Obstetrics and Gynaecology - Research Publications
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ItemMolecular and clinical predictors of improvement in progression-free survival with maintenance PARP inhibitor therapy in women with platinum-sensitive, recurrent ovarian cancer: A meta-analysis(WILEY, 2021-07-15)BACKGROUND: The authors performed a meta-analysis to better quantify the benefit of maintenance poly(ADP-ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum-sensitive, recurrent, high-grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild-type BRCA but homologous recombinant-deficient (HRD), homologous recombinant-proficient (HRP), and baseline clinical prognostic characteristics. METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression-free survival were pooled across trials using the inverse variance weighted method. RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23-0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17-0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12-0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild-type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31-0.56); and, in those who had wild-type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49-0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab. CONCLUSIONS: In platinum-sensitive, recurrent, high-grade ovarian cancer, maintenance PARPi improves progression-free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy.
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ItemNo Preview AvailableAboriginal children's health, playgroup participation and early learning outcomes in two remote Northern Territory communities(SAGE Publications, 2021-03-09)Objectives: This study aimed to explore the impact of early health risks on young Aboriginal children’s attendance in playgroups and their early learning outcomes. Design: The study used a cross-sectional design to identify associations between children’s early health characteristics, their attendance at a Families as First Teachers (FaFT) playgroup and their early learning outcomes. Setting: A total of 128 Aboriginal children from two remote Northern Territory (NT) communities attending FaFT playgroups participated in the study. Method: Health data were coded as risk factors and associated with children’s attendance and learning outcome data. Results: Children in the cohort experienced relatively high rates of health risks: ear infections (otitis media, 57%), anaemia (37%), skin infections (28%), low birthweight (22%), low weight for age (19%) and a high proportion were born to teenage mothers (26%). However, these rates were lower than previously recorded rates for Aboriginal children in remote NT communities. Despite the presence of multiple health risks, low weight for age was the only risk factor found to be negatively associated with children’s learning outcomes (language skills) and only two health risks (teenage motherhood and lower child haemoglobin levels) were negatively associated with children’s attendance at playgroup. Most children (65%) experienced one or two health risks during the study and no significant associations were found between the number of health risks experienced and children’s attendance or learning outcomes. Conclusion: The study highlights the importance of culturally responsive, evidence-based and integrated health and education programmes within remote Aboriginal Australian communities as a means to mitigate risks to poor learning and development outcomes.
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ItemNo Preview AvailableParent Mastery of Conversational Reading at Playgroup in Two Remote Northern Territory Communities(SPRINGER, 2021-01-21)This paper explores strategies that support Aboriginal parents’ mastery of evidence-based early learning strategies, and their impact on young Aboriginal children’s learning outcomes. The three-year study followed 32 parent-child dyads attending Families as First Teachers (FaFT) playgroups in two remote Northern Territory communities in 2015–2017. Trained FaFT staff provided parents with coaching in the use of Conversational Reading—an evidence-based shared reading strategy in first language—at FaFT. The study examined patterns of parent mastery across the three-year study period, the relationship between levels of parent-child participation at FaFT (program dosage) and parent mastery, and the impact of parent mastery of Conversational Reading on young Aboriginal children’s language and learning outcomes. By including measures of parent-child participation and parent mastery of key program strategies at three time points, the study also provides a picture of the fidelity of program implementation across the study period. The findings indicate that parents’ mastery of strategies (and thus the fidelity of program implementation) increased over time in line with the program dosage parents received. Higher levels of parent-child participation at FaFT and parent mastery of strategies at the end of the program were positively associated with children’s language and learning outcomes. This study demonstrates that the provision of coaching at playgroup is an effective way to build parent capacity in the implementation of evidence-based early learning strategies, and that supporting parent mastery of teaching strategies has the potential to improve the learning outcomes of young children in remote Aboriginal communities.
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ItemNo Preview AvailableDeveloping and Validating a Tool to Assess Young Children's Early Literacy Engagement(SAGE PUBLICATIONS LTD, 2021-03-31)There is growing recognition that literacy learning takes place in the years prior to formal schooling and that young children develop literacy-like behaviours through exposure to interactions in shared contexts in which literacy is a component. Despite this, there are few assessments that measure the very early literacy skills that children develop before 36 months of age. This article reports on the design and validation of a new instrument – the Early Literacy Engagement Assessment (ELEA). This tool was developed to provide insights into the impact of Conversational Reading, a key pedagogical strategy implemented at Families as First Teachers playgroups, on young children’s early receptive and expressive vocabulary and literacy skills. The instrument was trialled with 104 children living in locations across Melbourne, Victoria, and 39 Aboriginal children living in remote communities in the Northern Territory. The trial process was undertaken in two phases: (1) a technical assessment to test item consistency, characteristics and placement and (2) concurrent validity testing against items from the Clinical Evaluation of Language Fundamentals Preschool-2 tool. The findings from the trial and validation process indicate that overall the ELEA discriminates well between children of high and low ability, and it is a useful tool in the authentic assessment of expressive and receptive vocabulary skills in young children.
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ItemODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.(Springer Science and Business Media LLC, 2021-01-04)BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.
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ItemMismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer(WILEY, 2021-12-07)Endometrial cancer is common, and a subset recurs and requires additional treatment. Some of these are recognized as being susceptible to immune therapies and are said to have mismatch repair deficiency (dMMR). However, this clinical trial highlights which cases are more likely to respond well: those containing mutations in genes known as Lynch genes and also some with mutations in POLE/POLD1 ("ultra-hypermutation" genes). In contrast, the majority of dMMR endometrial cancers have silencing or DNA methylation of one of these genes, MLH1, and do not seem to be as responsive to single-agent immune therapy. The availability of combination therapies may be important to consider for these women.
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ItemPrevalence of Mycoplasma genitalium fluoroquinolone-resistance markers, and dual- class- resistance markers, in asymptomatic men who have sex with men(MICROBIOLOGY SOC, 2021-01-01)Introduction. Failure of fluoroquinolones, the principal treatment option for macrolide-resistant Mycoplasma genitalium infections, has recently emerged. This is of particular concern for men who have sex with men (MSM), who have high proportions of macrolide-resistant M. genitalium infections. Treatment failure with moxifloxacin is likely the result of single nucleotide polymorphisms (SNPs) in parC, whilst concurrent gyrA mutations may play a role.Gap Statement. The levels of fluoroquinolone resistance and dual-class (i.e. macrolide and fluoroquinolone) resistance in M. genitalium among asymptomatic MSM is unknown.Aim. To (i) determine the proportion of fluoroquinolone resistance and dual-class resistance in M. genitalium infections among asymptomatic MSM, (ii) explore any clinical and behavioural associations with fluoroquinolone resistance, and (iii) determine the distribution of antibiotic resistance among M. genitalium mgpB sequence types (STs).Methodology. M. genitalium positive samples (N=94) were obtained from 1001 asymptomatic MSM enrolled in a study at Melbourne Sexual Health Centre (Carlton, Australia) between August 2016 and September 2017. Sanger sequencing was performed to determine the proportion of M. genitalium infections with SNPs in parC that have previously been associated with failure of moxifloxacin (corresponding to amino changes S83I, D83R, D87Y and D87N) and in gyrA (corresponding to amino acid changes M95I, D99N, D99Y and D99G). Associations between clinical/behavioural factors and parC SNPs were examined. Strain typing was performed by sequencing a portion of the mgpB gene.Results. The proportion of MSM with infections harbouring parC and gyrA SNPs was 13.0 % [95 % confidence interval (CI): 6.8-23.2 %] and 4.7 % (95 % CI: 1.1-13.4 %), respectively; dual-class resistance was 13.0 %. No significant clinical/behavioural associations were found. Antibiotic resistance was not restricted to specific mgpB STs.Conclusion. One in eight (13 %) of asymptomatic MSM with M. genitalium had an infection with dual-class-resistance mutations. Typing by mgpB sequence suggested fluoroquinolone resistance is arising from independent mutation events. This study illustrates that asymptomatic MSM may act as a reservoir for antibiotic-resistant M. genitalium.
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ItemEpidemiology of pregnant patients with major trauma in Victoria(WILEY, 2021-06-23)OBJECTIVE: Trauma is one of the most common contributors to maternal and foetal morbidity and mortality. The aim of the present study was to describe the characteristics and outcomes of major trauma in pregnant patients using a population-based registry. METHODS: Registry-based study using data from the Victorian State Trauma Registry (VSTR), a population-based database of all hospitalised major trauma (death due to injury, Injury Severity Score [ISS] ≥12, admission to an intensive care unit [ICU] for more than 24 h and requiring mechanical ventilation for at least part of their ICU stay or urgent surgery) in Victoria, Australia, from 1 July 2007 to 30 June 2019. Pregnant patients with major trauma were identified on the VSTR. We summarised patient data using descriptive statistics. RESULTS: Over the 12-year study period, there were 63 pregnant major trauma patients. Fifty-two (82.5%) patients sustained injuries resulting from road transport collisions. The maternal survival rate was 98.4% and the foetal survival rate was 88.9%. Thoracic injury was the most common injury (25/63), followed by abdominal injury (23/63). Eighty-six percent of the third trimester patients (19/22) were transported directly to a major trauma service with capacity for definitive care of the pregnancy. CONCLUSION: The present study demonstrated road transport injury was the most common mechanism of injury and both maternal survival rates and foetal survival rates were high. This information is essential for trauma care system planning and public health initiatives to improve the clinical management and outcomes of pregnant women with major trauma.
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ItemPrimary HPV cervical screening: Clinical audit of outcomes of women seen at a tertiary referral centre for colposcopy in Australia(WILEY, 2021-05-07)BACKGROUND: Primary human papillomavirus (HPV) screening was introduced in Australia in December 2017. AIMS: Outcomes for women after positive HPV in their cervical screening test (CST). MATERIALS AND METHODS: A retrospective observational study of 4458 women seen at the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020. RESULTS: HPV16/18 was positive (considered higher-risk CST) in 42.2% of women in the study, 16.6% with reflex possible with high-grade squamous intraepithelial lesions (pHSIL) or worse and 54.9% with normal cytology. There were 24.8% of women with positive HPV16/18 who had histological confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+), 10.3% CIN2+ (including six cancers) among women with reflex negative cytology and 87.7% CIN2+ among women with reflex HSIL cytology. In women with positive HPV (not 16/18), CIN2+ was found in 60.2% with reflex pHSIL or worse cytology (higher risk) and 10.2% with reflex low-grade SIL (LSIL) or normal cytology (intermediate risk). Median waiting time to colposcopy with the intermediate-risk group went up to 181 days. Our colposcopists were able to achieve a positive predictive value (PPV) for CIN2+ of 69.9%, higher than 57.8% PPV in the National Cervical Screening Program (NCSP) 2020 monitoring report. Women with type 3 transformation zone on colposcopy could be followed up with CST if no HSIL was suspected on screening or at colposcopy as their risk of CIN2+ was only 2.5%. CONCLUSIONS: Our findings support direct referral to colposcopy for women with higher-risk CST, with all cancers confined to this group. The NCSP recommendation to refer for colposcopy only after three intermediate-risk CST will need monitoring with the LSIL triage group.
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ItemChanged ophthalmic workload following introduction of digital retinal photography for retinopathy of prematurity screening(WILEY, 2021-04-29)BACKGROUND: ROP screening is vital in care of premature infants but is considered burdensome, difficult and time consuming for ophthalmologists. This study assessed the reduction in workload following the introduction of nurse-led WFDRI to a large neonatal nursery. METHODS: We report a retrospective audit of 628 infants screened for ROP in the years 2010, 2013 and 2019 at the Royal Women's Hospital, Victoria. The last complete year of screening for ROP using binocular indirect ophthalmoscopy (BIO) alone (2010) was compared with two subsequent years after the introduction of nurse-led WFDRI. The main outcome measures were the time taken to report and document WFDRI and the time taken to undertake BIO examination of a premature infant and document the results. RESULTS: The ophthalmologist's time taken to conduct BIO, review images and document the results per 100 patient examinations was reduced from 16.7 hours before introduction of WFDRI to 3.7 hours. Similarly, the weekly time spent on this component of ROP screening fell from 2.3 hours per week to 0.8 and 1.0 hours per week after introduction of WFDRI. CONCLUSIONS: The introduction of nurse-led WFDRI has resulted in a dramatic and sustained reduction in ophthalmologist workload involved in ROP screening in a large Australian neonatal nursery. This may result in improved retention of the ophthalmic workforce required to undertake ROP screening.