Obstetrics and Gynaecology - Research Publications
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ItemLooking beyond human papillomavirus (HPV) genotype 16 and 18: Defining HPV genotype distribution in cervical cancers in Australia prior to vaccination(WILEY, 2017-10-15)Australia has implemented a high-coverage HPV vaccination program but has not, to date, established the distribution of HPV types that occur in cervical cancers in Australia. This information is important for determining the potential for cervical cancer prevention with both current and broader spectrum HPV vaccines. We analysed 847 cervical cancers diagnosed 2005 to 2015 in tertiary centres in the three most populous Australian states with resolution of specimens containing multiple HPV types using laser-capture microdissection. Archived FFPE tissue was reviewed by specialist pathologists, sandwich sectioned, and initially whole-tissue sections genotyped for HPV. Samples were first genotyped using SPF10-LiPA25 (version 1). Negative samples were screened with DNA ELISA kit HPV SPF10, followed by genotyping with SPF+ LiPA if ELISA positive. If still negative, samples were tested on a qPCR assay targeting the E6 region of HPV16, 18, 45 and 33. Of the 847 cancers (65.1% squamous, 28.7% adenocarcinoma, 4.3% adenosquamous, 2.0% other), 92.9% had HPV detected. Of the HPV-positive cancers, 607 of 787 (77.1%) contained HPV16 or 18, 125 of 787 (15.9%) contained HPV31/33/45/52 or 58, and 55 (7.0%) another HPV type. There was a strong correlation between HPV type and age, with younger women most likely to have HPV16/18 detected and least likely HPV negative. Our findings indicate that cervical cancers diagnosed in Australia more frequently contain HPV16/18 than in international series. This could be due to cervical screening in Australia increasing the proportion of adenocarcinomas, in which types 18 and 16 more strongly predominate, due to prevention of squamous cancers.
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ItemPostnatal probiotics and allergic disease in very preterm infants: Sub-study to the ProPrems randomized trial(WILEY, 2020-01)BACKGROUND: Probiotic supplementation to mothers and/or their term-born infants has been suggested to prevent allergic disease, in particular eczema; however, no studies have investigated probiotics for prevention of allergic diseases in very preterm infants. We evaluated the effect of a postnatal probiotic combination on development of allergic diseases in very preterm infants. METHODS: This sub-study was an a priori secondary outcome of the ProPrems multi-center, double-blind, placebo-controlled randomized trial (ANZCTR:12607000144415). ProPrems randomized 1099 very preterm infants to receive a probiotic combination or placebo from soon after birth until discharge from hospital or term corrected age (CA), whichever was earlier. Allergic disease (eczema, atopic eczema, food allergy, wheeze, atopic sensitization) was assessed in a subgroup of ProPrems infants (n = 281) as close to 12 months CA as possible by questionnaire, clinical examination, and skin prick tests to common allergens. RESULTS: There was no difference in eczema incidence between the probiotic and placebo groups (35[30%] of 118 infants vs 37[27%] of 137 infants, respectively, absolute difference 2.65%, 95% CI -8.45 to 13.75). Similarly, the incidence of atopic eczema (6[5%] of 118 vs 3[2%] of 137), food allergy (4[3%] of 124 vs 2[1%] of 154), wheeze (39[31%] of 127 vs 45[29%] of 154), and atopic sensitization (14[13%] of 106 vs 13[11%] of 123) were similar between the probiotic and placebo groups. CONCLUSION: This study found no effect of postnatal administration of a probiotic combination on the incidence of allergic diseases or atopic sensitization in the first 2 years of life in children born very preterm. Evidence that probiotics are effective for prevention of allergic disease in premature infants remains lacking; adequately powered randomized controlled trials evaluating probiotic supplementation for allergy prevention in very preterm infants are needed.
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ItemTelomerase activity in cervical scrapes of women with high-grade cervical disease: A nested case-control study(SPANDIDOS PUBL LTD, 2018-01)Epidemiological information on telomerase activity (TA) and development of cervical lesions is scarce. A nested case-control study was carried out within a cohort of Colombian women tested for Human Papillomavirus (HPV). Measurement of TA was done in cervical scrapes of 25 women who developed High Grade Squamous Intraepithelial Lesion (HGSIL) during the first 6 years of follow-up and was compared with that of 104 control women who maintained normal cytology during the entire follow-up. TA was measured by a telomerase repeat amplification protocol-ELISA. TA and HPV infections were significantly more frequent in cases than in controls. Likewise, 68% of the cases were positive for both TA and HPV compared with only 7.7% of the controls (P<0.0001). Factors independently associated with increased odds of HGSIL included TA, high risk HPV (hrHPV) infections and multiple parities. When restricted to hrHPV positive women, TA was strongly associated with increased odds of HGSIL (adjusted odds ratio=37.94, 95% confidence interval, 1.64-678.1). In addition to an infection with hrHPV, TA appears to be a significant cofactor for HGSIL.
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ItemUse of Pristinamycin for Macrolide-Resistant Mycoplasma genitalium Infection(CENTERS DISEASE CONTROL, 2018-02)High levels of macrolide resistance and increasing fluoroquinolone resistance are found in Mycoplasma genitalium in many countries. We evaluated pristinamycin for macrolide-resistant M. genitalium in a sexual health center in Australia. Microbiologic cure was determined by M. genitalium-specific 16S PCR 14-90 days after treatment began. Of 114 persons treated with pristinamycin, infection was cured in 85 (75%). This percentage did not change when pristinamycin was given at daily doses of 2 g or 4 g or at 3 g combined with 200 mg doxycycline. In infections with higher pretreatment bacterial load, treatment was twice as likely to fail for each 1 log10 increase in bacterial load. Gastrointestinal side effects occurred in 7% of patients. Pristinamycin at maximum oral dose, or combined with doxycycline, cured 75% of macrolide-resistant M. genitalium infections. Pristinamycin is well-tolerated and remains an option where fluoroquinolones have failed or cannot be used.
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ItemIncreasing Macrolide and Fluoroquinolone Resistance in Mycoplasma genitalium(CENTERS DISEASE CONTROL, 2017-05)Escalating resistance to azithromycin and moxifloxacin is being reported for Mycoplasma genitalium in the Asia-Pacific region. Analyzing 140 infections, we found pretreatment fluoroquinolone-resistance mutations in parC (13.6%) and gyrA (5%). ParC S83 changes were associated with moxifloxacin failure. Combined macrolide/fluoroquinolone-resistance mutations were in 8.6% of specimens, for which recommended therapies would be ineffective.
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ItemContaminated fingers: a potential cause of Chlamydia trachomatis-positive urine specimens(BMJ PUBLISHING GROUP, 2018-02)OBJECTIVES: The detection of an STI agent in a urogenital tract (UGT) specimen from a young child is regarded as being indicative of sexual abuse. However, the probabilities of contamination events that could conceivably lead to STI positive specimens in the absence of sexual contact are unclear. The objective was to estimate the potential for fingers that have come in contact with Chlamydia trachomatis-positive urine to detectably contaminate C. trachomatis-negative urine. METHODS: The study design was based on self-experimentation. Dilutions of C. trachomatis elementary bodies (EBs) were prepared. A participant contacted an EB dilution then a urine surrogate specimen. The experiment was performed by three participants using three C. trachomatis isolates, of genotype E, F and B. Two surrogate urine contact methods were used to mimic contamination of a carer assisting with a child's urine collection. All EB dilutions and urine surrogate specimens were subjected to C. trachomatis assay and quantification in a real-time PCR-based diagnostic system. RESULTS: The amplimer crossing point (Cq) for EB dilutions was 10.0±1.6 less than for corresponding finger contacted urine specimens, which corresponds to ~10 µL of EB suspension transferred. This was largely independent of participant identity, C. trachomatis strain or EB dilution. Hand decontamination led to large reductions in EBs transferred, but transfer remained consistently detectable. Recent Cq data from C. trachomatis-positive clinical urine specimens were collated, and 20% clearly contained sufficient C. trachomatis to detectably contaminate another specimen by finger-mediated transfer, as in this experiment. CONCLUSIONS: This study directly demonstrated the potential for urine contaminated fingers to convert a C. trachomatis-negative urine specimen to C. trachomatis positive as a result of contact. Accordingly, procedures for urine specimen collection, particularly from children, need to be designed to prevent contamination.
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ItemProspective Evaluation of ResistancePlus MG, a New Multiplex Quantitative PCR Assay for Detection of Mycoplasma genitalium and Macrolide Resistance(AMER SOC MICROBIOLOGY, 2017-06)Mycoplasma genitalium is a significant pathogen for which first-line treatment is becoming less effective due to increased resistance to macrolides. As conventional culture and antimicrobial susceptibility testing is not feasible for routine detection of this pathogen, molecular markers such as detection of mutations in the 23S rRNA gene have been described to predict resistance. Recently, a novel multiplex quantitative PCR (qPCR) assay, ResistancePlus MG, has been described for the simultaneous detection of Mycoplasma genitalium and macrolide resistance. In the current study, the clinical performance of the assay was evaluated on 1,089 consecutive urine and anogenital swab samples in symptomatic and asymptomatic male and female patients. Overall, 6.0% were positive for M. genitalium, with 63.1% having macrolide resistance-associated mutations. Compared to the laboratory-validated qPCR method targeting the 16S rRNA gene and Sanger sequencing to determine 23S rRNA mutations, the sensitivity and specificity of M. genitalium detection were 98.5% and 100% and for detection of macrolide resistance mutations were 100.0% and 96.2%, respectively. This assay offers a considerable advantage in clinical settings for M. genitalium testing by making the results of macrolide resistance and mutation analyses simultaneously available, which is increasingly important with escalating macrolide resistance.
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ItemVaccine-preventable anal human papillomavirus in Australian gay and bisexual men(ELSEVIER SCIENCE BV, 2017-06)OBJECTIVE: HPV causes ~90% of anal cancer and HPV16 is the type most commonly associated with anal cancer. Gay and bisexual men (GBM) are at greatly increased risk. We investigated patterns of vaccine-preventable anal HPV in older GBM. METHODS: The Study of the Prevention of Anal Cancer (SPANC) is an ongoing, prospective cohort study of HIV-positive and HIV-negative Australian GBM. Participants completed questionnaires and underwent an anal swab for HPV genotyping using Roche Linear Array. We analysed baseline data from SPANC by HPV type, mean number of types, stratified by age and HIV status. RESULTS: Anal HPV results from 606 (98.2%) of 617 participants (median age 49 years, 35.7% HIV-positive) showed 525 (86.7%) had ≥1 HPV type and 178 (29.4%) had HPV16. Over one third of participants (214, 35.3%) had no nonavalent vaccine-preventable types detected. Two (0.3%) participants had all quadrivalent types and none had all nonavalent vaccine types. HIV-positive participants (p<0.001) and younger participants (p=0.059) were more likely to have more vaccine-preventable HPV types detected. CONCLUSION: Anal HPV was highly prevalent in this largely community-based GBM cohort. Vaccine-preventable HPV16 was detected in approximately one third of participants. These findings suggest that the potential efficacy of HPV vaccination of older GBM should be explored.
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ItemHPV genotype-specific concordance between EuroArray HPV, Anyplex II HPV28 and Linear Array HPV Genotyping test in Australian cervical samples(ELSEVIER SCIENCE BV, 2017-12)PURPOSE: To compare human papillomavirus genotype-specific performance of two genotyping assays, Anyplex II HPV28 (Seegene) and EuroArray HPV (EuroImmun), with Linear Array HPV (Roche). METHODS: DNA extracted from clinican-collected cervical brush specimens in PreservCyt medium (Hologic), from 403 women undergoing management for detected cytological abnormalities, was tested on the three assays. Genotype-specific agreement were assessed by Cohen's kappa statistic and Fisher's z-test of significance between proportions. RESULTS: Agreement between Linear Array and the other 2 assays was substantial to almost perfect (κ = 0.60 - 1.00) for most genotypes, and was almost perfect (κ = 0.81 - 0.98) for almost all high-risk genotypes. Linear Array overall detected most genotypes more frequently, however this was only statistically significant for HPV51 (EuroArray; p = 0.0497), HPV52 (Anyplex II; p = 0.039) and HPV61 (Anyplex II; p=0.047). EuroArray detected signficantly more HPV26 (p = 0.002) and Anyplex II detected more HPV42 (p = 0.035) than Linear Array. Each assay performed differently for HPV68 detection: EuroArray and LA were in moderate to substantial agreement with Anyplex II (κ = 0.46 and 0.62, respectively), but were in poor disagreement with each other (κ = -0.01). CONCLUSIONS: EuroArray and Anyplex II had similar sensitivity to Linear Array for most high-risk genotypes, with slightly lower sensitivity for HPV 51 or 52.
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ItemDefining the genetic susceptibility to cervical neoplasia-A genome-wide association study(PUBLIC LIBRARY SCIENCE, 2017-08)A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.