Comprehensive observational study evaluating the enduring effectiveness of 4CMenB, the meningococcal B vaccine against gonococcal infections in the Northern Territory and South Australia, Australia: study protocol.

INTRODUCTION: The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections. METHODS AND ANALYSES: This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4-7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison. ETHICS AND DISSEMINATION: The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).

Chlamydia retesting remains low among young women in Australia: an observational study using sentinel surveillance data, 2018-2022.

BACKGROUND: Chlamydia remains the most notified bacterial sexually transmissible infection in Australia with guidelines recommending testing for re-infection at 3months post treatment. This paper aimed to determine chlamydia retesting and repeat positivity rates within 2-4months among young women in Australia, and to evaluate what factors increase or decrease the likelihood of retesting. METHODS: Chlamydia retesting rates among 16-29-year-old women were analysed from Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of sexually transmissible infection and bloodborne virus (ACCESS) sentinel surveillance data (n =62 sites). Among women with at least one positive test between 1 January 2018 and 31 August 2022, retesting counts and proportions within 2-4months were calculated. Logistic regression was performed to assess factors associated with retesting within 2-4months. RESULTS: Among 8758 women who were positive before 31 August 2022 to allow time for follow up, 1423 (16.2%) were retested within 2-4months, of whom 179 (12.6%) tested positive. The odds of retesting within 2-4months were 25% lower if tested in a coronavirus disease 2019 (COVID-9) pandemic year (2020-2022) (aOR=0.75; 95% CI 0.59-0.95). Among 9140 women with a positive test before 30 November 2022, 397 (4.3%) were retested too early (within 7days to 1month) and 81 (20.4%) of those were positive. CONCLUSIONS: Chlamydia retesting rates remain low with around a sixth of women retested within 2-4months in line with guidelines. Re-infection is common with around one in eight retesting positive. An increase in retesting is required to reduce the risk of reproductive complications and onward transmission.

Engineered Polymer-siRNA Polyplexes Provide Effective Treatment of Lung Inflammation.

Uncontrolled inflammation is responsible for acute and chronic diseases in the lung. Regulating expression of pro-inflammatory genes in pulmonary tissue using small interfering RNA (siRNA) is a promising approach to combatting respiratory diseases. However, siRNA therapeutics are generally hindered at the cellular level by endosomal entrapment of delivered cargo and at the organismal level by inefficient localization in pulmonary tissue. Here we report efficient anti-inflammatory activity in vitro and in vivo using polyplexes of siRNA and an engineered cationic polymer (PONI-Guan). PONI-Guan/siRNA polyplexes efficiently deliver siRNA cargo to the cytosol for highly efficient gene knockdown. Significantly, these polyplexes exhibit inherent targeting to inflamed lung tissue following intravenous administration in vivo. This strategy achieved effective (>70%) knockdown of gene expression in vitro and efficient (>80%) silencing of TNF-α expression in lipopolysaccharide (LPS)-challenged mice using a low (0.28 mg/kg) siRNA dosage.

COX-2 upregulation by tumour cells post-chemotherapy fuels the immune evasive dark side of cancer inflammation.

Cytotoxic therapies, such as chemotherapy and radiotherapy, are mainstays of cancer treatment for both early and unresectable, advanced disease. In addition to debulking the tumour mass through direct killing of proliferating tumour cells, these treatments can promote tumour control via immune-stimulating effects. Nonetheless, chemoresistance and tumour relapse remain huge clinical problems, suggesting that induction of anti-cancer immunity post-cytotoxic therapy is often weak, not durable and/or overcome by immune evasive mechanisms. In our recent study (Nat Commun 13:2063), we demonstrate that cancer cell-intrinsic activation of the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway post-chemotherapy treatment is a prevalent phenomenon which profoundly alters the inflammatory properties of the treated cancer cells. Of particular translational relevance, our findings support a model whereby upregulation of COX-2 expression and activity post-chemotherapy impairs the efficacy of the combination of PD-1 blockade and chemotherapy. Accordingly, pharmacological inhibition of COX-2 with celecoxib, an anti-inflammatory drug already used clinically, unleashed tumour control in preclinical models when given alongside chemoimmunotherapy combinations.

Real-world trends in incidence of bacterial sexually transmissible infections among gay and bisexual men using HIV pre-exposure prophylaxis (PrEP) in Australia following nationwide PrEP implementation: an analysis of sentinel surveillance data.

BACKGROUND: Although data from large implementation trials suggest that sexually transmissible infection (STI) risk increases among gay and bisexual men who initiate HIV pre-exposure prophylaxis (PrEP), there are few data on the trends in population-level STI incidence in the years following widespread PrEP implementation. We aimed to describe trends in bacterial STI incidence among gay and bisexual men using PrEP across Australia in the context of broad PrEP availability through Australia's subsidised medicines scheme. METHODS: We analysed linked clinical data from HIV-negative gay and bisexual men aged 16 years or older who had been prescribed PrEP across a sentinel surveillance clinical network, including 37 clinics in Australia, between Jan 1, 2016, and Dec 31, 2019. Patients were included if they had STI testing at least twice during the observation period. Repeat testing methods were used to calculate chlamydia, gonorrhoea, syphilis, and any STI incidence rates during individuals' periods of PrEP use. Incidence rate ratios (IRRs) for estimated change in incidence per half calendar year (6-month) period were calculated using negative binomial regression. Secondary analyses compared STI incidence rates across individuals initiating PrEP in each year from 2016 to 2019, as well as by length of time using PrEP (per each additional 6 months of PrEP use). FINDINGS: 22 730 men were included in the analyses. During the observation period, 11 351 chlamydia infections were diagnosed in 6630 (30·1%) of 22 034 men over 25 991·2 person-years of PrEP use (incidence rate 43·7 cases [95% CI 42·9-44·5] per 100 person-years). Chlamydia incidence decreased from 48·7 cases per 100 person-years in July-December, 2016, to 42·0 cases per 100 person-years in July-December, 2019 (IRR for estimated change per 6-month period 0·98 [95% CI 0·97-0·99]; p=0·0031). 9391 gonorrhoea infections were diagnosed in 5885 (26·9%) of 21 845 men over 24 858·7 person-years of PrEP use (incidence rate 37·8 cases [95% CI 37·0-38·5] per 100 person-years). Gonorrhoea incidence decreased from 45·5 cases per 100 person-years in July-December, 2016, to 37·2 cases per 100 person-years in July-December, 2019 (IRR 0·97 [95% CI 0·96-0·98]; p<0·0001). Declines in chlamydia and gonorrhoea incidence were most prominent in the first 18 months of observation and incidence was stable thereafter. 2062 syphilis infections were diagnosed in 1488 (7·7%) of 19 262 men over 21 978·9 person-years of PrEP use (incidence rate 9·4 cases [95% CI 9·0-9·8] per 100 person-years). Syphilis incidence increased from 6·2 cases per 100 person-years in July-December, 2016, to 9·8 cases per 100 person-years in July-December, 2019 (IRR 1·08 [95% CI 1·05-1·10]; p<0·0001). INTERPRETATION: Chlamydia and gonorrhoea incidence among gay and bisexual men using PrEP were highest in the early months of PrEP implementation in Australia and stabilised at slightly lower rates thereafter following wider PrEP uptake. Lower prospective STI risk among people initiating PrEP in later years contributed to the observed trends in STI incidence. Widespread PrEP implementation can contribute to increased STI screening and detection. FUNDING: Australian Department of Health, National Health and Medical Research Council.

Borcs6 is required for endo-lysosomal degradation during early development.

Early development and differentiation require precise control of cellular functions. Lysosomal degradation is a critical component of normal cellular homeostasis, allowing for degradation of signaling molecules, proteins, and other macromolecules for cellular remodeling and signaling. Little is known about the role of lysosomal function in mammalian embryos before gastrulation. Borcs6 is a protein involved in lysosomal trafficking as well as endo-lysosomal and autophagosome fusion. Here, we show that Borcs6 is necessary for efficient endo-lysosomal degradation in the early embryo. Although embryos lacking Borcs6 are developmentally comparable to control littermates at E5.5, they are characterized by large cells containing increased levels of late endosomes and abnormal nuclei. Furthermore, these embryos display a skewed ratio of extraembryonic and embryonic cell lineages, are delayed by E6.5, and do not undergo normal gastrulation. These results demonstrate the essential functions of lysosomal positioning and fusion with endosomes during early embryonic development and indicate that the early lethality of BORCS6 mutant embryos is primarily due to defects in the HOPS-related function of BORC rather than lysosomal positioning.

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations.

Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.

Human papillomavirus prevalence and risk factors among Australian women 9-12 years after vaccine program introduction.

BACKGROUND: In Australia, high and widespread uptake of the quadrivalent human papillomavirus (HPV) vaccine has led to substantial population-level reductions in the prevalence of quadrivalent vaccine targeted HPV genotypes 6/11/16/18 in women aged ≤ 35 years. We assessed risk factors for HPV detection among 18-35 year old women, 9-12 years after vaccine program introduction. METHODS: Women attending health services between 2015 and 2018 provided a self-collected vaginal specimen for HPV genotyping (Roche Linear Array) and completed a questionnaire. HPV vaccination status was validated against the National Register. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were calculated for factors associated with HPV detection. RESULTS: Among 1564 women (median age 24 years; IQR 21-27 years), Register-confirmed ≥ 1-dose vaccine coverage was highest at 69.3% and 68.1% among women aged 18-21 and 22-24 years respectively, decreasing to 42.9% among those aged 30-35 years. Overall prevalence of quadrivalent vaccine-targeted HPV types was very low (2.0%; 95% CI: 1.4-2.8%) and influenced only by vaccination status (5.5% among unvaccinated compared with 0.7% among vaccinated women; aOR = 0.13 (95% CI: 0.05-0.30)). Prevalence of remaining HPV types, at 40.4% (95% CI: 38.0-42.9%), was influenced by established risk factors for HPV infection; younger age-group (p-trend < 0.001), more recent (p < 0.001) and lifetime sexual partners (p-trend < 0.001), but not vaccination status. Prevalence of HPV31/33/45, which shared risk factors with that of non-vaccine targeted HPV types, was also lower among vaccinated (4%) compared with unvaccinated (7%) women (aOR = 0.51; 95% CI: 0.29-0.89), indicative of cross-protection. CONCLUSION: Vaccination has changed the epidemiology of HPV infection in Australian women, having markedly reduced the prevalence of vaccine-targeted types, including amongst women with known risk factors for infection. Vaccinated women appear to be benefiting from modest cross-protection against types 31/33/45 afforded by the quadrivalent HPV vaccine. These results reinforce the importance of HPV vaccination.

Anti-Inflammatory Drugs Remodel the Tumor Immune Environment to Enhance Immune Checkpoint Blockade Efficacy.

Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX2/PGE2/EP2-4 pathway with widely used nonsteroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from nonresponders shortly after treatment and identified acute IFNγ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T-cell activation. Our findings establish the COX2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot. SIGNIFICANCE: Through performing in-depth profiling of mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.See related commentary by Melero et al., p. 2372.This article is highlighted in the In This Issue feature, p. 2355.

Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade.

Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.

A Pilot, Double-Blind, Randomized, Controlled Trial of High-Dose Intravenous Vitamin C for Vasoplegia After Cardiac Surgery.

OBJECTIVE: To conduct a pilot feasibility and physiologic efficacy study of high-dose vitamin C in patients with vasoplegia after cardiac surgery. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Two tertiary intensive care units (ICUs). PARTICIPANTS: Post-cardiac surgery patients with vasoplegia. INTERVENTIONS: The authors randomly assigned the patients to receive either high-dose intravenous vitamin C (1,500 mg every 6 hours) or placebo. The primary outcome was time from randomization to resolution of vasoplegia. Secondary outcomes included total norepinephrine equivalent dose in the first 2 days, ICU length of stay, ICU mortality, and in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: The authors studied 50 patients (25 patients in each arms). The mean (standard deviation) time to resolution of vasoplegia was 27.0 (16.5) hours in the vitamin C group versus 34.7 (41.1) hours in the placebo group (mean decrease with vitamin C of 7.7 hours, 95% confidence interval -10.5 to 25.9, p = 0.40). The median (interquartile range) norepinephrine equivalent dose in the first 2 days was 64.9 (23.5-236.5) µg/kg versus 47.4 (21.4-265.9) µg/kg in the vitamin C and placebo group (p = 0.75). The median duration of ICU admission was similar (1.4 [0.5-2.5] days and 1.5 [0.5-3.3] days in the vitamin C and placebo group; p = 0.36). Only 1 patient, in the vitamin C arm, died. CONCLUSION: In patients with post-cardiac surgery vasoplegia, high-dose vitamin C infusion was feasible, appeared safe, and, within the limitations of a pilot study, did not achieve statistically faster resolution of vasoplegia.

Interest in Switching to On-Demand HIV Pre-Exposure Prophylaxis (PrEP) Among Australian Users of Daily PrEP: An Online Survey.

We surveyed 970 PrEPX study participants to evaluate interest in switching from daily to on-demand PrEP in a study setting. Interested respondents (n = 469, 48%) more commonly reported PrEP cessation (adjusted odds ratio [aOR], 3.0; P < .001), difficulty with adherence (aOR, 1.6; P = .029), infrequent sex (aOR, 3.7; P < .001), and toxicity concerns (aOR, 2.7; P < .001).

A national study of the clinical management of HIV-positive women in Australia: what are the successes and where are the gaps?

Background Women comprise ~10% of people living with HIV in Australia, so are often underrepresented in research. METHODS: This study invited clinicians providing care to women living with HIV to complete an anonymous survey containing questions related to four key areas: HIV (including diagnosis, treatment and virological outcomes), reproductive health (including sexual activity, contraception, pregnancy and outcomes) and linkage and retention in care. RESULTS: In total, 484 surveys were received, with responses from all states and territories. Most women living with HIV in Australia are on treatment (>90%) and virologically suppressed (>90% have a viral load <50 copies mL-1). Almost 75% of women have had at least one switch in treatment (with toxicity almost as common as simplification as the indication). Treatment interruption is also relatively common, but is more likely the longer a woman has been diagnosed, if she is on benefits (P = 0.007) and is the primary carer of children without a partner (P = 0.001). In Australia, women living with HIV are a diverse heterogeneous group, with over 70 different countries of birth and almost half speaking a language other than English at home. Mental health diagnosis was the most common co-morbid condition identified. A total of 21% of women were post-menopausal, with 42% reporting symptoms to their healthcare provider, but only 17% were receiving treatment for symptoms attributed to menopause. CONCLUSIONS: As well as strategies to support women vulnerable to treatment interruption, important areas for future investment in research and clinical care include co-morbid mental health and menopause symptoms and treatment.

Preventing Hypoglycemia Following Treatment of Hyperkalemia in Hospitalized Patients.

Hypoglycemia is a serious complication following treatment of hyperkalemia with intravenous insulin. The aims of this study were to determine the incidence of hypoglycemia (≤3.9 mmol/l, 70 mg/dL) and severe hypoglycemia (<3.0 mmol/l, 54 mg/dL) in noncritical care inpatients following treatment of hyperkalemia and to establish the risk factors predisposing to this complication. This was a single-center observational study reviewing the Electronic Patient Records of hyperkalemia treatment with intravenous insulin on the general wards of a large UK teaching hospital. A total of 662 episodes of hyperkalemia treated with insulin/dextrose were included. Among these episodes, 116 treatments (17.5%) resulted in hypoglycemia and 47 (7.1%) resulted in severe hypoglycemia. Lower pretreatment capillary blood glucose level, older age, and lower bodyweight were associated with a higher risk of posttreatment hypoglycemia. The incidence of hypoglycemia following hyperkalemia treatment in hospitalized patients is unacceptably high. Identifying individuals at high risk of hypoglycemia and adjusting prescriptions may reduce the incidence.

Protocol for an HIV Pre-exposure Prophylaxis (PrEP) Population Level Intervention Study in Victoria Australia: The PrEPX Study.

Background: Pre-exposure prophylaxis (PrEP) is the use of HIV anti-retroviral therapy to prevent HIV transmission in people at high risk of HIV acquisition. PrEP is highly efficacious when taken either daily, or in an on-demand schedule. In Australia co-formulated tenofovir-emtricitabine is registered for daily use for PrEP, however, this co-formulation is not listed yet on the national subsidized medicines list. We describe a study protocol that aims to demonstrate if the provision of PrEP to up to 3800 individuals at risk of HIV in Victoria, Australia reduces HIV incidence locally by 25% generally and 30% among GBM. Methods: PrEPX is a population level intervention study in Victoria, Australia in which generic PrEP will be delivered to 3800 individuals for up to 36 months. Study eligibility is consistent with the recently updated 2017 Australian PrEP guidelines. Participants will attend study clinics, shared care clinics, or outreach clinics for quarterly HIV/STI screening, biannual renal function tests and other clinical care as required. Study visits and STI diagnoses will be recorded electronically through the ACCESS surveillance system. At each study visit participants will be invited to complete behavioral surveys that collect demographics and sexual risk data. Diagnosis and behavioral data will be compared between PrEPX participants and other individuals testing within the ACCESS surveillance system. A subset of participants will complete in depth surveys and interviews to collect attitudes, beliefs and acceptability data. Participating clinics will provide clinic level data on implementation and management of PrEPX participants. The population level impact on HIV incidence will be assessed using Victorian HIV notification data. Discussion: This study will collect evidence on the real world impact of delivery of PrEP to 3800 individuals at risk of acquiring HIV in Victoria. This study will provide important information for the broader implementation of PrEP planning upon listing of the tenofovir-emtricitabine on the national subsidized list of medicines. The study is registered on the Australian New Zealand Clinical Trials Registry (ACTRN12616001215415).

What is the result of vaginal cleansing with chlorhexidine during labour on maternal and neonatal infections? A systematic review of randomised trials with meta-analysis.

BACKGROUND: Infection with vaginal microorganisms during labour can lead to maternal and neonatal mortality and morbidity. The objective of this systematic review is to review the effectiveness of intrapartum vaginal chlorhexidine in the reduction of maternal and neonatal colonisation and infectious morbidity. METHODS: Search strategy - Eight databases were searched for articles published in any language from inception to October 2016. Selection criteria - Randomised controlled trials were included. Data Collection and analysis - Publications were assessed for inclusion. Data were extracted and assessed for risk of bias. Relative risks from individual studies were pooled using a random effects model and the heterogeneity of treatment was evaluated using Chi2 and I2 tests. RESULTS: Eleven randomised controlled trials (n = 20,101) evaluated intrapartum vaginal chlorhexidine interventions. Meta-analysis found no significant differences between the intervention and control groups for any of the four outcomes: maternal or neonatal colonization or infection. The preferred method for chlorhexidine administration was vaginal irrigation. CONCLUSIONS: Meta-analysis did not demonstrate improved maternal or neonatal outcomes with intrapartum vaginal chlorhexidine cleansing, however this may be due to the limitations of the available studies. A larger, multicentre randomised controlled trial, powered to accurately evaluate the effect of intrapartum vaginal chlorhexidine cleansing on neonatal outcomes may still be informative; the technique of douching may be the most promising.

The efficacy of azithromycin and doxycycline treatment for rectal chlamydial infection: a retrospective cohort study in South Australia.

BACKGROUND: There are ongoing concerns about treatment failure with azithromycin for the treatment of rectal chlamydia. AIM: To investigate treatment efficacy of two treatments for rectal chlamydial infection. METHODS: We performed a retrospective analysis of all patients diagnosed with rectal chlamydial infection between 2009 and 2015 in Adelaide, Australia. Patients were treated with either azithromycin (1 g single dose) or doxycycline (100 mg twice a day for 10 days) and returned for repeat testing 14-180 days after treatment commenced. Log-binomial models were used to estimate the relative risk (RR) of recurrent rectal chlamydia associated with the treatment with azithromycin versus doxycycline. RESULTS: In men, rectal chlamydia prevalence was 6.7%, and in women, it was 8.1%. Of the 526 patients diagnosed with rectal chlamydial infections, 419 (79.7%), 93 (17.7%) and 14 (2.6%) patients were treated with doxycycline, azithromycin or other medication respectively. Of these patients, 173 (41.3%) of 419 doxycycline-treated patients and 31 (33.3%) of 93 azithromycin-treated patients were retested between 14 and 180 days after treatment commenced (P = 0.16). Among these patients, the repeat rectal chlamydia test was less commonly positive in those treated with doxycycline (5.8%; 95% confidence interval (CI) 0.03-0.10) compared with those treated with azithromycin (19.4%; 95% CI 0.09-0.36) and (P = 0.01). In the multivariate analysis, azithromycin-treated patients had a significantly higher risk of a positive test in the 14 and 180 days after treatment commenced (adjusted relative risk (aRR) 2.96, 95% CI 1.16-7.57). CONCLUSION: The findings suggest that doxycycline may be more effective than azithromycin in treating rectal chlamydial infections.

Early sexual experiences of teenage heterosexual males in Australia: a cross-sectional survey.

OBJECTIVE: There are limited data on the patterns of early sexual behaviours among Australian teenage heterosexual boys. This study describes the nature and onset of early sexual experiences in this population through a cross-sectional survey. DESIGN: A cross-sectional survey between 2014 and 2015 SETTING: Major sexual health clinics and community sources across Australia PARTICIPANTS: Heterosexual men aged 17-19 years RESULTS: There were 191 men in the study with a median age of 19.1 years. Median age at first oral sex was 16.4 years (IQR: 15.5-17.7) and 16.9 years (IQR: 16.0-18.0) for first vaginal sex. Most men had engaged in oral sex (89.5%) and vaginal sex (91.6%) in the previous 12 months with 32.6% reporting condom use at last vaginal sex. Of the total lifetime female partners for vaginal sex reported by men as a group (n=1187): 54.3% (n=645) were the same age as the man, 28.3% (n=336) were a year or more younger and 17.4% (n=206) were a year or more older. Prior anal sex with females was reported by 22% with 47% reporting condom use at last anal sex. Median age at first anal sex was 18.2 years (IQR: 17.3-18.8). Anal sex with a female was associated with having five or more lifetime female sexual partners for oral and vaginal sex. CONCLUSIONS: These data provide insights into the trajectory of sexual behaviours experienced by teenage heterosexual boys following sexual debut, findings which can inform programme promoting sexual health among teenage boys.