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1.  Study protocol: Asking QUestions about Alcohol in pregnancy (AQUA): a longitudinal cohort study of fetal effects of low to moderate alcohol exposure 
Despite extensive research, a direct correlation between low to moderate prenatal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorders has been elusive. Conflicting results are attributed to a lack of accurate and detailed data on PAE and incomplete information on contributing factors. The public health effectiveness of policies recommending complete abstinence from alcohol during pregnancy is challenged by the high frequency of unplanned pregnancies, where many women consumed some alcohol prior to pregnancy recognition. There is a need for research evidence emphasizing timing and dosage of PAE and its effects on child development.
Asking QUestions about Alcohol (AQUA) is a longitudinal cohort aiming to clarify the complex effects of low to moderate PAE using specifically developed and tested questions incorporating dose, pattern and timing of exposure. From 2011, 2146 pregnant women completed a questionnaire at 8-18 weeks of pregnancy. Further prenatal data collection took place via a questionnaire at 26-28 weeks and 35 weeks gestation. Extensive information was obtained on a large number of risk factors to assist in understanding the heterogeneous nature of PAE effects. 1571 women (73%) completed all three pregnancy questionnaires. A biobank of DNA from maternal and infant buccal cells, placental biopsies and cord blood mononuclear cells will be used to examine epigenetic state at birth as well as genetic factors in the mother and child. Participants will be followed up at 12 and 24 months after birth to assess child health and measure infant behavioural and sensory difficulties, as well as family environment and parenting styles. A subgroup of the cohort will have 3D facial photography of their child at 12 months and a comprehensive developmental assessment (Bayley Scales of Infant & Toddler Development, Bayley-III) at two years of age.
Using detailed, prospective methods of data collection, the AQUA study will comprehensively examine the effects of low to moderate alcohol consumption throughout pregnancy on child health and development, including the role of key mediators and confounders. These data will ultimately contribute to policy review and development, health professional education and information about alcohol consumption for pregnant women in the future.
PMCID: PMC4168250  PMID: 25187010
Prenatal alcohol exposure; Fetal alcohol spectrum disorders; Cohort studies; Epidemiology; Pregnancy; Child health; Genetics; Epigenetics
2.  Fetal alcohol spectrum disorder: development of consensus referral criteria for specialist diagnostic assessment in Australia 
BMC Pediatrics  2014;14:178.
Fetal alcohol spectrum disorder (FASD) is known to be under-recognised in Australia. The use of standard methods to identify when to refer individuals who may have FASD for specialist assessment could help improve the identification of this disorder. The purpose of this study was to develop referral criteria for use in Australia.
An online survey about FASD screening and diagnosis in Australia, which included 23 statements describing criteria for referral for fetal alcohol syndrome (FAS) and FASD based on published recommendations for referral in North America, was sent to 139 health professionals who had expertise or involvement in FASD screening or diagnosis. Survey findings and published criteria for referral were subsequently reviewed by a panel of 14 investigators at a consensus development workshop where criteria for referral were developed.
Among the 139 health professionals who were sent the survey, 103 (74%) responded, and 90 (65%) responded to the statements on criteria for referral. Over 80% of respondents agreed that referral for specialist evaluation should occur when there is evidence of significant prenatal alcohol exposure, defined as 7 or more standard drinks per week and at least 3 standard drinks on any one day, and more than 70% agreed with 13 of the 16 statements that described criteria for referral other than prenatal alcohol exposure. Workshop participants recommended five independent criteria for referral: confirmed significant prenatal alcohol exposure; microcephaly and confirmed prenatal alcohol exposure; 2 or more significant central nervous system (CNS) abnormalities and confirmed prenatal alcohol exposure; 3 characteristic FAS facial anomalies; and 1 characteristic FAS facial anomaly, growth deficit and 1 or more CNS abnormalities.
Referral criteria recommended for use in Australia are similar to those recommended in North America. There is a need to develop resources to raise awareness of these criteria among health professionals and evaluate their feasibility, acceptability and capacity to improve the identification of FASD in Australia.
PMCID: PMC4123492  PMID: 25005425
Fetal alcohol spectrum disorder; Referral; Consensus
3.  Improving family communication after a new genetic diagnosis: a randomised controlled trial of a genetic counselling intervention 
BMC Medical Genetics  2014;15:33.
Genetic information given to an individual newly diagnosed with a genetic condition is likely to have important health implications for other family members. The task of communicating with these relatives commonly falls to the newly diagnosed person. Talking to relatives about genetic information can be challenging and is influenced by many factors including family dynamics. Research shows that many relatives remain unaware of relevant genetic information and the possible impact on their own health. This study aims to evaluate whether a specific genetic counselling intervention for people newly diagnosed with a genetic condition, implemented over the telephone on a number of occasions, could increase the number of at-risk relatives who make contact with genetics services after a new genetic diagnosis within a family.
This is a prospective, multi-centre randomised controlled trial being conducted at genetics clinics at five public hospitals in Victoria, Australia. A complex genetic counselling intervention has been developed specifically for this trial. Probands (the first person in a family to present with a diagnosis of a genetic condition) are being recruited and randomised into one of two arms – the telephone genetic counselling intervention arm and the control arm receiving usual care. The number of at-risk relatives for each proband will be estimated from a family pedigree collected at the time of diagnosis. The primary outcome will be measured by comparing the proportion of at-risk relatives in each arm of the trial who make subsequent contact with genetics services.
This study, the first randomised controlled trial of a complex genetic counselling intervention to enhance family communication, will provide evidence about how best to assist probands to communicate important new genetic information to their at-risk relatives. This will inform genetic counselling practice in the context of future genomic testing.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000642381.
PMCID: PMC3995589  PMID: 24628824
Genetic counselling; Family communication; Genetic diagnosis; Disclosure
4.  Response of HT29 Colorectal Xenograft Model to Cediranib Assessed with 18F-FMISO PET, Dynamic Contrast-Enhanced and Diffusion-Weighted MRI 
NMR in biomedicine  2012;26(2):151-163.
Cediranib (AZD2171, AstraZeneca, UK) is a small-molecule pan-VEGFR inhibitor. The tumor response to short-term cediranib treatment was studied using dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI at 7 T as well as 18F-fluoromisonidazle (18F-FMISO) PET and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline, then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow up imaging performed 2 hours after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, endothelial cell marker CD31, smooth muscle actin (SMA), intercapillary distance (ICD) and tumor necrosis. DCE-MRI-derived parameters decreased significantly in cediranib-treated tumors relative to pre-treatment values: the muscle-normalized initial area under the gadolinium concentration curve (nIAUC90) by 48% (p = 0.002), the enhancing fraction (EnF) by 43% (p = 0.003) and Ktrans by 57% (p = 0.003), but remained unchanged in controls. No change between pre- and post-treatment tumor apparent diffusion coefficient (ADC) in either cediranib- or vehicle-treated group was observed over the course of this study. 18F-FMISO SUVmean decreased by 33% (p = 0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31-positive vessels (59 per mm2), the fraction of SMA-positive vessels (80 to 87%) and ICD (0.17 mm) were similar in cediranib- and vehicle-treated groups. The fraction of perfused blood vessels in cediranib-treated tumors (81±7%) was lower than in vehicle controls (91±3%, p = 0.02). The necrotic fraction was slightly higher in cediranib-treated rats (34±12%) than in controls (26±10%, p = 0.23). These findings suggest that short-term treatment with cediranib causes a decrease of tumor perfusion/permeability across the tumor cross-section, but changes in vascular morphology, vessel density or tumor cellularity do not manifest at this early time point.
PMCID: PMC3524412  PMID: 22777834
Cediranib; HT29 Tumors; Dynamic Contrast-Enhanced Magnetic Resonance Imaging; Diffusion Magnetic Resonance Imaging; Histological Analysis
5.  Limb lengthening and peripheral nerve function—factors associated with deterioration of conduction 
Acta Orthopaedica  2013;84(6):579-584.
Background and purpose
Limb lengthening is performed for a diverse range of orthopedic problems. A high rate of complications has been reported in these patients, which include motor and sensory loss as a result of nerve damage. We investigated the effect of limb lengthening on peripheral nerve function.
Patients and methods
36 patients underwent electrophysiological testing at 3 points: (1) preoperatively, (2) after application of external fixator/corticotomy but before lengthening, and (3) after lengthening. The limb-length discrepancy was due to a congenital etiology (n = 19), a growth disturbance (n = 9), or a traumatic etiology (n = 8).
2 of the traumatic etiology patients had significant changes evident on electrophysiological testing preoperatively. They both deteriorated further with lengthening. 7 of the 21 patients studied showed deterioration in nerve function after lengthening, but not postoperatively, indicating that this was due to the lengthening process and not to the surgical procedure. All of these patients had a congenital etiology for their leg-length discrepancy.
As detailed electrophysiological tests were carried out before surgery, after surgery but before lengthening, and finally after completion of lengthening, it was possible to distinguish between the effects of the operation and the effects of lengthening on nerve function. The results indicate that the etiology, site (femur or tibia), and nerve (common peroneal or tibial) had a bearing on the risk of nerve injury and that these factors had a far greater effect than the total amount of lengthening.
PMCID: PMC3851673  PMID: 24171677
6.  Recommendations from a consensus development workshop on the diagnosis of fetal alcohol spectrum disorders in Australia 
BMC Pediatrics  2013;13:156.
Fetal alcohol spectrum disorders (FASD) are underdiagnosed in Australia, and health professionals have endorsed the need for national guidelines for diagnosis. The aim of this study was to develop consensus recommendations for the diagnosis of FASD in Australia.
A panel of 13 health professionals, researchers, and consumer and community representatives with relevant expertise attended a 2-day consensus development workshop to review evidence on the screening and diagnosis of FASD obtained from a systematic literature review, a national survey of health professionals and community group discussions. The nominal group technique and facilitated discussion were used to review the evidence on screening and diagnosis, and to develop consensus recommendations for the diagnosis of FASD in Australia.
The use of population-based screening for FASD was not recommended. However, there was consensus support for the development of standard criteria for referral for specialist diagnostic assessment. Participants developed consensus recommendations for diagnostic categories, criteria and assessment methods, based on the adaption of elements from both the University of Washington 4-Digit Diagnostic Code and the Canadian guidelines for FASD diagnosis. Panel members also recommended the development of resources to: facilitate consistency in referral and diagnostic practices, including comprehensive clinical guidelines and assessment instruments; and to support individuals undergoing assessment and their parents or carers.
These consensus recommendations provide a foundation for the development of guidelines and other resources to promote consistency in the diagnosis of FASD in Australia. Guidelines for diagnosis will require review and evaluation in the Australian context prior to national implementation as well as periodic review to incorporate new knowledge.
PMCID: PMC3849849  PMID: 24083778
Fetal alcohol spectrum disorder; Diagnosis; Consensus
7.  An exploration of genetic health professionals' experience with direct-to-consumer genetic testing in their clinical practice 
Direct-to-consumer genetic testing (DTC-GT) allows individuals to obtain genetic tests directly from companies without necessarily involving health professionals. This study explores genetic health professionals' opinions of health-related DTC-GT and the reported frequency of individuals presenting to clinical genetics services after undertaking testing. Genetic counsellors and clinical geneticists, members of the Human Genetics Society of Australasia, completed an online survey in mid 2011. The 130 genetic counsellors (estimated response fraction=43%) and 38 clinical geneticists (estimated response fraction=46%) had mixed opinions regarding DTC-GT, with only 7% confident in accurately interpreting and explaining DTC-GT results. Nineteen respondents (11%) reported one or more client(s) referred to them after undertaking DTC-GT. Descriptions of 25 clients were extracted from responses, and respondents reported that all clients were concerned for the health of either themselves or family members. Most clients presented to genetic clinics specifically as a result of their DTC-GT (96%) and were self or GP referred (92%). Respondents perceived that their clients typically undertook DTC-GT because they wanted to identify monogenic conditions, including carrier testing and/or know their susceptibility or predisposition for complex conditions (88%). The majority of clients needed help interpreting DTC-GT results (80%), however in general were not questioning the validity of their DTC-GT results (92%) nor seeking further genetic testing (84%). Currently, DTC-GT is not a major reason for referral to clinical genetics services in Australia and New Zealand and the majority of genetic health professionals lack confidence in being able to accurately interpret and explain DTC-GT results.
PMCID: PMC3400727  PMID: 22317975
direct-to-consumer; health professional; genetic testing; genetic counsellor; attitudes
8.  Involving consumers and the community in the development of a diagnostic instrument for fetal alcohol spectrum disorders in Australia 
Australia’s commitment to consumer and community participation in health and medical research has grown over the past decade. Participatory research models of engagement are the most empowering for consumers.
As part of a project to develop a diagnostic instrument for fetal alcohol spectrum disorders (FASD) in Australia (FASD Project), the Australian FASD Collaboration (Collaboration), including a consumer advocate and two consumer representatives, was established. On completion of the FASD Project an on-line survey of Collaboration members was conducted to assess their views on consumer involvement. Women in the community were also invited to participate in Community Conversations to discuss real life situations regarding communications with health professionals about alcohol and pregnancy. Community Conversation feedback was analysed qualitatively and attendees were surveyed about their views of the Community Conversation process.
The on-line survey was completed by 12 members of the Collaboration (71%). Consumer and community participation was considered important and essential, worked well, and was integral to the success of the project. The 32 women attending the Community Conversations generated 500 statements that made reference to prevention, how information and messages are delivered, and appropriate support for women. Nearly all the attendees at the Community Conversations (93%) believed that they had an opportunity to put forward their ideas and 96% viewed the Community Conversations as a positive experience.
The successful involvement of consumers and the community in the FASD Project can be attributed to active consumer and community participation, which included continued involvement throughout the project, funding of participation activities, and an understanding of the various contributions by the Collaboration members.
PMCID: PMC3733745  PMID: 23898969
Consumer participation; Fetal alcohol spectrum disorder; Research
9.  The attitudes of people with sarcoma and their family towards genomics and incidental information arising from genetic research 
The study aimed to examine attitudes of individuals diagnosed with sarcoma and their family members towards genetics, genomic research and incidental information arising as a result of participating in genetic research.
A questionnaire was administered to 1200 individuals from the International Sarcoma Kindred Study (ISKS). Respondents were divided into three groups: individuals affected with sarcoma (probands), their spouses and family members.
Approximately half of all research participants felt positively towards new discoveries in human genetics. Overall, more were positive in their attitudes towards genetic testing for inherited conditions (60%) but family members were less so. Older participants reported more highly positive attitudes more often than younger participants. Males were less likely to feel positive about new genetic discoveries and more likely to believe they could modify genetic risk by altering lifestyle factors. Almost all ISKS participants believed participants would like to be given ancillary information arising as a result of participating in genetic research.
The only difference between the study groups was the decreased likelihood of family members being highly positive about genetic testing. This may be important if predictive testing for sarcoma becomes available. Generally ISKS research participants supported the notion of returning incidental genetic information to research participants.
PMCID: PMC3751730  PMID: 23898988
10.  Health and development of ART conceived young adults: a study protocol for the follow-up of a cohort 
Reproductive Health  2013;10:15.
Use of assisted reproductive technologies (ART) continues to increase, yet little is known of the longer term health of ART conceived offspring. There are some adverse birth outcomes associated with ART conception but the subsequent developmental trajectory is unclear. Undertaking research in this area is challenging due the sensitive nature of the topic and the time elapsed since birth of the ART conceived young adults. The aim of this report is to describe a research protocol, including design and ethical considerations, used to compare the physical and psychosocial health outcomes of ART conceived young adults aged 18-28 years, with their spontaneously conceived peers.
This is a retrospective cohort study of mothers who conceived with ART in Victoria, Australia and gave birth to a singleton child between 1982 and 1992. A current address for each mother was located and a letter of invitation to participate in the study was sent by registered mail. Participation involved completing a telephone interview about her young adult offspring’s health and development from birth to the present. Mothers were also asked for consent for the researcher to contact their son/daughter to invite them to complete a structured telephone interview about their physical and psychosocial health. A comparison group of women living in Victoria, Australia, who had given birth to a spontaneously conceived singleton child between 1982 and 1992 was recruited from the general population using random digit dialling. Data were collected from them and their young adult offspring in the same way. Regression analyses were used to evaluate relationships between ART exposure and health status, including birth defects, chronic health conditions, hospital admissions, growth and sexual development. Psychosocial wellbeing, parental relationships and educational achievement were also assessed. Factors associated with the age of disclosure of ART conception were explored with the ART group only.
The conceptualization and development of this large project posed a number of methodological, logistical and ethical challenges which we were able to overcome. The lessons we learnt can assist others who are investigating the long-term health implications for ART conceived offspring.
PMCID: PMC3605346  PMID: 23497379
Assisted reproductive technology; In vitro fertilization; Health; Development; Psychological adjustment; Follow-up
11.  A modified Delphi study of screening for fetal alcohol spectrum disorders in Australia 
BMC Pediatrics  2013;13:13.
There is little reliable information on the prevalence of fetal alcohol spectrum disorders (FASD) in Australia and no coordinated national approach to facilitate case detection. The aim of this study was to identify health professionals’ perceptions about screening for FASD in Australia.
A modified Delphi process was used to assess perceptions of the need for, and the process of, screening for FASD in Australia. We recruited a panel of 130 Australian health professionals with experience or expertise in FASD screening or diagnosis. A systematic review of the literature was used to develop Likert statements on screening coverage, components and assessment methods which were administered using an online survey over two survey rounds.
Of the panel members surveyed, 95 (73%) responded to the questions on screening in the first survey round and, of these, 81 (85%) responded to the second round. Following two rounds there was consensus agreement on the need for targeted screening at birth (76%) and in childhood (84%). Participants did not reach consensus agreement on the need for universal screening at birth (55%) or in childhood (40%). Support for targeted screening was linked to perceived constraints on service provision and the need to examine the performance, costs and benefits of screening.
For targeted screening of high risk groups, we found highest agreement for siblings of known cases of FASD (96%) and children of mothers attending alcohol treatment services (93%). Participants agreed that screening for FASD primarily requires assessment of prenatal alcohol exposure at birth (86%) and in childhood (88%), and that a checklist is needed to identify the components of screening and criteria for referral at birth (84%) and in childhood (90%).
There is an agreed need for targeted but not universal screening for FASD in Australia, and sufficient consensus among health professionals to warrant development and evaluation of standardised methods for targeted screening and referral in the Australian context. Participants emphasised the need for locally-appropriate, evidence-based approaches to facilitate case detection, and the importance of ensuring that screening and referral programs are supported by adequate diagnostic and management capacity.
PMCID: PMC3583688  PMID: 23347677
12.  A Quantitative Comparison of the Influence of Individual versus Population-Derived Vascular Input Functions on DCE-MRI in Small Animals 
For quantitative analysis of DCE-MRI data, the time course of the concentration of the contrast agent in the blood plasma, or vascular input function (VIF), is required. We compared pharmacokinetic parameters derived using individual and population-based VIFs in mice for two different contrast agents, Gd-DTPA and P846. Eleven mice with subcutaneous 4T1 breast cancer xenografts were imaged at 7T. A pre-contrast T1 map was acquired along with dynamic T1-weighted gradient echo images before, during, and after a bolus injection of contrast agent delivered via a syringe pump. Each animal's individual VIF (VIFind) and derived population-averaged VIF (VIFpop) were used to extract parameters from the signal-time curves of tumor tissue at both the region of interest (ROI) and voxel level. The results indicate that for both contrast agents, Ktrans values estimated using VIFpop have a high correlation (CCC > 0.85) with Ktrans values estimated using VIFind on both an ROI and voxel level. This work supports the validity of using of a population-based VIF with a stringent injection protocol in pre-clinical DCE-MRI studies.
PMCID: PMC3179805  PMID: 21688316
DCE-MRI; vascular input function; tumor; pharmacokinetics; mice
13.  MRI measurements of vessel calibre in tumour xenografts: Comparison with vascular corrosion casting 
Microvascular Research  2012;84(3):323-329.
Vessel size index (Rv, μm) has been proposed as a quantitative magnetic resonance imaging (MRI) derived imaging biomarker in oncology, for the non-invasive assessment of tumour blood vessel architecture and vascular targeted therapies. Appropriate pre-clinical evaluation of Rv in animal tumour models will improve the interpretation and guide the introduction of the biomarker into clinical studies. The objective of this study was to compare Rv measured in vivo with vessel size measurements from high-resolution X-ray computed tomography (μCT) of vascular corrosion casts measured post mortem from the same tumours, with and without vascular targeted therapy. MRI measurements were first acquired from subcutaneous SW1222 colorectal xenografts in mice following treatment with 0 (n = 6), 30 (n = 6) or 200 mg/kg (n = 3) of the vascular disrupting agent ZD6126. The mice were then immediately infused with a low viscosity resin and, following polymerisation and maceration of surrounding tissues, the resulting tumour vascular casts were dissected and subsequently imaged using an optimised μCT imaging approach. Vessel diameters were not measurable by μCT in the 200 mg/kg group as the high dose of ZD6126 precluded delivery of the resin to the tumour vascular bed. The mean Rv for the three treatment groups was 24, 23 and 23.5 μm respectively; the corresponding μCT measurements from corrosion casts from the 0 and 30 mg/kg cohorts were 25 and 28 μm. The strong association between the in vivo MRI and post mortem μCT values supports the use of Rv as an imaging biomarker in clinical trials of investigational vascular targeted therapies.
► Non-invasive quantitation of vessel calibre in tumour xenografts in vivo ► Assessment of tumour vessel calibre response to a vascular disrupting agent ► Generation of vascular corrosion casts from the same tumours imaged by MRI ► Quantitation of vessel calibre from corrosion casts by microCT ► Excellent agreement between the in vivo MRI and post mortem microCT vessel calibres
PMCID: PMC3657196  PMID: 22921880
14.  Consensus diagnostic criteria for fetal alcohol spectrum disorders in Australia: a modified Delphi study 
BMJ Open  2012;2(5):e001918.
To evaluate health professionals' agreement with components of published diagnostic criteria for fetal alcohol spectrum disorders (FASD) in order to guide the development of standard diagnostic guidelines for Australia.
A modified Delphi process was used to assess agreement among health professionals with expertise or experience in FASD screening or diagnosis. An online survey, which included 36 Likert statements on diagnostic methods, was administered over two survey rounds. For fetal alcohol syndrome (FAS), health professionals were presented with concepts from the Institute of Medicine (IOM), University of Washington (UW), Centers for Disease Control (CDC), revised IOM and Canadian diagnostic criteria. For partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND), and alcohol-related birth defects (ARBD), concepts based on the IOM and the Canadian diagnostic criteria were compared.
130 Australian and 9 international health professionals.
Of 139 health professionals invited to complete the survey, 103 (74.1%) responded, and 74 (53.2%) completed one or more questions on diagnostic criteria. We found consensus agreement among participants on the diagnostic criteria for FAS, with the UW criteria most commonly endorsed when compared with all other published criteria for FAS. When health professionals were presented with concepts based on the Canadian and IOM diagnostic criteria, we found consensus agreement but no clear preference for either the Canadian or IOM criteria for the diagnosis of PFAS, and no consensus agreement on diagnostic criteria for ARND. We also found no consensus on the IOM diagnostic criteria for ARBD.
Participants indicated clear support for use of the UW diagnostic criteria for FAS in Australia. These findings should be used to develop guidelines to facilitate improved awareness of, and address identified gaps in the infrastructure for, FASD diagnosis in Australia.
PMCID: PMC3488737  PMID: 23100447
15.  Beware the painful nerve palsy; neurostenalgia, a diagnosis not to be missed 
We present a case of painful radial nerve palsy following application of a humeral lengthening frame. At re-operation, the radial nerve was found to be compressed against a distal pin. This was re-sited providing immediate pain relief and a gradual resolution of the radial nerve palsy. Pain in association with a nerve palsy should alert the clinician to the possibility of nerve compression that may benefit from urgent decompression.
PMCID: PMC3482437  PMID: 23054745
Neurostenalgia; Limb lengthening; Decompression; Radial nerve
16.  Health professionals’ perceptions about the adoption of existing guidelines for the diagnosis of fetal alcohol spectrum disorders in Australia 
BMC Pediatrics  2012;12:69.
Despite the availability of five guidelines for the diagnosis of fetal alcohol spectrum disorders (FASD), there is no national endorsement for their use in diagnosis in Australia. In this study we aimed to describe health professionals’ perceptions about the adoption of existing guidelines for the diagnosis of FASD in Australia and identify implications for the development of national guidelines.
We surveyed 130 Australian and 9 international health professionals with expertise or involvement in the screening or diagnosis of FASD. An online questionnaire was used to evaluate participants’ familiarity with and use of five existing diagnostic guidelines for FASD, and to assess their perceptions about the adoption of these guidelines in Australia.
Of the 139 participants surveyed, 84 Australian and 8 international health professionals (66.2%) responded to the questions on existing diagnostic guidelines. Participants most frequently reported using the University of Washington 4-Digit Diagnostic Code (27.2%) and the Canadian guidelines (18.5%) for diagnosis. These two guidelines were also most frequently recommended for adoption in Australia: 32.5% of the 40 participants who were familiar with the University of Washington 4-Digit Diagnostic Code recommended adoption of this guideline in Australia, and 30.8% of the 26 participants who were familiar with the Canadian guidelines recommended adoption of this guideline in Australia. However, for the majority of guidelines examined, most participants were unsure whether they should be adopted in Australia. The adoption of existing guidelines in Australia was perceived to be limited by: their lack of evidence base, including the appropriateness of established reference standards for the Australian population; their complexity; the need for training and support to use the guidelines; and the lack of an interdisciplinary and interagency model to support service delivery in Australia.
Participants indicated some support for the adoption of the University of Washington or Canadian guidelines for FASD diagnosis; however, concerns were raised about the adoption of these diagnostic guidelines in their current form. Australian diagnostic guidelines will require evaluation to establish their validity in the Australian context, and a comprehensive implementation model is needed to facilitate improved diagnostic capacity in Australia.
PMCID: PMC3416706  PMID: 22697051
17.  Comparisons of the Efficacy of a Jak1/2 Inhibitor (AZD1480) with a VEGF Signaling Inhibitor (Cediranib) and Sham Treatments in Mouse Tumors Using DCE-MRI, DW-MRI, and Histology1 
Neoplasia (New York, N.Y.)  2012;14(1):54-64.
Jak1/2 inhibition suppresses STAT3 phosphorylation that is characteristic of many cancers. Activated STAT3 promotes the transcription of factors that enhance tumor growth, survival, and angiogenesis. AZD1480 is a novel small molecule inhibitor of Jak1/2, which is a key mediator of STAT3 activation. This study examined the use of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) biomarkers in assessing early tumor response to AZD1480. Cediranib (AZD2171), a vascular endothelial growth factor signaling inhibitor, was used as a comparator. Thirty mice were injected with Calu-6 lung cancer cells and randomized into the three treatment groups: AZD1480, cediranib, and sham. DW-MRI and DCE-MRI protocols were performed at baseline and at days 3 and 5 after treatment. The percent change from baseline measurements for Ktrans, ADC, and ve were calculated and compared with hematoxylin and eosin (H&E), CD31, cParp, and Ki-67 histology data. Decreases in Ktrans of 29% (P < .05) and 53% (P < .05) were observed at days 3 and 5, respectively, for the cediranib group. No significant changes in Ktrans occurred for the AZD1480 group, but a significant increase in ADC was demonstrated at days 3 (63%, P < .05) and 5 (49%, P < .05). CD31 staining indicated diminished vasculature in the cediranib group, whereas significantly increased cParp staining for apoptotic activity and extracellular space by image analysis of H&E were present in the AZD1480 group. These imaging biomarker changes, and corresponding histopathology, support the use of ADC, but not Ktrans, as a pharmacodynamic biomarker of response to AZD1480 at these time points.
PMCID: PMC3281942  PMID: 22355274
18.  Outcomes for offspring of men having ICSI for male factor infertility 
Asian Journal of Andrology  2011;14(1):116-120.
Since the introduction of intracytoplasmic sperm injection (ICSI) using single sperm isolated from testicular tissue in men with obstructive and non-obstructive azoospermia, or using ejaculated sperm in those with poor semen quality, there have been concerns that this might have adverse effects on the offspring compared to conventional in vitro fertilisation (IVF) and natural conceptions. ICSI is done for reasons other than male factor infertility, and on the whole has not been shown to have any more negative effects than those seen with IVF. There have however, been very few studies of ICSI with a focus on, or large enough numbers to examine, the specific outcomes associated with male factor infertility. From the limited information available in relation to the source of the sperm and aetiology of infertility in the presence of ICSI, there appears to be no increased risk of congenital malformations. There is, however, a small increase in both de novo and inherited chromosome abnormalities. In terms of growth and neurodevelopment, there are very few studies, and so far, no adverse outcomes have been found in young children whose fathers have a sperm defect. The origin of the sperm used in ICSI does not have a major influence on the early life outcomes for the offspring, but transgenerational and epigenetic effects remain unknown. When the male factor infertility is known or thought to be due to a Y-chromosome deletion, this information should be given to the young male offspring at a time that will ensure his own reproductive health and plans are optimized.
PMCID: PMC3735141  PMID: 22157986
congenital malformations; ICSI; male factor infertility; neurodevelopment; offspring outcomes; Y-chromosome deletions
19.  Assessing the risks and benefits of diagnosing genetic conditions with variable phenotypes through population screening: Klinefelter syndrome as an example 
Journal of Community Genetics  2010;1(1):41-46.
Consideration of postnatal population-based genetic screening programs is becoming increasingly common. Assessing the medical and psychosocial impacts of this can be particularly complex for genetic conditions with variable phenotypes, especially when outcomes may be more related to quality of life rather than reducing physical morbidity and mortality. In this article, we present a framework for assessing these impacts, by comparing diagnosis and non-diagnosis at different age points. We use the example of Klinefelter syndrome, a common yet frequently under-diagnosed genetic condition for which interventions are available. This framework can be used to supplement established screening guidelines and inform decision-making.
PMCID: PMC3185979  PMID: 22422359
Klinefelter syndrome; Genetic testing; Genetic screening; 47,XXY
20.  Vitamin D status during Pregnancy and Aspects of Offspring Health 
Nutrients  2010;2(3):389-407.
Low maternal vitamin D levels during pregnancy have been linked to various health outcomes in the offspring, ranging from periconceptional effects to diseases of adult onset. Maternal and infant cord 25(OH)D levels are highly correlated. Here, we review the available evidence for these adverse health effects. Most of the evidence has arisen from observational epidemiological studies, but randomized controlled trials are now underway. The evidence to date supports that women should be monitored and treated for vitamin D deficiency during pregnancy but optimal and upper limit serum 25(OH)D levels during pregnancy are not known.
PMCID: PMC3257641  PMID: 22254029
vitamin D; ultraviolet radiation; sun exposure; pregnancy; offspring health
21.  Exploring general practitioners' experience of informing women about prenatal screening tests for foetal abnormalities: A qualitative focus group study 
Recent developments have made screening tests for foetal abnormalities available earlier in pregnancy and women have a range of testing options accessible to them. It is now recommended that all women, regardless of their age, are provided with information on prenatal screening tests. General Practitioners (GPs) are often the first health professionals a woman consults in pregnancy. As such, GPs are well positioned to inform women of the increasing range of prenatal screening tests available. The aim of this study was to explore GPs experience of informing women of prenatal genetic screening tests for foetal abnormality.
A qualitative study consisting of four focus groups was conducted in metropolitan and rural Victoria, Australia. A discussion guide was used and the audio-taped transcripts were independently coded by two researchers using thematic analysis. Multiple coders and analysts and informant feedback were employed to reduce the potential for researcher bias and increase the validity of the findings.
Six themes were identified and classified as 'intrinsic' if they occurred within the context of the consultation or 'extrinsic' if they consisted of elements that impacted on the GP beyond the scope of the consultation. The three intrinsic themes were the way GPs explained the limitations of screening, the extent to which GPs provided information selectively and the time pressures at play. The three extrinsic factors were GPs' attitudes and values towards screening, the conflict they experienced in offering screening information and the sense of powerlessness within the screening test process and the health care system generally. Extrinsic themes reveal GPs' attitudes and values to screening and to disability, as well as raising questions about the fundamental premise of testing.
The increasing availability and utilisation of screening tests, in particular first trimester tests, has expanded GPs' role in facilitating women's informed decision-making. Recognition of the importance of providing this complex information warrants longer consultations to respond to the time pressures that GPs experience. Understanding the intrinsic and extrinsic factors that impact on GPs may serve to shape educational resources to be more appropriate, relevant and supportive.
PMCID: PMC2442835  PMID: 18507850
22.  Health behaviour modelling for prenatal diagnosis in Australia: a geodemographic framework for health service utilisation and policy development 
Despite the wide availability of prenatal screening and diagnosis, a number of studies have reported no decrease in the rate of babies born with Down syndrome. The objective of this study was to investigate the geodemographic characteristics of women who have prenatal diagnosis in Victoria, Australia, by applying a novel consumer behaviour modelling technique in the analysis of health data.
A descriptive analysis of data on all prenatal diagnostic tests, births (1998 and 2002) and births of babies with Down syndrome (1998 to 2002) was undertaken using a Geographic Information System and socioeconomic lifestyle segmentation classifications.
Most metropolitan women in Victoria have average or above State average levels of uptake of prenatal diagnosis. Inner city women residing in high socioeconomic lifestyle segments who have high rates of prenatal diagnosis spend 20% more on specialist physician's fees when compared to those whose rates are average. Rates of prenatal diagnosis are generally low amongst women in rural Victoria, with the lowest rates observed in farming districts. Reasons for this are likely to be a combination of lack of access to services (remoteness) and individual opportunity (lack of transportation, low levels of support and income). However, there are additional reasons for low uptake rates in farming areas that could not be explained by the behaviour modelling. These may relate to women's attitudes and choices.
A lack of statewide geodemographic consistency in uptake of prenatal diagnosis implies that there is a need to target health professionals and pregnant women in specific areas to ensure there is increased equity of access to services and that all pregnant women can make informed choices that are best for them. Equally as important is appropriate health service provision for families of children with Down syndrome. Our findings show that these potential interventions are particularly relevant in rural areas.
Classifying data to lifestyle segments allowed for practical comparisons of the geodemographic characteristics of women having prenatal diagnosis in Australia at a population level. This methodology may in future be a feasible and cost-effective tool for service planners and policy developers.
PMCID: PMC1574302  PMID: 16945156
23.  Evaluation of a decision aid for prenatal testing of fetal abnormalities: a cluster randomised trial [ISRCTN22532458] 
BMC Public Health  2006;6:96.
By providing information on the relative merits and potential harms of the options available and a framework to clarify preferences, decision aids can improve knowledge and realistic expectations and decrease decisional conflict in individuals facing decisions between alternative forms of action. Decision-making about prenatal testing for fetal abnormalities is often confusing and difficult for women and the effectiveness of decision aids in this field has not been established. This study aims to test whether a decision aid for prenatal testing of fetal abnormalities, when compared to a pamphlet, improves women's informed decision-making and decreases decisional conflict.
A cluster designed randomised controlled trial is being conducted in Victoria, Australia. Fifty General Practitioners (GPs) have been randomised to one of two arms: providing women with either a decision aid or a pamphlet. The two primary outcomes will be measured by comparing the difference in percentages of women identified as making an informed choice and the difference in mean decisional conflict scores between the two groups. Data will be collected from women using questionnaires at 14 weeks and 24 weeks gestation.
The sample size of 159 women in both arms of the trial has been calculated to detect a difference of 18% (50 to 68%) in informed choice between the two groups. The required numbers have been adjusted to accommodate the cluster design, miscarriage and participant lost – to – follow up.
Baseline characteristics of women will be summarised for both arms of the trial. Similarly, characteristics of GPs will be compared between arms.
Differences in the primary outcomes will be analysed using 'intention-to-treat' principles. Appropriate regression techniques will adjust for the effects of clustering and include covariates to adjust for the stratifying variable and major potential confounding factors.
The findings from this trial will make a significant contribution to improving women's experience of prenatal testing and will have application to a variety of maternity care settings. The evaluation of a tailored decision aid will also have implications for pregnancy care providers by identifying whether or not such a resource will support their role in providing prenatal testing information.
PMCID: PMC1479329  PMID: 16611368

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