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Basal cell carcinoma and squamous cell carcinoma are the most common skin cancers, and have genetic overlap with melanoma, pigmentation traits, autoimmune diseases, and blood biochemistry biomarkers. In this multi-trait genetic analysis of over 300,000 participants from Europe, Australia and the United States, we reveal 78 risk loci for basal cell carcinoma (19 previously unknown and replicated) and 69 for squamous cell carcinoma (15 previously unknown and replicated). The previously unknown risk loci are implicated in cancer development and progression (e.g. CDKL1), pigmentation (e.g. TPCN2), cardiometabolic (e.g. FADS2), and immune-regulatory pathways for innate immunity (e.g. IFIH1), and HIV-1 viral load modulation (e.g. CCR5). We also report an optimised polygenic risk score for effective risk stratification for keratinocyte cancer in the Canadian Longitudinal Study of Aging (794 cases and 18139 controls), which could facilitate skin cancer surveillance e.g. in high risk subpopulations such as transplantees. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers and have genetic overlap. Here, the authors use a multi-trait genetic and phenotypic analysis to reveal susceptibility loci for BCC and SCC, and report an optimised polygenic risk score for risk stratification. [ABSTRACT FROM AUTHOR]

Despite the mental health and substance use burden among people living with HIV (PLHIV) in the Asia–Pacific, data on their associations with HIV clinical outcomes are limited. This cross-sectional study of PLHIV at five sites assessed depression and substance use using PHQ-9 and ASSIST. Among 864 participants, 88% were male, median age was 39 years, 97% were on ART, 67% had an HIV viral load available and < 1000 copies/mL, 19% had moderate-to-severe depressive symptoms, and 80% had ever used at least one substance. Younger age, lower income, and suboptimal ART adherence were associated with moderate-to-severe depressive symptoms. Moderate-to-high risk substance use, found in 62% of users, was associated with younger age, being male, previous stressors, and suboptimal adherence. Our findings highlight the need for improved access to mental health and substance use services in HIV clinical settings. [ABSTRACT FROM AUTHOR]

Background: As people living with HIV now have a life expectancy approaching that of the general population, clinical care focuses increasingly on the management and prevention of comorbidities and conditions associated with aging. We aimed to assess the prevalence of physical function (PF) limitation among gay and bisexual men (GBM) and determine whether HIV is associated with severe PF limitation in this population. Methods: We analysed cross-sectional data from GBM aged ≥55 years in the Australian Positive and Peers Longevity Evaluation Study who completed a self-administered survey on health and lifestyle factors. PF was measured using the Medical Outcomes Study–Physical Functioning scale. Factors associated with severe PF limitation were assessed using logistic regression. Results: The survey was completed by 381 men: 186 without HIV and 195 with HIV. Median age was 64.3 years for GBM without HIV and 62.1 years for GBM with HIV. Compared with men without HIV, those with HIV had higher proportions of severe (13.3% vs 8.1%) and moderate-to-severe (26.7% vs 24.2%) PF limitation. Severe PF limitation commonly involved difficulty with vigorous activity (95% with severe PF limitation described being limited a lot), climbing several flights of stairs (68.4% limited a lot), bending, kneeling or stooping (60.5% limited a lot), and walking 1 km (55.0% limited a lot). In a model adjusted for age, body mass index, typical duration of physical activity, psychological distress, and number of comorbidities, we found a significant association between HIV and severe PF limitation (adjusted odds ratio 3.3 vs not having HIV, 95% confidence interval 1.3–8.7). Conclusions: The biological mechanisms underlying this association require further investigation, particularly given the growing age of the HIV population and inevitable increase in the burden of PF limitation. We assessed physical function among gay and bisexual men in Australia aged ≥55 years using a self-administered survey. The survey was completed by 381 men: 186 without HIV and 195 with HIV. Compared with men without HIV, those with HIV had higher proportions of severe (13.3% vs 8.1%) and moderate-to-severe (26.7% vs 24.2%) physical function limitation. The mechanisms underlying this association require investigation, particularly given the rapidly increasing age of the HIV population. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanomas are common cancers in white‐skinned populations, and early detection is promoted as a means of reducing morbidity and mortality. There is concern that increased skin screening is leading to overdiagnosis of indolent melanomas with low risk of lethality. The extent of melanoma overdiagnosis associated with screening is unknown. Objectives: To estimate possible overdiagnosis by comparing subsequent melanoma incidence and biopsy rates among people subjected to skin screening those who were not. Methods: We recruited 43 762 residents of Queensland, Australia, aged 40–69 years, with no prior history of melanoma, selected at random from a population register in 2010. At baseline, participants completed a comprehensive melanoma risk factor survey and were asked if their skin had been examined by a doctor in the 3 years prior to baseline. We calculated incidence and relative risk of histologically confirmed melanoma (invasive and in situ) in years 2–7 of follow‐up, obtained through linkage to the cancer registry. In secondary analyses, we measured biopsy rates in years 2–6 of follow‐up. We used propensity score analysis to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: In total, 28 155 participants underwent skin screening prior to baseline. We observed 967 first‐incident melanomas (381 invasive) during 197 191 person‐years of follow‐up. Those screened had higher rates of melanoma (aHR 1·29, 95% CI 1·02–1·63) and subsequent skin biopses (aHR 1·85, 95% CI 1·69–2·04) than unscreened participants. The higher risk associated with skin screening was evident for in situ melanoma (aHR 1·45, 95% CI 1·09–1·92) but not invasive melanoma (aHR 1·05, 95% CI 0·72–1·54). In secondary analyses, where screening was defined as having a skin biopsy in the first year after baseline, we observed significantly increased risks of melanoma (aHR 1·53, 95% CI 1·23–1·89) and subsequent biopsies (aHR 2·64, 95% CI 2·46–2·84) relative to those who did not have a biopsy. Conclusions: People who undergo skin screening subsequently experience higher rates of biopsies and melanoma (especially in situ melanoma), even after adjusting for all known risk factors, consistent with overdiagnosis. What is already known about this topic?Cutaneous melanomas are common cancers in white‐skinned populations for which early detection is promoted as a means of reducing morbidity and mortality.There is concern that increased surveillance is leading to the overdiagnosis of indolent melanomas that are not destined to be lethal.The extent of melanoma overdiagnosis associated with surveillance is not known. What does this study add?People subjected to skin examinations by a doctor or who undergo skin biopsies subsequently have higher numbers of biopsies and higher rates of melanoma than people not subjected to either, even after adjusting for all known risk factors.These findings suggest that heightened surveillance leads to a proportion of melanomas being diagnosed that otherwise may not have come to clinical attention. [ABSTRACT FROM AUTHOR]

Background: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood.Objective: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.Methods: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts.Results: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61-2.71, P = 2.08 × 10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77-3.21, P = 1.07 × 10-8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83-0.94, P = 6.93 × 10-5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90).Conclusion: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting. [ABSTRACT FROM AUTHOR]

Background and Objectives: Most of the 233 worldwide cases of variant Creutzfeldt–Jakob disease (vCJD) have been reported in the United Kingdom and 3 have been associated with transfusion‐transmission. To mitigate the potential vCJD risk to blood safety, Australian Red Cross Lifeblood imposes restrictions on blood donation from people with prior residency in, or extended travel to, the United Kingdom during the risk period 1980–1996. We have modified a previously published methodology to estimate the transfusion‐transmission risk of vCJD associated with fresh component transfusion in Australia if the UK residence deferral was removed. Materials and Methods: The prevalence of current pre‐symptomatic vCJD infection in the United Kingdom by age at infection and genotype was estimated based on risk of exposure to the bovine spongiform encephalopathy agent for the period 1980–1996. These results were used to estimate the age‐specific prevalence of undiagnosed, pre‐symptomatic vCJD in the Australian population in the current year due to prior UK residency or travel. The primary model outputs were the 2020 vCJD risks/unit of vCJD contamination, transfusion‐transmission (infections) and clinical cases. Results: The overall (prior UK residency in and travel to United Kingdom, 1980–1996) mean risk of contamination per unit was 1 in 29,900,000. The risks of resulting vCJD transmission (infection) and clinical case were 1 in 389,000,000 and 1 in 1,450,000,000, respectively. Conclusion: Our modelling suggests that removing the Lifeblood donation deferral for travel to, or UK residence, would result in virtually no increased risk of vCJD transfusion‐transmission and would be a safe and effective strategy for increasing the donor base. [ABSTRACT FROM AUTHOR]

The aim of this report is to describe our experience in endovascular treatment of May-Thurner syndrome. We report three cases of iliocaval stenosis treated endovascularly at our institution. We included three patients age range from 41 to 85 years with two presenting with acute deep vein thrombosis and associated limb swelling and one with chronic lower limb symptoms. We reviewed the technical success, complications, and stent patency on follow-up, latter was monitored be serial imaging. The three cases of iliocaval stenosis were treated with endovascular stenting with follow-up imaging follow-up period ranged from 6 to 13 months (mean 5.6 months) with two out of the three cases maintaining stent patency. One case was complicated by intraprocedural reopening of previously venous bleed. Clinical symptoms resolved with no recurrence in two out of three cases. One case experienced symptomatic in-stent thrombosis following endovascular treatment. Endovascular treatment of iliocaval stenosis appears effective in immediate technical success. Periprocedural attention to anticoagulation and stent position are important in preventing in-stent restenosis. [ABSTRACT FROM AUTHOR]

Introduction: Viral load (VL) testing is still challenging to monitor treatment responses of antiretroviral therapy (ART) for HIV treatment programme in Asia. We assessed the association between routine VL testing and virological failure (VF) and determine factors associated with switching to second‐line regimen. Methods: Among 21 sites from the TREAT Asia HIV Observational Database (TAHOD), people living with HIV (PLHIV) aged ≥18 years initiating ART from 2003 to 2021 were included. We calculated the average number of VL tests per patient per year between the date of ART initiation and the most recent visit. If the median average number of VL tests was ≥ 0.80 per patient per year, the site was classified as a routine VL site. A site with a median < 0.80 was classified into the non‐routine VL sites. VF was defined as VL ≥1000 copies/ml during first‐line therapy. Factors associated with VF were analysed using generalized estimating equations with Poisson distribution. Results: Of 6277 PLHIV starting ART after 2003, 3030 (48%) were from 11 routine VL testing sites and 3247 (52%) were from 10 non‐routine VL testing sites. The median follow‐up was 9 years (IQR 5–13). The median age was 35 (30–42) years; 68% were male and 5729 (91%) started non‐nucleoside reverse‐transcriptase inhibitor‐based regimen. The median pre‐ART CD4 count in PLHIV from routine VL sites was lower compared to non‐routine VL sites (144 vs. 156 cells/mm3, p <0.001). Overall, 1021 subsequent VF at a rate of 2.15 (95% CI 2.02–2.29) per 100 person‐years (PY). VF was more frequent at non‐routine VL sites (adjusted incidence rate ratio 2.85 [95% CI 2.27–3.59]) compared to routine VL sites. Other factors associated with an increased rate of VF were age <50 years and CD4 count <350 cells/mm3. A total of 817 (13%) patients switched to second‐line regimen at a rate of 1.44 (95% CI 1.35–1.54) per 100 PY. PLHIV at routine VL monitoring sites were at higher risk of switching than those at non‐routine VL sites (adjusted sub‐hazard ratio 1.78 95% CI [1.17–2.71]). Conclusions: PLHIV from non‐routine VL sites had a higher incidence of persistent VF and a low switching regimen rate, reflecting possible under‐utilized VL testing. [ABSTRACT FROM AUTHOR]

Background A syphilis outbreak among Australian Aboriginal and Torres Strait Islander people (respectfully referred to as Aboriginal) has resulted in almost 4000 notifications by 2020, with several congenital syphilis cases and infant deaths. Outbreak control efforts became coordinated under a National enhanced test and treat response in 2017. We evaluated the impact of these efforts and of expansion of testing interventions on syphilis prevalence. Methods We developed an individual-based mathematical model of infectious syphilis transmission among young heterosexual Aboriginal people aged 15–34 years living in and moving between regional and remote areas, and we assessed the impact of existing and hypothetical outbreak control responses on syphilis prevalence. Results The increased testing coverage achieved through the response (from 18% to 39% over 2011–2020) could stabilize the epidemic from 2021. To return to pre-outbreak prevalence (<0.24%) by 2025, testing coverage must reach 60%. The addition of annual community-wide screening, where 30% of youth in communities are tested over 6 weeks, would reduce prevalence to the pre-outbreak level within 4 years. If testing coverage had been scaled-up to 60% at the start of outbreak in mid-2011, the outbreak would have been mitigated. Conclusions Our results suggest that to control the syphilis outbreak, the response needs to be delivered to enable the maximum coverage of testing to be reached in the shortest time to reduce the prevalence to pre-outbreak levels. Reduction could be hastened with community-wide screening at similar time periods across all communities together with increases in annual testing coverage. [ABSTRACT FROM AUTHOR]

Summary: Background: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS‐based risk prediction, particularly assessment of calibration (comparing predicted to observed risks). Objectives: To evaluate PRS‐based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. Methods: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case‐cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single‐nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta‐analysis (PRS68), 50 SNPs significant in the 2020 meta‐analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten‐year melanoma risks were calculated from population‐level cancer registry data by age group and sex, with and without PRS adjustment. Results: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62–0·68] and MCCS (E/O = 0·63, 95% CI 0·56–0·72). For UKB, calibration was improved by PRS adjustment, with PRS50‐adjusted risks E/O = 0·91, 95% CI 0·87–0·95. The discriminative ability for PRS68‐ and PRS50‐adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07–0·10, P < 0·0001), and higher than for PRS45‐adjusted risks (Δ area under the curve 0·02–0·04, P < 0·001). Conclusions: A PRS derived from a larger, more diverse meta‐analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations. [ABSTRACT FROM AUTHOR]

We investigated oral fluid testing (OFT) among men who have sex with men (MSM) to increase HIV testing in Bali, Indonesia. We distributed OFT in January–December 2018 to 813 MSM in Bali. Supervised testing was offered first, and unsupervised was only offered to an individual who declined supervised testing. Included participants were MSM who did not have a HIV test result in the last 6 months and declined referral to facility-based testing. Of 813 participants, 93% (765/813) chose supervised testing and 7% (57/813) unsupervised. The OFT result was reactive for 83 (10%), of whom 52/83 (63%) underwent confirmatory testing with 47/52 (90%) found HIV positive. Among confirmed positives, 43/47 (92%) were enrolled in HATI study cohort, of whom 39 (91%) started treatment. At six months follow up, 25/39 (64%) of those initiating treatment were still receiving it, and all had a suppressed viral load. There was an increase in the mean number of MSM tested for HIV by HATI study Bali sites per month, from 100 (95%CI: 85–112) before the intervention to 152 (95% CI: 130–172) during the intervention. Our findings show the potential utility of offering HIV oral fluid self-test kits to scale-up HIV testing in MSM. Trial registration: ClinicalTrials.gov identifier: NCT03429842. [ABSTRACT FROM AUTHOR]

Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk‐marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual‐level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29‐1.55; QSkin OR 1.58, 95% CI: 1.29‐1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33‐1.44; QSkin OR 1.20, 95% CI: 1.05‐1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28‐1.55; QSkin OR 1.44, 95% CI: 1.19‐1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases. [ABSTRACT FROM AUTHOR]

Objectives: We investigated weight changes following antiretroviral therapy (ART) initiation, the development of metabolic syndrome (MetS) and its association with all‐cause mortality among Asian adults living with HIV. Methods: Participants enrolled in a regional Asian HIV‐infected cohort with weight and height measurements at ART initiation were eligible for inclusion in the analysis. Factors associated with weight changes and incident MetS (according to the International Diabetic Federation (IDF) definition) were analysed using linear mixed models and Cox regression, respectively. Competing‐risk regression models were used to investigate the association of MetS with all‐cause mortality. Results: Among 4931 people living with HIV (PLWH), 66% were male. At ART initiation, the median age was 34 [interquartile range (IQR) 29–41] years, and the median (IQR) weight and body mass index (BMI) were 55 (48–63) kg and 20.5 (18.4–22.9) kg/m2, respectively. At 1, 2 and 3 years of ART, overall mean (± standard deviation) weight gain was 2.2 (±5.3), 3.0 (±6.2) and 3.7 (±6.5) kg, respectively. Participants with baseline CD4 count ≤ 200 cells/µL [weight difference (diff) = 2.2 kg; 95% confidence interval (CI) 1.9–2.5 kg] and baseline HIV RNA ≥ 100 000 HIV‐1 RNA copies/mL (diff = 0.6 kg; 95% CI 0.2–1.0 kg), and those starting with integrase strand transfer inhibitor (INSTI)‐based ART (diff = 2.1 kg; 95% CI 0.7–3.5 kg vs. nonnucleoside reverse transcriptase inhibitors) had greater weight gain. After exclusion of those with abnormal baseline levels of MetS components, 295/3503 had incident MetS [1.18 (95% CI 1.05–1.32)/100 person‐years (PY)]. The mortality rate was 0.7 (95% CI 0.6–0.8)/100 PY. MetS was not significantly associated with all‐cause mortality in the adjusted model (P = 0.236). Conclusions: Weight gain after ART initiation was significantly higher among those initiating ART with lower CD4 count, higher HIV RNA and an INSTI‐based regimen after controlling for baseline BMI. Greater efforts to identify and manage MetS among PLWH are needed. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to describe time trends in cancer incidence in people living with HIV (PLHIV) in Australia between 1982 and 2012. Methods: A population‐based prospective study was conducted using data linkage between the national HIV and cancer registries. Invasive cancers identified in PLHIV were grouped into AIDS‐defining cancers (ADCs), infection‐related non‐ADCs (NADCs), and non‐infection‐related NADCs. Crude and age‐standardized incidence rates of cancers were calculated and compared over five time periods: 1982–1995, 1996–1999, 2000–2004, 2005–2008 and 2009–2012, roughly reflecting advances in HIV antiretroviral therapy. Standardized incidence ratios (SIRs) compared with the Australian general population were calculated for each time period. Generalized linear models were developed to assess time trends in crude and age‐standardized incidences. Results: For ADCs, the crude and age‐standardized incidences of Kaposi sarcoma and non‐Hodgkin lymphoma substantially declined over time (P‐trend < 0.001 for all) but SIRs remained significantly elevated. For infection‐related NADCs, there were significant increases in the crude incidences of anal, liver and head and neck cancers. Age‐standardized incidences increased for anal cancer (P‐trend = 0.002) and liver cancer (P‐trend < 0.001). SIRs were significantly elevated for anal cancer, liver cancer and Hodgkin lymphoma. For non‐infection‐related NADCs, the crude incidence of colorectal, lung and prostate cancers increased over time, but age‐standardized incidences remained stable. Conclusions: Continuous improvements and high coverage of antiretroviral therapy have reduced the incidence of ADCs in PLHIV in Australia. Clinical monitoring of anal and liver cancers in people living with HIV should be performed, given the increasing incidence of these cancers. [ABSTRACT FROM AUTHOR]

Background: Financial incentives and audit/feedback are widely used in primary care to influence clinician behaviour and increase quality of care. While observational data suggest a decline in quality when these interventions are stopped, their removal has not been evaluated in a randomised controlled trial (RCT), to our knowledge. This trial aimed to determine whether chlamydia testing in general practice is sustained when financial incentives and/or audit/feedback are removed.Methods and Findings: We undertook a 2 × 2 factorial cluster RCT in 60 general practices in 4 Australian states targeting 49,525 patients aged 16-29 years for annual chlamydia testing. Clinics were recruited between July 2014 and September 2015 and were followed for up to 2 years or until 31 December 2016. Clinics were eligible if they were in the intervention group of a previous cluster RCT where general practitioners (GPs) received financial incentives (AU$5-AU$8) for each chlamydia test and quarterly audit/feedback reports of their chlamydia testing rates. Clinics were randomised into 1 of 4 groups: incentives removed but audit/feedback retained (group A), audit/feedback removed but incentives retained (group B), both removed (group C), or both retained (group D). The primary outcome was the annual chlamydia testing rate among 16- to 29-year-old patients, where the numerator was the number who had at least 1 chlamydia test within 12 months and the denominator was the number who had at least 1 consultation during the same 12 months. We undertook a factorial analysis in which we investigated the effects of removal versus retention of incentives (groups A + C versus groups B + D) and the effects of removal versus retention of audit/feedback (group B + C versus groups A + D) separately. Of 60 clinics, 59 were randomised and 55 (91.7%) provided data (group A: 15 clinics, 11,196 patients; group B: 14, 11,944; group C: 13, 11,566; group D: 13, 14,819). Annual testing decreased from 20.2% to 11.7% (difference -8.8%; 95% CI -10.5% to -7.0%) in clinics with incentives removed and decreased from 20.6% to 14.3% (difference -7.1%; 95% CI -9.6% to -4.7%) where incentives were retained. The adjusted absolute difference in treatment effect was -0.9% (95% CI -3.5% to 1.7%; p = 0.2267). Annual testing decreased from 21.0% to 11.6% (difference -9.5%; 95% CI -11.7% to -7.4%) in clinics where audit/feedback was removed and decreased from 19.9% to 14.5% (difference -6.4%; 95% CI -8.6% to -4.2%) where audit/feedback was retained. The adjusted absolute difference in treatment effect was -2.6% (95% CI -5.4% to -0.1%; p = 0.0336). Study limitations included an unexpected reduction in testing across all groups impacting statistical power, loss of 4 clinics after randomisation, and inclusion of rural clinics only.Conclusions: Audit/feedback is more effective than financial incentives of AU$5-AU$8 per chlamydia test at sustaining GP chlamydia testing practices over time in Australian general practice.Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12614000595617. [ABSTRACT FROM AUTHOR]

Background People who inject drugs are at greater risk of hepatitis C virus (HCV) infection and hospitalization, yet admissions are not utilized for HCV treatment initiation. We aimed to assess the extent to which people with HCV notification, including those with evidence of recent drug dependence, are hospitalized while eligible for direct-acting antiviral (DAA) therapy, and treatment uptake according to hospitalization in the DAA era. Methods We conducted a longitudinal, population-based cohort study of people living with HCV in the DAA era (March 2016–December 2018) through analysis of linked databases in New South Wales, Australia. Kaplan-Meier estimates were used to report HCV treatment uptake by frequency, length, and cause-specific hospitalization. Results Among 57 467 people, 14 938 (26%) had evidence of recent drug dependence, 50% (n = 7506) of whom were hospitalized while DAA eligible. Incidence of selected cause-specific hospitalization was highest for mental health-related (15.84 per 100 person-years [PY]), drug-related (15.20 per 100 PY), and injection-related infectious disease (9.15 per 100 PY) hospitalizations, and lowest for alcohol use disorder (4.58 per 100 PY) and liver-related (3.13 per 100 PY). In total, 65% (n = 4898) of those who were hospitalized had been admitted ≥2 times, and 46% (n = 3437) were hospitalized ≥7 days. By the end of 2018, DAA therapy was lowest for those hospitalized ≥2 times, for ≥7 days, and those whose first admission was for injection-related infectious disease, mental health disorders, and drug-related complications. Conclusions Among people who have evidence of recent drug dependence, frequent hospitalization—particularly mental health, drug, and alcohol admissions—presents an opportunity for engagement in HCV care. [ABSTRACT FROM AUTHOR]

The ability to treat gonorrhoea with current first-line drugs is threatened by the global spread of extensively drug resistant (XDR) Neisseria gonorrhoeae (NG) strains. In Australia, urban transmission is high among men who have sex with men (MSM) and importation of an XDR NG strain in this population could result in an epidemic that would be difficult and costly to control. An individual-based, anatomical site-specific mathematical model of NG transmission among Australian MSM was developed and used to evaluate the potential for elimination of an imported NG strain under a range of case-based and population-based test-and-treat strategies. When initiated upon detection of the imported strain, these strategies enhance the probability of elimination and reduce the outbreak size compared with current practice (current testing levels and no contact tracing). The most effective strategies combine testing targeted at regular and casual partners with increased rates of population testing. However, even with the most effective strategies, outbreaks can persist for up to 2 years post-detection. Our simulations suggest that local elimination of imported NG strains can be achieved with high probability using combined case-based and population-based test-and-treat strategies. These strategies may be an effective means of preserving current treatments in the event of wider XDR NG emergence. Author summary: In most high-income settings, gonorrhoea is endemic among men who have sex with men (MSM). While gonorrhoea remains readily treatable with antibiotics, there are major concerns about the threat of antimicrobial resistance arising from recent reports of treatment failure with first-line therapy and limited remaining treatment options. Here we investigated the potential for test-and-treat response strategies to eliminate such strains before their prevalence reaches a level requiring a shift to new first line therapies. Rather than directly consider resistance, we explore the mitigating effect of various test-and-treat measures on outbreaks of a generic imported strain which remains treatable. This is done within the framework of a realistic mathematical model of gonorrhoea spread in an MSM community that captures cases, anatomical sites of infection and sexual contacts at an individual level, calibrated to relevant Australian epidemiological data. The results indicate that strategies such as partner testing and treatment in combination with elevated asymptomatic community testing are highly effective in mitigating outbreaks but can take up to 2 years to achieve elimination. As there are currently no clear alternative drugs of proven efficacy and safety to replace ceftriaxone in first-line therapy, these promising results suggest potential for use of these outbreak response strategies to preserve current treatment recommendations. [ABSTRACT FROM AUTHOR]

Background: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest.Methods: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma.Results: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma.Conclusions: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance. [ABSTRACT FROM AUTHOR]

Background: People living with HIV (PLHIV) have an elevated risk of atherosclerotic cardiovascular disease (ASCVD) compared to their uninfected peers. Expanding statin use may help alleviate this burden. We evaluated the cost-effectiveness of reducing the recommend statin initiation threshold for primary ASCVD prevention among PLHIV in Thailand. Methods: Our decision analytic microsimulation model randomly selected (with replacement) individuals from the TREAT Asia HIV Observational Database (data collected between 1/January/2013 and 1/September/2019). Direct medical costs and quality-adjusted life-years were assigned in annual cycles over a lifetime horizon and discounted at 3% per year. We assumed the Thai healthcare sector perspective. The study population included PLHIV aged 35–75 years, without ASCVD, and receiving antiretroviral therapy. Statin initiation thresholds evaluated were 10-year ASCVD risk ≥10% (control), ≥7.5% and ≥5%. Results: A statin initiation threshold of ASCVD risk ≥7.5% resulted in accumulation of 0.015 additional quality-adjusted life-years compared with an ASCVD risk threshold ≥10%, at an extra cost of 3,539 Baht ($US113), giving an incremental cost-effectiveness ratio of 239,000 Baht ($US7,670)/quality-adjusted life-year gained. The incremental cost-effectiveness ratio comparing ASCVD risk ≥5% to ≥7.5% was 349,000 Baht ($US11,200)/quality-adjusted life-year gained. At a willingness-to-pay threshold of 160,000 Baht ($US5,135)/quality-adjusted life-year gained, a 30.8% reduction in the average cost of low/moderate statin therapy led to the ASCVD risk threshold ≥7.5% becoming cost-effective compared with current practice. Conclusions: Reducing the recommended 10-year ASCVD risk threshold for statin initiation among PLHIV in Thailand would not currently be cost-effective. However, a lower threshold could become cost-effective with greater preference for cheaper statins. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites.Methods: In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants.Results: Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13-1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03-1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort.Conclusion: Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites. [ABSTRACT FROM AUTHOR]

Bacterial small RNAs (sRNAs) play a vital role in pathogenesis by enabling rapid, efficient networks of gene attenuation during infection. In recent decades, there has been a surge in the number of proposed and biochemically-confirmed sRNAs in both Gram-positive and Gram-negative pathogens. However, limited homology, network complexity, and condition specificity of sRNA has stunted complete characterization of the activity and regulation of these RNA regulators. To streamline the discovery of the expression of sRNAs, and their post-transcriptional activities, we propose an integrative in vivo data-mining approach that couples DNA protein occupancy, RNA-seq, and RNA accessibility data with motif identification and target prediction algorithms. We benchmark the approach against a subset of well-characterized E. coli sRNAs for which a degree of in vivo transcriptional regulation and post-transcriptional activity has been previously reported, finding support for known regulation in a large proportion of this sRNA set. We showcase the abilities of our method to expand understanding of sRNA RseX, a known envelope stress-linked sRNA for which a cellular role has been elusive due to a lack of native expression detection. Using the presented approach, we identify a small set of putative RseX regulators and targets for experimental investigation. These findings have allowed us to confirm native RseX expression under conditions that eliminate H-NS repression as well as uncover a post-transcriptional role of RseX in fimbrial regulation. Beyond RseX, we uncover 163 putative regulatory DNA-binding protein sites, corresponding to regulation of 62 sRNAs, that could lead to new understanding of sRNA transcription regulation. For 32 sRNAs, we also propose a subset of top targets filtered by engagement of regions that exhibit binding site accessibility behavior in vivo. We broadly anticipate that the proposed approach will be useful for sRNA-reliant network characterization in bacteria. Such investigations under pathogenesis-relevant environmental conditions will enable us to deduce complex rapid-regulation schemes that support infection. [ABSTRACT FROM AUTHOR]

Background: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 109 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear.Objective: To estimate the long-term risk difference for cancer with the immediate ART strategy.Design: Multinational prospective cohort study.Setting: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.Participants: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).Measurements: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500 × 109 cells/L) ART initiation strategies.Results: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 109 cells/L and less than 350 × 109 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer.Limitation: Potential residual confounding due to observational study design.Conclusion: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.Primary Funding Source: Highly Active Antiretroviral Therapy Oversight Committee. [ABSTRACT FROM AUTHOR]