Obstetrics and Gynaecology - Research Publications

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    Human papillomavirus seroprevalence and seroconversion following baseline detection of nine human papillomavirus types in young women.
    Brown, DR ; Castellsagué, X ; Ferris, D ; Garland, SM ; Huh, W ; Steben, M ; Wheeler, CM ; Saah, A ; Luxembourg, A ; Li, S ; Velicer, C (Elsevier BV, 2022-06)
    BACKGROUND: Estimates of the humoral immune response to incident human papillomavirus (HPV) infections are limited. METHODS: In this post hoc analysis of 3875 women aged 16-23 years from a 4-valent HPV vaccine trial (NCT00092482), HPV seroprevalence on day 1 was measured with a 9-valent HPV (HPV 6/11/16/18/31/33/45/52/58) competitive Luminex immunoassay and compared with cervical/external genital HPV detection by polymerase chain reaction. In the control group, among women who were HPV DNA‒negative on day 1, seroconversion following initial HPV detection was estimated using Kaplan-Meier methods. RESULTS: Type-specific HPV seropositivity among women with no day 1 cervical/external genital HPV detection was 0.6%-3.6%. Women with any 9-valent HPV (9vHPV) cervical/external genital detection (796/3875; 20.5%) had concordant seropositivity ranging from 13.4% (HPV 45) to 38.5% (HPV 6). Among women in the control group who were negative for all HPV types on day 1, seroconversion by month 30 after initial detection ranged from 29% (HPV 45) to 75% (HPV 16). CONCLUSIONS: Humoral immune response to HPV is variable and dynamic, depending on type-specific exposure. This longitudinal analysis provides insight into the relationship between incident infection and seropositivity. CLINICALTRIALS: gov; NCT00092482 https://clinicaltrials.gov/ct2/show/NCT00092482.
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    Identifying preeclampsia-associated genes using a control theory method
    Li, X ; Liu, L ; Whitehead, C ; Li, J ; Thierry, B ; Le, TD ; Winter, M (OXFORD UNIV PRESS, 2022-07-27)
    Preeclampsia is a pregnancy-specific disease that can have serious effects on the health of both mothers and their offspring. Predicting which women will develop preeclampsia in early pregnancy with high accuracy will allow for improved management. The clinical symptoms of preeclampsia are well recognized, however, the precise molecular mechanisms leading to the disorder are poorly understood. This is compounded by the heterogeneous nature of preeclampsia onset, timing and severity. Indeed a multitude of poorly defined causes including genetic components implicates etiologic factors, such as immune maladaptation, placental ischemia and increased oxidative stress. Large datasets generated by microarray and next-generation sequencing have enabled the comprehensive study of preeclampsia at the molecular level. However, computational approaches to simultaneously analyze the preeclampsia transcriptomic and network data and identify clinically relevant information are currently limited. In this paper, we proposed a control theory method to identify potential preeclampsia-associated genes based on both transcriptomic and network data. First, we built a preeclampsia gene regulatory network and analyzed its controllability. We then defined two types of critical preeclampsia-associated genes that play important roles in the constructed preeclampsia-specific network. Benchmarking against differential expression, betweenness centrality and hub analysis we demonstrated that the proposed method may offer novel insights compared with other standard approaches. Next, we investigated subtype specific genes for early and late onset preeclampsia. This control theory approach could contribute to a further understanding of the molecular mechanisms contributing to preeclampsia.
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    A Novel Approach to Enhance the Regenerative Potential of Circulating Endothelial Progenitor Cells in Patients with End-Stage Kidney Disease
    Badawi, A ; Jefferson, OC ; Huuskes, BM ; Ricardo, SD ; Kerr, PG ; Samuel, CS ; Murthi, P (MDPI, 2022-04-01)
    Circulating bone marrow-derived endothelial progenitor cells (EPCs) facilitate vascular repair in several organs including the kidney but are progressively diminished in end-stage kidney disease (ESKD) patients, which correlates with cardiovascular outcomes and related mortality. We thus determined if enhancing the tissue-reparative effects of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) with the vasculogenic effects of recombinant human relaxin (RLX) could promote EPC proliferation and function. CD34+ EPCs were isolated from the blood of healthy and ESKD patients, cultured until late EPCs had formed, then stimulated with BM-MSC-derived condition media (CM; 25%), RLX (1 or 10 ng/mL), or both treatments combined. Whilst RLX alone stimulated EPC proliferation, capillary tube formation and wound healing in vitro, these measures were more rapidly and markedly enhanced by the combined effects of BM-MSC-derived CM and RLX in EPCs derived from both healthy and ESKD patients. These findings have important clinical implications, having identified a novel combination therapy that can restore and enhance EPC number and function in ESKD patients.
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    Suppression of the ABCA1 Cholesterol Transporter Impairs the Growth and Migration of Epithelial Ovarian Cancer.
    Gao, J ; Jung, M ; Williams, RT ; Hui, D ; Russell, AJ ; Naim, AJ ; Kamili, A ; Clifton, M ; Bongers, A ; Mayoh, C ; Ho, G ; Scott, CL ; Jessup, W ; Haber, M ; Norris, MD ; Henderson, MJ ; On Behalf Of Australian Ovarian Cancer Study, (MDPI AG, 2022-04-08)
    BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with over 80% of cases already disseminated at diagnosis and facing a dismal five-year survival rate of 35%. EOC cells often spread to the greater omentum where they take-up cholesterol. Excessive amounts of cholesterol can be cytocidal, suggesting that cholesterol efflux through transporters may be important to maintain homeostasis, and this may explain the observation that high expression of the ATP-binding cassette A1 (ABCA1) cholesterol transporter has been associated with poor outcome in EOC patients. METHODS: ABCA1 expression was silenced in EOC cells to investigate the effect of inhibiting cholesterol efflux on EOC biology through growth and migration assays, three-dimensional spheroid culture and cholesterol quantification. RESULTS: ABCA1 suppression significantly reduced the growth, motility and colony formation of EOC cell lines as well as the size of EOC spheroids, whilst stimulating expression of ABCA1 reversed these effects. In serous EOC cells, ABCA1 suppression induced accumulation of cholesterol. Lowering cholesterol levels using methyl-B-cyclodextrin rescued the effect of ABCA1 suppression, restoring EOC growth. Furthermore, we identified FDA-approved agents that induced cholesterol accumulation and elicited cytocidal effects in EOC cells. CONCLUSIONS: Our data demonstrate the importance of ABCA1 in maintaining cholesterol balance and malignant properties in EOC cells, highlighting its potential as a therapeutic target for this disease.
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    Novel probe-based melting curve assays for the characterization of fluoroquinolone resistance in Mycoplasma genitalium
    Tickner, JA ; Bradshaw, CS ; Murray, GL ; Whiley, DM ; Sweeney, EL (OXFORD UNIV PRESS, 2022-03-30)
    BACKGROUND: Mycoplasma genitalium infection is a sexually transmitted infection that has rapidly become resistant to mainstay treatments. While individualized treatment approaches have been recommended and adopted for macrolides, individualized therapy for fluoroquinolones has not yet been explored, due to a lack of commercial molecular assays and a lack of confidence in specific mutations associated with resistance. In another recent study, we defined a clear role and diagnostic utility in focusing on the absence of resistance mutations to inform microbial cure with fluoroquinolone antimicrobials. METHODS: We developed two proof-of-concept molecular tests that focus on detection of M. genitalium and characterization of WT parC sequences that are strongly linked to fluoroquinolone susceptibility. RESULTS: We screened a total of 227 M. genitalium-positive samples using novel molecular beacon and dual hybridization probe assays. These assays were able to detect M. genitalium and characterize fluoroquinolone susceptibility in 143/227 (63%) samples, based on clear differences in melting peak temperatures. The results of these molecular assays were in 100% agreement with 'gold standard' Sanger sequencing. Additionally, WT parC sequences were readily distinguished from M. genitalium samples harbouring parC mutations of known or suspected clinical significance. The ability of the assays to successfully characterize fluoroquinolone susceptibility and resistance was reduced in low M. genitalium load samples. CONCLUSIONS: These proof-of-concept assays have considerable potential to improve individualized treatment approaches and rationalize tests of cure for M. genitalium infection. The ability to initiate individualized treatment in up to two-thirds of cases will enhance antimicrobial stewardship for this challenging pathogen.
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    Mismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer
    Antill, Y ; Buchanan, DD ; Scott, CL (WILEY, 2021-12-07)
    LAY SUMMARY: 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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    Prevalence of Mycoplasma genitalium fluoroquinolone-resistance markers, and dual- class- resistance markers, in asymptomatic men who have sex with men
    Chua, T-P ; Bodiyabadu, K ; Machalek, DA ; Garland, SM ; Bradshaw, CS ; Plummer, EL ; Danielewski, J ; Vodstrcil, LA ; Doyle, ML ; Murray, GL (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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    Epidemiology of pregnant patients with major trauma in Victoria
    Sato, N ; Cameron, P ; Thomson, BNJ ; Read, D ; McLellan, S ; Woodward, A ; Beck, B (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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    Primary HPV cervical screening: Clinical audit of outcomes of women seen at a tertiary referral centre for colposcopy in Australia
    Chin, FHX ; Wrede, CDH ; Richards, A ; Steele, A ; Vicario, E ; McNally, OM ; Tan, JHJ (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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    Changed ophthalmic workload following introduction of digital retinal photography for retinopathy of prematurity screening
    Tram, JS ; Golding, BM ; Lim, C ; Kuschel, CA ; Elder, JE (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.