine Foundation (FMF) algorithm, at a large practice in Sydney, Australia, from May 2014 to February 2017. Distributions of mean UtA-PI multiples of the median (MoM) on a logarithmic scale were plotted in relation to the normal median with 95% CI for each operator and for each month. Central tendency and dispersion and cumulative sum charts were produced. Mean UtA-PI MoM values between 0.95 and 1.05 were considered ideal and those between 0.90 and 1.10 were considered acceptable. The screen-positive rates for preterm pre-eclampsia in different groups of sonographers according to their mean log10 UtA-PI MoM were calculated and compared using the chi-square test. RESULTS: A total of 21 010 women attended for first-trimester ultrasound and had screening for pre-eclampsia. The overall median UtA-PI MoM was 1.042 (interquartile range (IQR), 0.85-1.26). Of 46 sonographers, 42 (91.3%) performed more than 50 examinations and, of those, 41 (97.6%) measured UtA-PI within the acceptable range. Sonographers measuring UtA-PI MoM on average below 0.95 and those measuring it above 1.05 had, respectively, lower and higher screen-positive rates when compared with those with measurements within the 0.95-1.05 UtA-PI MoM interval (7.2% and 13.2% vs 11.2%, respectively, P < 0.001). CONCLUSION: UtA Doppler is measured well among trained operators when following an established protocol. While slight variations are expected, systematic error in this measurement impacts on the screen-positive rate. Therefore, a quality control process should be in place and retraining of staff may be required. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Association between fetal fraction on cell-free DNA testing and first-trimester markers for pre-eclampsia.

OBJECTIVES: To evaluate the association between fetal fraction on cell-free DNA (cfDNA) testing and first-trimester markers for pre-eclampsia, and to investigate the possible association of low fetal fraction with increased risks for pre-eclampsia (PE) and fetal growth restriction (FGR). METHODS: This was a retrospective cohort study including all women with a singleton pregnancy who had risk calculation for PE and FGR between 11 + 0 and 13 + 6 weeks' gestation and who also had cfDNA as a primary or secondary screening test for chromosomal abnormalities at any gestational age at two fetal medicine clinics in Sydney and Melbourne, Australia, between March 2013 and May 2017. Logarithmically transformed fetal fraction results were adjusted for gestational age and maternal characteristics. Associations with mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI), pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), and risks for PE < 34 weeks, PE < 37 weeks and FGR < 37 weeks were analyzed using correlation analysis and univariable and multivariable linear regressions. RESULTS: In total, 4317 singleton pregnancies that underwent cfDNA testing with fetal fraction reported were included. Significant prediction of fetal fraction was provided by gestational age, conception by in-vitro fertilization, maternal age, body mass index, chronic hypertension, diabetes mellitus, South Asian ethnicity and being parous without history of PE or FGR. Fetal fraction was associated inversely with MAP and UtA-PI and associated positively with PAPP-A and PlGF. The lower the fetal fraction, the higher were the risks for PE < 34 weeks, PE < 37 weeks and FGR < 37 weeks (P < 0.001 for all). CONCLUSIONS: There is a significant association between fetal fraction result and first-trimester markers for adverse pregnancy outcome. Low fetal fraction is associated with an increased risk for pregnancy complication, but its capacity to act an as independent first-trimester marker in an algorithm for screening for PE and FGR requires further research. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Implications of failure to achieve a result from prenatal maternal serum cell-free DNA testing: a historical cohort study.

OBJECTIVE: To investigate the pregnancy outcomes in a cohort of women who failed to obtain a result in non-invasive prenatal testing (NIPT). DESIGN: Historical cohort study. SETTING: A multicentre private practice in Sydney, Australia. POPULATION: Women who failed to obtain a result from NIPT (n = 131). METHODS: The maternal characteristics, antenatal investigations and pregnancy outcomes for these women were compared with those who obtained a result at the same practice and to the general Australian obstetric population. MAIN OUTCOME MEASURES: Antenatal investigations: pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotrophin (ß-hCG), placental growth factor (PlGF), uterine artery pulsatility index (PI), mean arterial pressure (MAP). Pregnancy outcomes: chromosomal abnormality, pre-eclampsia, gestational diabetes, small-for-gestational-age (SGA), preterm delivery. RESULTS: Only 1.1% of NIPT samples failed to return a result. This cohort was significantly older and had significantly increased weight compared with the general Australian obstetric population. Pregnancy outcomes were available for 94% of the cohort. There were significantly higher rates of chromosomal aneuploidies (6.5% versus 0.2%, P < 0.0001), pre-eclampsia (11% versus 1.5%, P < 0.0001) and gestational diabetes (23% versus 7.5%, P < 0.0001) compared with the general obstetric population. Rates of preterm delivery and SGA were elevated but did not reach significance. Antenatal investigations demonstrated decreased PAPP-A MoM (0.75 versus 1.14, P < 0.0001), decreased free ß-hCG (0.71 versus 1.01, P < 0.0001) and increased uterine artery PI (1.79 versus 1.65, P = 0.02). CONCLUSION: Women who fail to obtain a result from NIPT are at increased risk of adverse pregnancy outcomes, in particular chromosomal aneuploidy, gestational diabetes and pre-eclampsia. FUNDING: None received. TWEETABLE ABSTRACT: Women who fail to obtain a result from cell-free DNA NIPT are at increased risk of adverse pregnancy outcomes.

Assessing quality standards in measurement of uterine artery pulsatility index at 11 to 13 + 6 weeks' gestation.

OBJECTIVES: To assess the effect of audit and feedback on the performance of first-trimester uterine artery pulsatility index (UtA-PI) measurement, to determine whether operator experience affects performance and whether an operator's measurement profile affects the screen-positive rate for early-onset pre-eclampsia (PE). METHODS: This was a prospective cohort study in which UtA-PI measurements were collected between 11 to 13 + 6 weeks' gestation by 12 operators and were entered into individualized calculators to convert them to multiples of a locally-derived median (MoM). Individual sonographer cumulative sum (CUSUM) and target charts were generated to assess central tendency and dispersion to identify systematic measurement errors and deviation from expected measurement performance. Six of the operators received regular feedback whilst the remaining six received no feedback. Each group consisted of four experienced operators and two relatively inexperienced operators. The average MoM for each operator was compared with their respective screen-positive rates for early-onset PE. RESULTS: The group that received feedback performed better than that which received none, with results more closely matching the expected measurement distribution. UtA-PI measurements were comparable between the experienced and inexperienced sonographers (mean log10 lowest PI MoM, -0.0089 vs 0.0124, respectively); however the inexperienced sonographers had a higher overall screen-positive rate for early-onset PE (10.0% vs 2.7%, respectively). There was a significant positive correlation between the mean MoM for each operator and the screen-positive rate (r = 0.63). CONCLUSIONS: CUSUM and target graphs are an effective method of audit for first-trimester UtA-PI measurement. Feedback to operators resulted in improved measurement performance, which will ultimately result in improved screening accuracy for PE.

Prenatal diagnosis using combined quantitative fluorescent polymerase chain reaction and array comparative genomic hybridization analysis as a first-line test: results from over 1000 consecutive cases.

OBJECTIVES: First, to assess the performance of a prenatal diagnostic service using quantitative fluorescent polymerase chain reaction (QF-PCR) and array comparative genomic hybridization (aCGH) as first-line investigations. Second, to determine the incidence of copy number variants (CNVs) by indication for testing, with particular reference to ultrasound and biochemical parameters measured in combined first-trimester screening. METHODS: All patients undergoing invasive prenatal testing at a specialist prenatal screening service in Sydney, Australia, were included in the study. All samples underwent QF-PCR and targeted aCGH. RESULTS: Of 1049 cases, CNVs were reported in 156 (14.9%). Preliminary QF-PCR identified abnormalities in 104 of these cases. Of the remaining 52 cases, 20 could have been detected on karyotype testing, leaving 32 cases (3.1%) with CNVs only detectable by aCGH, of which 13 (1.2%) were pathogenic. Variants of unknown significance (VOUS) were seen in only three cases. Fetal structural abnormalities identified in the first trimester were the group most likely to be associated with pathogenic CNVs (11.8%). CONCLUSIONS: Combining QF-PCR and aCGH is an effective first-tier prenatal testing regime that does not require conventional karyotyping. The incidence of VOUS in this study was very low owing to appropriate aCGH targeting and specific reporting criteria that reduced the number of potentially difficult counseling encounters. Pathogenic CNVs are positively correlated with the presence of fetal structural abnormalities, but not with enlarged nuchal translucency or abnormal first-trimester serology results.

Reducing inter-rater variability in the assessment of nuchal translucency image quality.

INTRODUCTION: Standardization of first-trimester nuchal translucency (NT) image acquisition is crucial to the success of screening for Down syndrome. Rigorous audit of operator performance and constructive feedback from assessors maintain standards. This process relies on good inter-rater agreement on image assessment. We describe the Australian approach to NT image assessment and evaluate the impact of a targeted intervention on inter-rater agreement. METHODS: Between 2002 and 2008 a group of experienced practitioners met nine times to compare their assessment of a series of NT images. Each assessor had previously scored the images according to a system described in 2002. Inter-rater agreement was evaluated before and after an intervention where the assessors were required to refer to a detailed resource manual designed to reduce the subjectivity inherent in image assessment. RESULTS: There was a statistical improvement in inter-rater agreement for all elements of image assessment (original scores and individual component scores) after the intervention, apart from horizontal fetal position. However, even after the intervention, inter-rater agreement levels generally remained moderate (kappa range: 0.14-0.58). CONCLUSIONS: This study has shown that provision of detailed resource documentation to experienced assessors can significantly improve inter-rater agreement in all facets of NT image assessment. It also highlights areas of image assessment that require critical review. It is recommended that all audit bodies regularly review their inter-rater agreement to ensure consistent feedback to operators who submit images for expert peer review.

First-trimester fetal nasal bone audit: evaluation of a novel method of image assessment.

OBJECTIVES: Absence of the nasal bone has been recognized to be a strong ultrasound marker for Down syndrome and its inclusion in combined first-trimester screening would increase the sensitivity and specificity of this test. We describe the development of a method of image scoring that should allow reliable assessment of practitioners submitting themselves to peer review for nasal bone imaging. METHODS: Twenty sonographers submitted 20 images demonstrating the presence of the nasal bone for quality assurance audit. Image quality was compared with the criteria described by The Fetal Medicine Foundation. Three raters scored the images on four separate occasions. On the first two occasions all 400 images were assessed qualitatively and given a simple pass/fail score. On the third and fourth occasions, five images from each of the 20 sets were scored objectively for five criteria by each of the three raters, with a cut-off applied to the scores generated. The reliability of these image assessment techniques was compared statistically. RESULTS: Through quantitative assessment, 84% of images were judged in the same manner by three raters on two separate occasions and in 94% of cases five of these six ratings drew the same conclusion. Rates of intrarater and inter-rater agreement were significantly better using quantitative rather than qualitative techniques. CONCLUSIONS: This study has shown that clearly defined assessment criteria together with a quantitative scoring method improve the reliability of expert peer review. The quantitative method is recommended as the basis for future nasal bone image audit.

Construction of modern Australian first trimester ultrasound dating and growth charts.

Accurate pregnancy dating is vital to obstetric management. However, first trimester fetal charts commonly used in Australia rely on data reported more than three decades ago. This study reports first trimester dating and growth charts for crown-rump length between 5 and 14 weeks of gestation and biparietal diameter between 9 and 14 weeks of gestation on an Australia population using modern real-time ultrasound equipment. All consenting eligible women attending a large Sydney clinic for first trimester ultrasound between March 2005 and December 2006 were recruited. Measurements were carried out to Australasian Society for Ultrasound in Medicine standard protocols. Statistical analyses were undertaken using polynomial regression models and thorough diagnostic checks made. Overall 396 eligible women consented to the study, with 268 between 9 and 14 weeks of gestation. The average participant age was 34 years (range 22-45 years), 371 and all yielded valid biometry measurements. Equations, means and 90% reference intervals for crown-rump length measurements and biparietal diameter measurements were derived using polynomial regression models. Thorough residual and diagnostic checks were made. Once validated by others, we believe they will warrant consideration for use by Australasian Society for Ultrasound in Medicine.

Which bank? A guardian model for regulation of embryonic stem cell research in Australia.

In late 2005 the Legislation Review: Prohibition of Human Cloning Act 2002 (Cth) and the Research Involving Human Embryos Act 2002 (Cth) recommended the establishment of an Australian stem cell bank. This article aims to address a lack of discussion of issues surrounding stem cell banking by suggesting possible answers to the questions of whether Australia should establish a stem cell bank and what its underlying philosophy and functions should be. Answers are developed through an analysis of regulatory, scientific and intellectual property issues relating to embryonic stem cell research in the United Kingdom, United States and Australia. This includes a detailed analysis of the United Kingdom Stem Cell Bank. It is argued that a "guardian" model stem cell bank should be established in Australia. This bank would aim to promote the maximum public benefit from human embryonic stem cell research by providing careful regulatory oversight and addressing ethical issues, while also facilitating research by addressing practical scientific concerns and intellectual property issues.

The Nudix hydrolase superfamily.

Nudix hydrolases are found in all classes of organism and hydrolyse a wide range of organic pyrophosphates, including nucleoside di- and triphosphates, dinucleoside and diphosphoinositol polyphosphates, nucleotide sugars and RNA caps, with varying degrees of substrate specificity. Some superfamily members, such as Escherichia coli MicrotT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In prokaryotes and simple eukaryo tes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Mammals have around 24 Nudix genes, several of which encode more than one variant. This review integrates the sizeable recent literature on these proteins with information from global functional genomic studies to provide some insights into the possible roles of different superfamily members in cellular metabolism and homeostasis and to stimulate discussion and further research into this ubiquitous protein family.

Synthesis of dinucleoside tetraphosphates in transfected cells by a firefly luciferase reporter gene.

The firefly luciferase gene is widely used as a reporter gene and its expression is generally considered to be non-toxic. In addition to its light-producing reaction, luciferase can synthesise dinucleoside polyphosphates, intracellular signalling molecules, in vitro. Here we show that COS-7 cells transfected with a luciferase expression vector accumulate up to 0.5 mM adenine-containing dinucleoside tetraphosphates (Ap4N) during the 24 h following luciferin addition. The optimal external concentration of luciferin was 0.4-0.6 mM. In agreement with its poor ability to synthesise adenine-containing dinucleoside triphosphates in vitro, the level of these compounds did not increase after transfection. Consequently, the results of experiments involving luciferase-mediated light production by live cells should now be viewed in the light of the possible effects of an increased intracellular Ap4N concentration on the properties of the system under investigation. This observation also points to a useful non-invasive procedure for the specific enhancement of intracellular Ap4N for studies directed at understanding the functions of these compounds.

Cloning, characterisation and crystallisation of a diadenosine 5',5"'-P(1),P(4)-tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans.

Asymmetrically cleaving diadenosine 5',5"'-P(1),P(4)-tetraphosphate (Ap4A) hydrolase activity has been detected in extracts of adult Caenorhabditis elegans and the corresponding cDNA amplified and expressed in Escherichia coli. As expected, sequence analysis shows the enzyme to be a member of the Nudix hydrolase family. The purified recombinant enzyme behaves as a typical animal Ap4A hydrolase. It hydrolyses Ap4A with a K(m) of 7 microM and k(cat) of 27 s(-1) producing AMP and ATP as products. It is also active towards other adenosine and diadenosine polyphosphates with four or more phosphate groups, but not diadenosine triphosphate, always generating ATP as one of the products. It is inhibited non-competitively by fluoride (K(i)=25 microM) and competitively by adenosine 5'-tetraphosphate with Ap4A as substrate (K(i)=10 nM). Crystals of diffraction quality with the morphology of rectangular plates were readily obtained and preliminary data collected. These crystals diffract to a minimum d-spacing of 2 A and belong to either space group C222 or C222(1). Phylogenetic analysis of known and putative Ap4A hydrolases of the Nudix family suggests that they fall into two groups comprising plant and Proteobacterial enzymes on the one hand and animal and archaeal enzymes on the other. Complete structural determination of the C. elegans Ap4A hydrolase will help determine the basis of this grouping.

Similarities not differences: an exploration of the impact of change upon a group of nursing lecturers within a university setting.

The concepts of collaboration and partnership currently have extensive impact upon health care providers and higher education institutions. One of the challenges is to develop networks which will foster partnerships able to react, and contribute, to an ever-evolving educational culture. These themes are illustrated by using the example of one school of nursing and midwifery, and the collective experience of a number of its academic staff. By focusing on distinct features of collaboration (strategic planning, origins of change, group dynamics and building a community), the authors seek to explore the impact of an educational culture in an attempt to provide meaning to their recent experiences. In so doing, group identity is explored and the prospect for creating partnerships across disciplines ('similarities rather than differences') is considered.