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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 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]

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]

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: 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]

Background Persons living with human immunodeficiency virus (HIV) are at elevated risk of developing the malignant diseases that require allogeneic stem cell transplantation (ASCT). Recent data suggest that these individuals are also at an elevated risk of certain complications post-ASCT. This risk may result from preexisting HIV-related factors affecting dynamics of immune reconstitution post-ASCT. However, to date, there has been little work describing the dynamics of immune reconstitution post-ASCT in persons with HIV and none comparing these data to controls without HIV. Methods We assessed T-cell reconstitution in 6 ASCT with HIV recipients (HIV+ASCT) compared to a control population of 21 ASCT without HIV recipients. In a subset of HIV+ASCT recipients we performed additional flow cytometry profiling of CD8+ T-cell subsets and antigen specificity of reconstituting CD4+ and CD8+ T cells. Results We observe no difference in post-ASCT CD4+ T cells between HIV+ASCT and HIV-negative ASCT recipients, despite much lower pre-ASCT CD4+ T-cell counts in the HIV+ASCT group. In contrast, we observed significantly higher CD8+ T-cell numbers in the HIV+ASCT group post-ASCT. The reconstituting CD8+ T-cells were predominantly CD45RO+, whereas homing markers and antigen specificity of these cells varied between participants. Conclusion This study represents the most extensive characterization of immune-reconstitution post-ASCT in persons with HIV, and the first to our knowledge to compare these data to ASCT controls without HIV. The results indicate that immune reconstitution in this group can be affected by preexisting HIV infection and post-ASCT antigen exposure. [ABSTRACT FROM AUTHOR]

Background: Relations between different measures of human immunodeficiency virus-related immunosuppression and chronic kidney disease (CKD) remain unknown.Methods: Immunosuppression measures included baseline, current, time-lagged and nadir CD4, years and percentage of follow-up (%FU) with CD4 ≤200 cells/μL, and CD4 recovery. CKD was defined as confirmed estimated glomerular filtration rate <60 mL/minute/1.73 m2.Results: Of 33 791 persons, 2226 developed CKD. Univariably, all immunosuppression measures predicted CKD. Multivariably, the strongest predictor was %FU CD4 ≤200 cells/μL (0 vs >25%; incidence rate ratio [IRR], 0.77 [95% confidence interval [CI], .68-.88]), with highest effect in those at low D:A:D CKD risk (IRR, 0.45 [95% CI, .24-.80]) vs 0.80 [95% CI, .70-.93]).Conclusions: Longer immunosuppression duration most strongly predicts CKD and affects persons at low CKD risk more. [ABSTRACT FROM AUTHOR]

Background: Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach.Methods: We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height.Results: Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91-1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02-1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results.Conclusions: These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status. [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus (HIV)–positive gay and bisexual men (GBM) in Australia are well engaged in care. The World Health Organization's (WHO) hepatitis C virus (HCV) elimination target of an 80% reduction in incidence by 2030 may be reachable ahead of time in this population. Methods We predicted the effect of treatment and behavioral changes on HCV incidence among HIV-positive GBM up to 2025 using a HCV transmission model parameterized with Australian data. We assessed the impact of changes in behavior that facilitate HCV transmission in the context of different rates of direct-acting antiviral (DAA) use. Results HCV incidence in our model increased from 0.7 per 100 person-years in 2000 to 2.5 per 100 person-years in 2016 and had the same trajectory as previously reported clinical data. If the proportion of eligible (HCV RNA positive) patients using DAAs stays at 65% per year between 2016 and 2025, with high-risk sexual behavior and injecting drug use remaining at current levels, HCV incidence would drop to 0.4 per 100 person-years (85% decline from 2016). In the same treatment scenario but with substantial increases in risk behavior, HCV incidence would drop to 0.6 per 100 person-years (76% decline). If the proportion of eligible patients using DAAs dropped from 65% per year in 2016 to 20% per year in 2025 and risk behavior did not change, HCV incidence would drop to 0.7 per 100 person-years (70% reduction). Conclusions Reaching the WHO HCV elimination target by 2025 among HIV-positive GBM in Australia is achievable. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether use of contemporary protease inhibitors pose a similar risk of chronic kidney disease (CKD) as use of older protease inhibitors.Methods: Participants in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were followed up until the earliest occurrence of CKD, the last visit plus 6 months, or 1 February 2016. Adjusted Poisson regression was used to assess associations between CKD and the use of ritonavir-boosted atazanavir (ATV/r) or ritonavir-boosted darunavir (DRV/r).Results: The incidence of CKD (10.0/1000 person-years of follow-up; 95% confidence interval, 9.5-10.4/1000 person-years of follow-up) increased gradually with increasing exposure to ATV/r, but the relation was less clear for DRV/r. After adjustment, only exposure to ATV/r (adjusted incidence rate ratio, 1.4; 95% confidence interval, 1.2-1.6), but not exposure to DRV/r (1.0; .8-1.3), remained significantly associated with CKD.Conclusion: While DRV/r use was not significantly associated with CKD an increasing incidence with longer ATV/r use was confirmed. [ABSTRACT FROM AUTHOR]

Background Co-trimoxazole is recommended for all children with human immunodeficiency virus. In this analysis, we evaluate trends in pediatric co-trimoxazole use and survival on co-trimoxazole in children using antiretroviral therapy (ART). Methods We used data collected between January 1, 2006, and March 31, 2016, from the International Epidemiology Databases to Evaluate AIDS. Logistic regression was used to evaluate factors associated with using co-trimoxazole at ART initiation. Competing risk regression was used to assess factors associated with death. Results A total of 54113 children were included in this study. The prevalence of co-trimoxazole use at ART initiation increased from 66.5% in 2006 to a peak of 85.6% in 2010 and then declined to 48.5% in 2015–2016. A similar trend was observed among children who started ART with severe immunodeficiency. After adjusting for year of ART initiation, younger age (odds ratio [OR], 1.18 for <1 vs 1 to <5 years of age [95% confidence interval (CI), 1.09–1.28]), lower height-for-age z score (OR, 1.15 for less than −3 vs greater than −2 [95% CI, 1.08–1.22]), anemia (OR, 1.08 [95% CI, 1.02–1.15]), severe immunodeficiency (OR, 1.25 [95% CI, 1.18–1.32]), and receiving care in East Africa (OR, 8.97 vs Southern Africa [95% CI, 8.17–9.85]) were associated with a high prevalence of co-trimoxazole use. Survival did not differ according to co-trimoxazole use in children without severe immunodeficiency (hazard ratio, 1.01 for nonusers versus users [95% CI, 0.77–1.34]). Conclusions Recent declines in co-trimoxazole use may not be linked to the current shift toward early ART initiation. Randomized trial data might be needed to establish the survival benefit of co-trimoxazole in children without severe immunodeficiency. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have suggested that coffee intake may be associated with a reduction in cancer risk. Mendelian randomization (MR) studies can help clarify whether the observed associations are likely to be causal. Here we evaluated whether coffee intake is associated with: (i) overall risk of being diagnosed with/dying from any cancer; and (ii) risk of individual cancers.Methods: We identified 46 155 cases (of which 6998 were fatal) and 270 342 controls of White British ancestry from the UK Biobank cohort (UKB), based on ICD10 diagnoses. Individuals with benign tumours were excluded. Coffee intake was self-reported and recorded based on cup/day consumption. We conducted both observational and summary data MR analyses.Results: There was no observational association between coffee intake and overall cancer risk [odds ratio (OR) per one cup/day increase = 0.99, 95% confidence interval (CI) 0.98, 1.00] or cancer death (OR = 1.01, 0.99, 1.03); the estimated OR from MR is 1.01 (0.94, 1.08) for overall cancer risk and 1.11 (0.95, 1.31) for cancer death. The relationship between coffee intake and individual cancer risks were consistent with a null effect, with most cancers showing little or no associations with coffee. Meta-analysis of our MR findings with publicly available summary data on various cancers do not support a strong causal relationship between coffee and risk of breast, ovarian, lung or prostate cancer, upon correction for multiple testing.Conclusions: Taken together, coffee intake is not associated with overall risk of being diagnosed with or dying from cancer in UKB. For individual cancers, our findings were not statistically inconsistent with earlier observational studies, although for these we were unable to rule out a small effect on specific types of cancer. [ABSTRACT FROM AUTHOR]

Effect estimates from randomized trials and observational studies might not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a 3-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocols (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate our approach, we compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive for the human immunodeficiency virus from the Strategic Timing of Antiretroviral Therapy (START) randomized trial and the observational HIV-CAUSAL Collaboration. [ABSTRACT FROM AUTHOR]

Background Cancers are a major source of morbidity and mortality for human immunodeficiency virus (HIV)–infected persons, but the clinical benefits of smoking cessation are unknown. Methods Participants were followed from 1 January 2004 until first cancer diagnosis, death, or 1 February 2016. Smoking status was defined as ex-smoker, current smoker, and never smoker. Adjusted incidence rate ratios (aIRRs) were calculated using Poisson regression, adjusting for demographic and clinical factors. Results In total 35442 persons from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study contributed 309803 person-years of follow-up. At baseline, 49% were current smokers, 21% were ex-smokers, and 30% had never smoked. Incidence of all cancers combined (n = 2183) was highest <1 year after smoking cessation compared to never smokers (aIRR, 1.66 [95% confidence interval {CI}, 1.37–2.02]) and not significantly different from never smokers 1–1.9 years after cessation. Lung cancer incidence (n = 271) was elevated <1 year after cessation (aIRR, 19.08 [95% CI, 8.10–44.95]) and remained 8-fold higher 5 years after smoking cessation (aIRR, 8.69 [95% CI, 3.40–22.18]). Incidence of other smoking-related cancers (n = 622) was elevated in the first year after cessation (aIRR, 2.06 [95% CI, 1.42–2.99]) and declined to a level similar to nonsmokers thereafter. Conclusions Lung cancer incidence in HIV-infected individuals remained elevated >5 years after smoking cessation. Deterring uptake of smoking and smoking cessation efforts should be prioritised to reduce future cancer risk. [ABSTRACT FROM AUTHOR]

Background: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are increased in populations with immune dysfunction, including people living with HIV; however, there is little evidence for to what degree immunological and virological factors differently affect NHL and HL risk.Methods: Data from the Data Collection on Adverse events of Anti-HIV Drugs Study cohort were analyzed to identify independent risk factors for NHL and HL using hazard ratios (HRs), focusing on current and cumulative area under the curve (AUC) measures of immunological and virological status. Variables with different associations with NHL and HL were identified using marginal Cox models. All statistical tests were two-sided.Results: Among 41 420 people followed for 337 020 person-years, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] = 1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI = 0.38 to 0.52). Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 <100 vs > 599 cells/mm3 = 8.08, 95% CI = 5.63 to 11.61; HL = 4.58, 95% CI = 2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs < 50 copies/mL = 1.97, 95% CI = 1.50 to 2.59) and higher AUC of HIV-VL (aHR of NHL for highest vs lowest quintile = 2.91, 95% CI = 1.92 to 4.41) were associated with NHL only. Both current and AUC of HIV-VL were factors that had different associations with NHL and HL, where the hazard ratio for NHL was progressively higher than for HL with increasing HIV-VL category. Lower current CD4 cell count had a strong but similar association with both NHL and HL.Conclusions: CD4 depletion increased risk of both types of lymphomas while current and accumulated HIV-VL was associated with NHL only. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk. [ABSTRACT FROM AUTHOR]

Background: While the association between renal impairment and cardiovascular disease (CVD) is well established in the general population, the association remains poorly understood in human immunodeficiency virus (HIV)-positive individuals.Methods: Individuals with ≥2 estimated glomerular filtration rate (eGFR) measurements after 1 February 2004 were followed until CVD, death, last visit plus 6 months, or 1 February 2015. CVD was defined as the occurrence of centrally validated myocardial infarction, stroke, invasive cardiovascular procedures, or sudden cardiac death.Results: During a median follow-up duration of 8.0 years (interquartile range, 5.4-8.9 years) 1357 of 35 357 individuals developed CVD (incidence rate, 5.2 cases/1000 person-years [95% confidence interval {CI}, 5.0-5.5]). Confirmed baseline eGFR and CVD were closely related with 1.8% of individuals (95% CI, 1.6%-2.0%) with an eGFR > 90 mL/minute/1.73 m(2) estimated to develop CVD at 5 years, increasing to 21.1% (95% CI, 6.6%-35.6%) among those with an eGFR ≤ 30 mL/minute/1.73 m(2) The strong univariate relationship between low current eGFR and CVD was primarily explained by increasing age in adjusted analyses, although all eGFRs ≤ 80 mL/minute/1.73 m(2) remained associated with 30%-40% increased CVD rates, and particularly high CVD rates among individuals with an eGFR ≤ 30 mL/minute/1.73 m(2) (incidence rate ratio, 3.08 [95% CI, 2.04-4.65]).Conclusions: Among HIV-positive individuals in a large contemporary cohort, a strong relation between confirmed impaired eGFR and CVD was observed. This finding highlights the need for renal preventive measures and intensified monitoring for emerging CVD, particularly in older individuals with continuously low eGFRs. [ABSTRACT FROM AUTHOR]

Background. Female same-sex partnerships provide a unique opportunity to study the pathogenesis and transmissibility of bacterial vaginosis (BV) because it can be diagnosed in both members of the partnership. We conducted a nationwide community-enrolled cohort study of women who have sex with women, including women coenrolled with their regular female sexual partner (FSP), to investigate the BV incidence rate and factors associated with incident BV. Methods. Women who have sex with women, without prevalent BV in a cross-sectional study, were enrolled in a 24-month cohort study involving 3-monthly questionnaires and self-collected vaginal swabs that were scored by the Nugent method. We assessed the BV incidence rate per 100 woman-years (WY) and used univariate and multivariable Cox regression analysis to establish factors associated with BV acquisition. Results. Two hundred ninety-eight participants were enrolled in the cohort; 122 were coenrolled with their regular FSP. There were 51 incident cases of BV (rate, 9.75/100 WY; 95% confidence interval [CI], 7.41-12.83). Incident BV was associated with exposure to a new sexual partner (adjusted hazard ratio [AHR], 2.51; 95% CI, 1.30-4.82), a partner with BV symptoms (AHR, 3.99; 95% CI, 1.39-11.45), receptive oral sex (AHR, 3.52; 95% CI, 1.41-8.79), and onset of BV symptoms (AHR, 2.80; 95% CI, 1.39-5.61). Women coenrolled with their BV-negative partner had a greatly reduced risk of incident BV (AHR, 0.26; 95% CI, .11-.61), and high concordance of Nugent category (74%), which was predominantly normal vaginal flora throughout follow-up. Conclusions. These data highlight the strong influence of sexual relationships and behaviors on BV acquisition and the vaginal microbiota. They provide epidemiological evidence to support exchange of vaginal bacterial species between women and the concept that BV is sexually transmitted. [ABSTRACT FROM AUTHOR]

We performed a genome-wide association study and identified single-nucleotide polymorphism rs4698934 located in the intron of the TET2 gene on chromosome 4q24 nominally significantly associated with melanoma risk, and a novel somatic mutation of TET2 was identified in melanoma case.Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10–1.25); combined P = 7.70 × 10−7. This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma. [ABSTRACT FROM AUTHOR]

Background. A community-based study of women who have sex with women (WSW) was performed to determine the burden of bacterial vaginosis (BV), and behavioral factors influencing the vaginal microbiota of women and their female sexual partners (FSPs), as measured by Nugent score (NS).Methods. In a cross-sectional study of 18–55-year-old WSW recruited nationally, participants completed questionnaires and self-collected vaginal swab samples weekly on 3 occasions. BV was defined as an NS of 7–10. Factors associated with BV, stability of NS category, and concordance of these categories in coenrolled couples were examined with multivariable logistic regression analysis.Results. A total of 458 participants were recruited; 192 were coenrolled with their FSP (96 couples). BV was detected in 125 women (27%; 95% confidence interval [CI], 23%–32%). BV was associated with ≥4 lifetime FSPs (adjusted odds ratio [AOR], 1.9; 95% CI, 1.2–3.1), an FSP with BV symptoms (AOR, 2.9; 1.0–8.2) and smoking, with ≥30 cigarettes per week showing greatest odds (AOR, 2.7; 1.5–5.0). Of 428 women returning ≥2 swab samples, 375 (88%) had a stable NS category across all samples, predominantly reflecting normal flora. Coenrolled WSW were less likely to have BV (31% vs 23%; P = .07), and the majority (70%) were concordant for NS category (κ = 0.47; P ≤ .01), with most concordant for normal flora. Concordant NS category was associated with a relationship of >6 months (AOR, 4.7; 95% CI, 1.4–16.4) and frequent sexual contact (more than once per month; AOR, 2.7; 1.0–7.1).Conclusions. BV is associated with key behaviors and smoking practices in WSW, but longer-duration, sexually active WSW partnerships support a stable favorable vaginal microbiota. [ABSTRACT FROM PUBLISHER]

Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P < 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3ʹ untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82–0.96, P = 0.003, false discovery rate = 0.056). Further genotype–phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Recurrence of bacterial vaginosis over 6 months was significantly increased by remaining with a pretreatment sexual partner and inconsistent condom use, and halved with use of estrogen-containing contraceptives. Behavioral practices appear to play a significant role in modifying the effectiveness of antibiotic treatment of bacterial vaginosis.Background. Bacterial vaginosis (BV) recurrence posttreatment is common. Our aim was to determine if behaviors were associated with BV recurrence in women in a randomized controlled trial (RCT).Methods. Symptomatic 18- to 50-year-old females with BV (≥3 Amsel criteria and Nugent score [NS] = 4–10) were enrolled in a 3-arm randomized double-blind RCT Melbourne Sexual Health Centre, Australia, in 2009–2010. All 450 participants received oral metronidazole (7 days) and were equally randomized to vaginal clindamycin, lactobacillus-vaginal probiotic or vaginal placebo. At 1, 2, 3, and 6 months, participants self-collected vaginal smears and completed questionnaires. Primary endpoint was NS = 7–10. Cox regression was used to estimate hazard ratios (HRs) for risk of BV recurrence associated with baseline and longitudinal characteristics.Results. Four hundred four (90%) women with postrandomization data contributed to analyses. Cumulative 6-month BV recurrence was 28% (95% confidence interval [CI], 24%–33%) and not associated with treatment. After stratifying for treatment and adjusting for age and sex frequency, recurrence was associated with having the same pre-/posttreatment sexual partner (adjusted HR [AHR] = 1.9; 95% CI, 1.2–3.0), inconsistent condom use (AHR = 1.9; 95% CI, 1.0–3.3), and being non-Australian (AHR = 1.5; 95% CI, 1.0–2.1), and halved with use of an estrogen-containing contraceptive (AHR = 0.5; 95% CI, .3–.8).Conclusions. Risk of BV recurrence was increased with the same pre-/posttreatment sexual partner and inconsistent condom use, and halved with use of estrogen-containing contraceptives. Behavioral and contraceptive practices may modify the effectiveness of BV treatment.Clinical Trials Registration. ACTRN12607000350426. [ABSTRACT FROM PUBLISHER]

Background. Elevated macrophage inhibitory cytokine-1 (MIC-1/GDF15) levels in serum mediate anorexia and weight loss in some cancer patients and similarly elevated levels occur in chronic kidney disease (CKD). Serum MIC-1/GDF15 is also elevated in chronic inflammatory diseases and predicts atherosclerotic events independently of traditional risk factors. The relationship between chronic inflammation, decreasing body mass index (BMI) and increased mortality in CKD is not well understood and is being actively investigated. MIC-1/GDF15 may link these features of CKD.Methods. Cohorts of incident dialysis patients from Sweden (n = 98) and prevalent hemodialysis patients from the USA (n = 381) had serum MIC-1/GDF15, C-reactive protein (CRP) levels and BMI measured at study entry. Additional surrogate markers of nutritional adequacy, body composition and inflammation were assessed in Swedish patients. Patients were followed for all-cause mortality.Results. In the Swedish cohort, serum MIC-1/GDF15 was associated with decreasing BMI, measures of nutrition and markers of oxidative stress and inflammation. Additionally, high serum MIC-1/GDF15 levels identified patients with evidence of protein-energy wasting who died in the first 3 years of dialysis. The ability of serum MIC-1/GDF15 to predict mortality in the first 3 years of dialysis was confirmed in the USA cohort. In both cohorts, serum MIC-1/GDF15 level was an independent marker of mortality when adjusted for age, CRP, BMI, history of diabetes mellitus and/or cardiovascular disease and glomerular filtration rate or length of time on dialysis at study entry.Conclusions. MIC-1/GDF15 is a novel independent serum marker of mortality in CKD capable of significantly improving the mortality prediction of other established markers. MIC-1/GDF15 may mediate protein-energy wasting in CKD and represent a novel therapeutic target for this fatal complication. [ABSTRACT FROM PUBLISHER]

Of 682 antiretroviral-na_ve patients initiating antiretroviral therapy in a prospective, multicenter HIV-1 drug resistance monitoring study involving eight sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation(s) was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy in Asia.(See editorial commentary by Jordan on pages 1058–1060.)Of 682 antiretroviral-naïve patients initiating antiretroviral therapy in a prospective, multicenter human immunodeficiency virus type 1 (HIV-1) drug resistance monitoring study involving 8 sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy use in Asia. [ABSTRACT FROM AUTHOR]

Background. Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown.Methods. This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples.Results. Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2–16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4+ T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer.Conclusions. sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection. [ABSTRACT FROM PUBLISHER]

Background. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Methods. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with 130,000 person-years of exposure. Results. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. Conclusions. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provide. [ABSTRACT FROM AUTHOR]

Background: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART.Methods: Patients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii).Results: A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ).Conclusions: Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial. [ABSTRACT FROM AUTHOR]

Background. Toxicities observed with current combination antiretroviral therapy (CART) warrant a search for novel options, such as class-sparing regimens. Ritonavir-boosted double-protease inhibitor (PI)-only regimens are such an option but are prone to pharmacokinetic interactions. Methods. This 48-week randomized study examined the safety and efficacy of a switch in CART to a oncedaily regimen of saquinavir (SQV), ritonavir (RTV), and atazanavir (ATV) that did not include nucleoside reversetranscriptase inhibitors (NRTIs). The study also assessed the pharmacokinetic profile of a change in the SQV formulation, from 200 mg to 500 mg, in 2 regimens (SQV-RTV twice per day plus NRTIs [arm 1] and SQV-RTVATVo nce per day without NRTIs [arm 2]) in human immunodeficiency virus type 1-infected subjects (plasma human immunodeficiency virus RNA level, <50 copies/mL). [ABSTRACT FROM AUTHOR]

Background. Body composition changes complicate antiretroviral therapy. Improvements in lipoatrophy after a switch in nucleoside reverse-transcriptase inhibitors (NRTIs) have been demonstrated.We investigated 60 patients switching from failed NRTIs to ritonavir-boosted indinavir and efavirenz. Methods. Body composition (assessed by dual-energy x-ray absorptiometry scan and by single-slice computed tomography of the abdomen through the level of the fourth lumbar vertebra [L4] and the mid-right thigh) and fasted metabolics were measured at the baseline time-point at switch and at weeks 48 and 96 thereafter. Mitochondrial DNA and RNA were extracted from right-thigh subcutaneous fat and peripheral-blood mono nuclear cells (PBMCs) at weeks 0 and 48. The primary end point was the change in mean limb fat over 48 weeks. Results. At week 96, we observed increases in mean (standard deviation [SD]) limb fat (+620 [974] g; P = .003), L4 subcutaneous adipose tissue (+20 [35] cm² P<.001), mid-thigh subcutaneous adipose tissue (+5 [10] cm² and L4 visceral adipose tissue (+11 [34] cm² P = .01), but we also observed reduced lean limb mass (-831 [1100] g; P = .3). Mean (SD) mtDNA content in subcutaneous fat and in PBMCs increased (+109 [274] and +45 [100] copies/cell, respectively). Improved virological control or immune recovery did not explain the results. Triglyceride, total cholesterol, estimated low-density lipoprotein cholesterol, ratio of total cholesterol to high-density lipoprotein cholesterol, and blood glucose levels deteriorated (i.e., had increased by 206%, 67%, 58%, 19%, and 6%, respectively, at week 96). Conclusions. This regimen was associated with statistically significant but clinically modest increases in peripheral fat, visceral fat, and mitochondrial nucleic acid content. A predominantly adverse metabolic profile developed. [ABSTRACT FROM AUTHOR]

There is methodological debate as to whether cohorts defined by acquired immunodeficiency syndrome (AIDS) diagnosis can be used to estimate risks of cancer in persons with human immunodeficiency virus (HIV) before AIDS. The authors compared risks of non-AIDS-defining cancers before AIDS in persons with HIV using a cohort based on AIDS diagnosis and a second cohort based on HIV diagnosis. National population-based registries of AIDS and HIV diagnoses to August 1999 were matched separately with the National Cancer Registry in Australia. Four analyses were performed. In analysis 1, follow-up was from 5 years before AIDS registration in 8,118 persons with AIDS. Analysis 2 was similar but adjusted expected numbers of cancers for decreased survival. Analysis 3 was based on 7,061 persons registered with HIV, with follow-up from the reported date of diagnosis. Analysis 4 was based on 2,112 AIDS cases previously reported with HIV, with follow-up from 5 years before AIDS diagnosis. In all analyses, follow-up ended at cancer diagnosis, death, 6 months before AIDS, or the end of available cancer data, whichever occurred first. For 10 types of cancer there were at least three cases in any one of the analyses. For these cancers there was no systematic pattern such that one analysis produced consistently higher or lower estimates than the others. These analyses suggest that cancer risk in persons with HIV before AIDS diagnosis may be estimated reliably based on cancer experience 5 years before AIDS. [ABSTRACT FROM PUBLISHER]

Presents a randomized, controlled phase II trial comparing escalating doses of subcutaneous interleukin-2 (IL-2) plus antiretrovirals versus antiretroviral alone in HIV-infected patients with CD4[sup +] cell counts of 350 per cubic millimeter. Effects of the T cell-derived cytokine IL-2 on the immune system; Efficacy of the treatment groups; Side effects of subcutaneous IL-2 administration.

Background To improve melanoma early detection, tools to predict personal risk based on genetic information (polygenic risk scores, PRS) have been developed, but require external validation. Methods We analysed invasive melanoma incidence in UK Biobank (UKB; n = 395,647; 1,651 cases) and the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4,765; 303 cases). Three PRS were evaluated: 68 genetic variants (SNPs) at 54 loci from a 2020 meta-analysis (PRS68); 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50); 45 SNPs at 21 loci known pre-2020 (PRS45). 10-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. Results All PRS were strongly associated with melanoma incidence, including after adjustment for age, sex, ethnicity, and ease of tanning. Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in UKB (ratio expected/observed cases E/O=0.65, 95% confidence interval 0.62-0.68) and MCCS (E/O=0.65, 0.57-0.73). For UKB, this was reduced by PRS-adjustment, e.g. PRS50-adjusted risks E/O=0.91 (0.87-0.95). Discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (deltaAUC 0.07-0.1, p < 0.0001), and higher than for PRS45-adjusted risks (deltaAUC 0.02-0.04, p < 0.001). Conclusions A PRS derived from a larger, more diverse meta-analysis improves melanoma risk prediction compared to an earlier PRS. Re-calibration of absolute risks may be necessary for application to specific populations. Key messages A genetic score can improve prediction of melanoma risk and might help tailor melanoma prevention and early detection strategies to different risk levels. [ABSTRACT FROM AUTHOR]

Background A personal history of keratinocyte carcinoma (KC) has been reported as a risk factor for developing subsequent primary cutaneous and non-cutaneous malignancies. However most evidence to date stems from observational studies which are prone to bias, confounding and reverse causation. Our aim was to examine this association using different Mendelian randomization (MR) approaches. Methods We performed a one-sample MR analysis using individual-level data from the UK Biobank (n = 394,306). This analysis was then validated in an independent dataset in the QSkin cohort (n = 16,896). Using 64 independent genetic variants known to be associated with KC, we generated a polygenic risk score (PRS) for each participant in the UK Biobank and the QSkin cohort. We then performed two-sample MR analyses using genome-wide association study (GWAS) summary statistics. We tested the association between genetically predicted KC and risk of subsequent cancer using logistic regression. Results Results from one-sample MR analyses in the UK Biobank indicated that a personal history of KC was significantly associated with cancer overall (excluding melanoma) (OR: 1.15, 95% CI: 1.10-1.20, per doubling the prevalence of KC). The results from the two-sample MR corroborate the findings from the one-sample MR, although the risk estimate was lower (OR: 1.05, 95% CI: 1.03-1.07). Conclusions Our MR analyses suggest that genetically predicted KC is a risk factor for developing subsequent primary malignancies. Key messages A personal history of KC may serve as a proxy marker of inherited cancer risk. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) variants with reduced in vitro sensitivity to zidovudine, conferred by specific mutations in the viral reverse transcriptase, emerge during prolonged therapy. Late-stage disease and declining CD4 cell count are associated with more rapid emergence of these resistant variants. Isolates of HIV-1 from seroconverters were screened for the zidovudine-resistance marker mutation at codon 215. HIV-1 with the altered genotype was detected in 5 (8.2%) of 61 patients soon after onset of symptomatic primary illness and from the sex partner of 1 patient. These transmitted resistant viruses were either replaced by strains susceptible to zidovudine within a few months of infection or persisted for up to 1 year in the absence of prolonged zidovudine therapy. The resistant genotype persisted in 3 of 5 seroconverters but in 2 patients had reverted to wild type at 48 and 52 weeks. Primary infection with zidovudine-resistant variants of HIV-1 was not associated with a more severe symptomatic primary illness or more rapid CD4 cell decline at 1 year after infection. [ABSTRACT FROM PUBLISHER]

Analyses that adjust disease incidence data for reporting delays are often based on grouped data. A way of grouping data based on the quarter in which a case is reported, using all cases reported by a given cutoff date, is compared with the usual method of categorization based on a time-delay between diagnosis and reporting. The two methods of tabulation are illustrated using cases of the acquired immunodeficiency syndrome (AIDS) diagnosed and reported in Australia. A simple simulation study confirms that estimates of adjusted quarterly AIDS counts based on the quarter of report grouping are less variable than those based on the time-delay grouping. [ABSTRACT FROM AUTHOR]

This study used curve-fitting techniques to detail the dynamics of human immunodeficiency virus (HIV)-1 and its relationship to circulating T lymphocyte changes in a cohort of 41 male patients (mean age 36 ± 7 years) infected with HIV-1. The following characteristics of viral kinetics were obtained: virus load peak, 6.35 ± 0.71 log10 RNA copies/mL at 12.2 ±7.1 days; virus load drop from peak, 2.02 ± 0.93 log10 copies/mL; viral decay rate from peak, 0.071 ± 0.042 log10 RNA copies/mL/day; and steady state virus load, 4.57 ± 0.68 log10 copies/mL at 135 ± 81 days. Analysis of individual virus load curves revealed highly variable viral kinetics. Although these could be grouped into three distinct patterns, virus load and CD4 lymphocyte counts were similar in all patterns at 12 months, but the interval from infection to achievement of steady state virus load varied significantly. [ABSTRACT FROM PUBLISHER]

The relationship between the presence and severity of AIDS dementia complex (ADC) and the levels of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid (CSF) were assessed. Nineteen patients with ADC (stages 1–3), 6 without ADC (group 1), and 10 (group 2) without ADC but with cryptococcal meningitis or progressive multifocal leukoencephalopathy were studied. There was a significant relationship between increasing CSF virus burden and ADCseverity (P = .0006) but not with plasma burden and ADC severity. In group 2, CSF HIV-1 RNA levels in patients with cryptococcal meningitis were elevated. These results show that CSF HIV-1 RNA concentrations correlate well with ADCseverity but may also be increased by central nervous system infections, such as cryptococcal meningitis. [ABSTRACT FROM PUBLISHER]

Squamous cell carcinoma (SCC) of the eye occurs at substantially increased rates in individuals with human immunodeficiency virus (HIV) infection, but it has not been reported in individuals with iatrogenic or congenital immune deficiency. In a national, population-based cohort of 10180 renal transplantation patients from Australia with 86898 person-years of follow-up, we ascertained primary incident cancers diagnosed in 1982-2003 by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Standardized incidence ratios (SIRs) of cancer were calculated using age-, sex-, calendar year-, and state/territory-specific population cancer incidence rates. Statistical tests were two-sided. Five patients were diagnosed with ocular SCC after kidney transplantation (0.26 were expected), and the incidence was increased 20-fold (SIR = 19.5, 95% confidence interval [l] = 6.3 to 45.5). Compared with the entire cohort, the five patients with ocular SCC after transplantation were more likely to have resided in the subtropical state of Queensland (60% versus 17%, P= .04), to have had end-stage kidney disease as a result of glomerulonephritis (100% versus 46%, P = .02), and to have a history of cutaneous SCC (100% versus 29%, P= .002). The increased incidence of ocular SCC after kidney transplantation and after HIV infection strongly suggests that this neoplasm is an immune deficiency-associated cancer. Our data also support an interaction between immune suppression and sun exposure in the development of ocular SCC after kidney transplantation. [ABSTRACT FROM AUTHOR]

A response by Preeyaporn Srasuebkul and colleagues to a letter to the editor about their article on the use of prophylaxis in the antiretroviral therapy of the patients having advanced human immunodeficiency virus infection is presented.