Antiseptic mouthwash for gonorrhoea prevention (OMEGA): a randomised, double-blind, parallel-group, multicentre trial.

BACKGROUND: To address the increasing incidence of gonorrhoea and antimicrobial resistance, we compared the efficacy of Listerine and Biotène mouthwashes for preventing gonorrhoea among men who have sex with men (MSM). METHODS: The OMEGA trial was a multicentre, parallel-group, double-blind randomised controlled trial among MSM, done at three urban sexual health clinics and one general practice clinic in Australia. Men were eligible if they were diagnosed with oropharyngeal gonorrhoea by nucleic acid amplification test (NAAT) in the previous 30 days or were aged 16-24 years. They were randomly assigned to receive Listerine (intervention) or Biotène (control) via a computer-generated sequence (1:1 ratio, block size of four). Participants, clinicians, data collectors, data analysts, and outcome adjudicators were masked to the interventions after assignment. Participants were instructed to rinse and gargle with 20 mL of mouthwash for 60 s at least once daily for 12 weeks. Oropharyngeal swabs were collected by research nurses every 6 weeks, and participants provided saliva samples every 3 weeks, to be tested for Neisseria gonorrhoeae with NAAT and quantitative PCR. The primary outcome was proportion of MSM diagnosed with oropharyngeal N gonorrhoeae infection at any point over the 12-week period, defined as a positive result for either oropharyngeal swabs or saliva samples by NAAT, and the cumulative incidence of oropharyngeal gonorrhoea at the week 12 visit. A modified intention-to-treat analysis for the primary outcome was done that included men who provided at least one follow-up specimen over the 12-week study period. The trial was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12616000247471). FINDINGS: Between March 30, 2016, and Oct 26, 2018, 786 MSM were screened and 256 were excluded. 264 MSM were randomly assigned to the Biotène group and 266 to the Listerine group. The analysis population included 227 (86%) men in the Biotène group and 219 (82%) in the Listerine group. Oropharyngeal gonorrhoea was detected in ten (4%) of 227 of MSM in the Biotène group and in 15 (7%) of 219 in the Listerine group (adjusted risk difference 2·5%, 95% CI -1·8 to 6·8). The cumulative incidence of oropharyngeal gonorrhoea at the week 12 visit did not differ between the two mouthwash groups (adjusted risk difference 3·1%, 95% CI -1·4 to 7·7). INTERPRETATION: Listerine did not reduce the incidence of oropharyngeal gonorrhoea compared with Biotène. However, previous research suggests that mouthwash might reduce the infectivity of oropharyngeal gonorrhoea; therefore, further studies of mouthwash examining its inhibitory effect on N gonorrhoeae are warranted to determine if it has a potential role for the prevention of transmission. FUNDING: Australian National Health and Medical Research Council.

Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma.

Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Influence of Substance Use Disorders on 2-Year HIV Care Retention in the United States.

Substance use disorders (SUDs) are thought to predict care discontinuity, though magnitude and substance-specific variance of effects are unclear. This report of analytic work undertaken with a multi-regional American cohort of 9153 care enrollees addresses these gaps. Care retention was computed from 24-month post-linkage clinic visit documentation, with SUD cases identified from patient-report screening instruments. Two generalized estimating equations tested binary and hierarchial SUD predictors of retention, and potential effect modification by patient age-group, sex, and care site. Findings demonstrate: (1) detrimental SUD effect, equivalent to a nine percentage-point decrease in retention, with independent effects of age-group and care site; (2) substance-specific effect of marijuana UD associated with lower retention; and (3) age-modification of each effect on care discontinuity, with SUDs serving as a risk factor among 18-29 year-olds and protective factor among 60+ year-olds. Collective findings document patient attributes as influences that place particular subgroups at-risk to discontinue care.

Marijuana use and HIV treatment outcomes among PWH receiving care at an urban HIV clinic.

BACKGROUND: While marijuana use is prevalent among persons with HIV (PWH), few studies have examined the relationship between marijuana use and HIV treatment outcomes independent of alcohol and other drug use. METHODS: We conducted a prospective cohort study to examine the relationships between frequency of marijuana use and antiretroviral therapy (ART) adherence and viral suppression in patients enrolled in the Johns Hopkins HIV Clinical Cohort between September 2013 through November 2015 (N=1377). We categorized marijuana use as no use, none in the last 3months, monthly use or less, weekly/daily. Our outcomes of interest were use of ART, ≥90 ART adherence, and viral suppression (HIV1-RNA<200 copies). We conducted multivariable analyses to examine associations between the frequency of marijuana use and our treatment outcomes, using generalized estimating equations to account for repeated measures. Other independent variables of interest included alcohol use, other drug use, and depressive symptoms. Analyses were adjusted for age, race, sex and HIV acquisition risk factor. RESULTS: In multivariable analyses we found no statistically significant association between frequency of marijuana use and our treatment outcomes. Alcohol use, other drug use and depressive symptoms were associated with lower odds of ART adherence and viral suppression. CONCLUSIONS: In this sample of PWH in care, frequency of marijuana use independent of other substance use does not appear to be associated with negative HIV treatment outcomes. Our results indicate that unlike alcohol, other substances and depression, marijuana use may not be a barrier to the effective treatment of HIV.

Comprehensiveness of HIV care provided at global HIV treatment sites in the IeDEA consortium: 2009 and 2014.

INTRODUCTION: An important determinant of the effectiveness of HIV treatment programs is the capacity of sites to implement recommended services and identify systematic changes needed to ensure that invested resources translate into improved patient outcomes. We conducted a survey in 2014 of HIV care and treatment sites in the seven regions of the International epidemiologic Database to Evaluate AIDS (IeDEA) Consortium to evaluate facility characteristics, HIV prevention, care and treatment services provided, laboratory capacity, and trends in the comprehensiveness of care compared to data obtained in the 2009 baseline survey. METHODS: Clinical staff from 262 treatment sites in 45 countries in IeDEA completed a site survey from September 2014 to January 2015, including Asia-Pacific with Australia (n = 50), Latin America and the Caribbean (n = 11), North America (n = 45), Central Africa (n = 17), East Africa (n = 36), Southern Africa (n = 87), and West Africa (n = 16). For the 55 sites with complete data from both the 2009 and 2014 survey, we evaluated change in comprehensiveness of care. RESULTS: The majority of the 262 sites (61%) offered seven essential services (ART adherence, nutritional support, PMTCT, CD4+ cell count testing, tuberculosis screening, HIV prevention, and outreach). Sites that were publicly funded (64%), cared for adults and children (68%), low or middle Human Development Index (HDI) rank (68%, 68%), and received PEPFAR support (71%) were most often fully comprehensive. CD4+ cell count testing was universally available (98%) but only 62% of clinics offered it onsite. Approximately two-thirds (69%) of sites reported routine viral load testing (44-100%), with 39% having it onsite. Laboratory capacity to monitor antiretroviral-related toxicity and diagnose opportunistic infections varied widely by testing modality and region. In the subgroup of 55 sites with two surveys, comprehensiveness of services provided significantly increased across all regions from 2009 to 2014 (5.7 to 6.5, p < 0.001). CONCLUSION: The availability of viral load monitoring remains suboptimal and should be a focus for site capacity, particularly in East and Southern Africa, where the majority of those initiating on ART reside. However, the comprehensiveness of care provided increased over the past 5 years and was related to type of funding received (publicly funded and PEPFAR supported).

Prevalence and Factors Associated with Hazardous Alcohol Use Among Persons Living with HIV Across the US in the Current Era of Antiretroviral Treatment.

Hazardous alcohol use is associated with detrimental health outcomes among persons living with HIV (PLWH). We examined the prevalence and factors associated with hazardous alcohol use in the current era using several hazardous drinking definitions and binge drinking defined as ≥5 drinks for men versus ≥4 for women. We included 8567 PLWH from 7 U.S. sites from 2013 to 2015. Current hazardous alcohol use was reported by 27% and 34% reported binge drinking. In adjusted analyses, current and past cocaine/crack (odd ratio [OR] 4.1:3.3-5.1, p < 0.001 and OR 1.3:1.1-1.5, p < 0.001 respectively), marijuana (OR 2.5:2.2-2.9, p < 0.001 and OR 1.4:1.2-1.6, p < 0.001), and cigarette use (OR 1.4:1.2-1.6, p < 0.001 and OR 1.3:1.2-1.5, p < 0.001) were associated with increased hazardous alcohol use. The prevalence of hazardous alcohol use remains high in the current era, particularly among younger men. Routine screening and targeted interventions for hazardous alcohol use, potentially bundled with interventions for other drugs, remain a key aspect of HIV care.

Respecting patients is associated with more patient-centered communication behaviors in clinical encounters.

OBJECTIVE: Attitudes towards patients may influence how clinicians interact. We investigated whether respect for patients was associated with communication behaviors during HIV care encounters. METHODS: We analyzed audio-recordings of visits between 413 adult HIV-infected patients and 45 primary HIV care providers. The independent variable was clinician-reported respect for the patient and outcomes were clinician and patient communication behaviors assessed by the Roter Interaction Analysis System (RIAS). We performed negative binomial regressions for counts outcomes and linear regressions for global outcomes. RESULTS: When clinicians had higher respect for a patient, they engaged in more rapport-building, social chitchat, and positive talk. Patients of clinicians with higher respect for them engaged in more rapport-building, social chitchat, positive talk, and gave more psychosocial information. Encounters between patients and clinicians with higher respect for them had more positive clinician emotional tone [regression coefficient 2.97 (1.92-4.59)], more positive patient emotional tone [2.71 (1.75-4.21)], less clinician verbal dominance [0.81 (0.68-0.96)] and more patient-centeredness [1.28 (1.09-1.51)]. CONCLUSIONS: Respect is associated with positive and patient-centered communication behaviors during encounters. PRACTICE IMPLICATIONS: Clinicians should be mindful of their respectful attitudes and work to foster positive regard for patients. Educators should consider methods to enhance trainees' respect in communication skills training.

Characteristics and comprehensiveness of adult HIV care and treatment programmes in Asia-Pacific, sub-Saharan Africa and the Americas: results of a site assessment conducted by the International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration.

INTRODUCTION: HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide. METHODS: Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services. RESULTS: Most sites reported serving urban (61%; region range (rr): 33-100%) and both adult and paediatric populations (77%; rr: 29-96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services - nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother-to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) - were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services. CONCLUSIONS: This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care.

Surgeon-administered conscious sedation and local anesthesia for ambulatory anorectal surgery.

Anorectal procedures are often performed in an outpatient setting using a variety of anesthetic techniques. One technique that has not been well studied is surgeon-administered conscious sedation along with local anesthetic. The purpose of this study was to evaluate the use of this technique with emphasis on safety, efficacy, and patient satisfaction. Chart review was performed on 133 consecutive patients who had anorectal procedures at an outpatient surgery center. Additionally, 65 patients were enrolled prospectively and completed a satisfaction survey. Inclusively, charts of 198 patients who underwent outpatient anorectal surgery under conscious sedation and local anesthesia under the direction of a colorectal surgeon from 2004 through 2008 were reviewed. Parameters related to patient and procedural characteristics, safety, efficacy, and satisfaction were evaluated. Surgeon-administered sedation consisted of combined fentanyl and midazolam in 90 per cent. Eighty per cent of procedures were performed in the prone position and 23 per cent were in combination with an endoscopic procedure. Eighty-two per cent were classified as American Society of Anesthesiologists Grade 1 or 2. Transient mild hypoxemia or hypotension occurred in 4 and 3 per cent of the patients, respectively. Mean operative time was 29 minutes with a mean stay in the postanesthesia care unit of 37 minutes. There were no early major cardiac or respiratory complications. Ninety-seven per cent of the patients surveyed reported a high degree of satisfaction. Surgeon-administered conscious sedation with local anesthesia was well tolerated for outpatient anorectal surgeries. Additional studies are needed to confirm the safety and efficacy of this technique.

Estimating summer nutrient concentrations in Northeastern lakes from SPARROW load predictions and modeled lake depth and volume.

Global nutrient cycles have been altered by the use of fossil fuels and fertilizers resulting in increases in nutrient loads to aquatic systems. In the United States, excess nutrients have been repeatedly reported as the primary cause of lake water quality impairments. Setting nutrient criteria that are protective of a lakes ecological condition is one common solution; however, the data required to do this are not always easily available. A useful solution for this is to combine available field data (i.e., The United States Environmental Protection Agency (USEPA) National Lake Assessment (NLA)) with average annual nutrient load models (i.e., USGS SPARROW model) to estimate summer concentrations across a large number of lakes. In this paper we use this combined approach and compare the observed total nitrogen (TN) and total phosphorus (TN) concentrations in Northeastern lakes from the 2007 National Lake Assessment to those predicted by the Northeast SPARROW model. We successfully adjusted the SPARROW predictions to the NLA observations with the use of Vollenweider equations, simple input-output models that predict nutrient concentrations in lakes based on nutrient loads and hydraulic residence time. This allows us to better predict summer concentrations of TN and TP in Northeastern lakes and ponds. On average we improved our predicted concentrations of TN and TP with Vollenweider models by 18.7% for nitrogen and 19.0% for phosphorus. These improved predictions are being used in other studies to model ecosystem services (e.g., aesthetics) and dis-services (e.g. cyanobacterial blooms) for ~18,000 lakes in the Northeastern United States.

A multicenter study of physician mindfulness and health care quality.

PURPOSE: Mindfulness (ie, purposeful and nonjudgmental attentiveness to one's own experience, thoughts, and feelings) is associated with physician well-being. We sought to assess whether clinician self-rated mindfulness is associated with the quality of patient care. METHODS: We conducted an observational study of 45 clinicians (34 physicians, 8 nurse practitioners, and 3 physician assistants) caring for patients infected with the human immunodeficiency virus (HIV) who completed the Mindful Attention Awareness Scale and 437 HIV-infected patients at 4 HIV specialty clinic sites across the United States. We measured patient-clinician communication quality with audio-recorded encounters coded using the Roter Interaction Analysis System (RIAS) and patient ratings of care. RESULTS: In adjusted analyses comparing clinicians with highest and lowest tertile mindfulness scores, patient visits with high-mindfulness clinicians were more likely to be characterized by a patient-centered pattern of communication (adjusted odds ratio of a patient-centered visit was 4.14; 95% CI, 1.58-10.86), in which both patients and clinicians engaged in more rapport building and discussion of psychosocial issues. Clinicians with high-mindfulness scores also displayed more positive emotional tone with patients (adjusted ß = 1.17; 95% CI, 0.46-1.9). Patients were more likely to give high ratings on clinician communication (adjusted prevalence ratio [APR] = 1.48; 95% CI, 1.17-1.86) and to report high overall satisfaction (APR = 1.45; 95 CI, 1.15-1.84) with high-mindfulness clinicians. There was no association between clinician mindfulness and the amount of conversation about biomedical issues. CONCLUSIONS: Clinicians rating themselves as more mindful engage in more patient-centered communication and have more satisfied patients. Interventions should determine whether improving clinician mindfulness can also improve patient health outcomes.

Impact of generic antiretroviral therapy (ART) and free ART programs on time to initiation of ART at a tertiary HIV care center in Chennai, India.

Antiretroviral therapy (ART) access in the developing world has improved, but whether increased access has translated to more rapid treatment initiation among those who need it is unknown. We characterize time to ART initiation across three eras of ART availability in Chennai, India (1996-1999: pregeneric; 2000-2003: generic; 2004-2007: free rollout). Between 1996 and 2007, 11,171 patients registered for care at the YR Gaitonde Centre for AIDS Research and Education (YRGCARE), a tertiary HIV referral center in southern India. Of these, 5726 patients became eligible for ART during this period as per Indian guidelines for initiation of ART. Generalized gamma survival models were used to estimate relative times (RT) to ART initiation by calendar periods of eligibility. Time to initiation of ART among patients in Chennai, India was also compared to an HIV clinical cohort in Baltimore, USA. Median age of the YRGCARE patients was 34 years; 77% were male. The median CD4 at presentation was 140 cells/µl. After adjustment for demographics, CD4 and WHO stage, persons in the pregeneric era took 3.25 times longer (95% confidence interval [CI]: 2.53-4.17) to initiate ART versus the generic era and persons in the free rollout era initiated ART more rapidly than the generic era (RT: 0.73; 95% CI: 0.63-0.83). Adjusting for differences across centers, patients at YRGCARE took longer than patients in the Johns Hopkins Clinical Cohort (JHCC) to initiate ART in the pregeneric era (RT: 4.90; 95% CI: 3.37-7.13) but in the free rollout era, YRGCARE patients took only about a quarter of the time (RT: 0.31; 95% CI: 0.22-0.44). These data demonstrate the benefits of generic ART and government rollouts on time to initiation of ART in one developing country setting and suggests that access to ART may be comparable to developed country settings.

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells.

Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

Anti-angiogenic activity of cranberry proanthocyanidins and cytotoxic properties in ovarian cancer cells.

Cranberry extracts may provide beneficial health effects in the treatment of various diseases, including cancer. However, the underlying molecular mechanisms of antineoplastic properties are not understood. We report the effect of a proanthocyanidin (PAC)-rich isolate from cranberry (PAC-1) as a therapeutic agent with dual activity to target both ovarian cancer viability and angiogenesis in vitro. PAC-1 treatment of chemotherapy-resistant SKOV-3 cells blocked cell cycle progression through the G2/M phase, increased the generation of reactive oxygen species (ROS), and induced apoptosis through activation of intrinsic and extrinsic pathway components. Cytotoxicity of PAC-1 was partially based on ROS generation and could be blocked by co-treatment with antioxidant glutathione. PAC-1 reduced the cell viability of both SKOV-3 ovarian cancer cells and HUVEC endothelial cells in a dose-dependent manner and blocked the activation of the pro-survival factor AKT. Furthermore, PAC-1 blocked vascular endothelial growth factor (VEGF)-stimulated receptor phosphorylation in endothelial cells, which correlated with the inhibition of endothelial tube formation in vitro. Our findings suggest that PAC-1 exerts potent anticancer and anti-angiogenic properties and that highly purified PAC from cranberry can be further developed to treat ovarian cancer in combinational or single-agent therapy.

System-level analysis of neuroblastoma tumor-initiating cells implicates AURKB as a novel drug target for neuroblastoma.

PURPOSE: Neuroblastoma (NB) is an aggressive tumor of the developing peripheral nervous system that remains difficult to cure in the advanced stages. The poor prognosis for high-risk NB patients is associated with common disease recurrences that fail to respond to available therapies. NB tumor-initiating cells (TICs), isolated from metastases and primary tumors, may escape treatment and contribute to tumor relapse. New therapies that target the TICs may therefore prevent or treat tumor recurrences. EXPERIMENTAL DESIGN: We undertook a system-level characterization of NB TICs to identify potential drug targets against recurrent NB. We used next-generation RNA sequencing and/or human exon arrays to profile the transcriptomes of 11 NB TIC lines from six NB patients, revealing genes that are highly expressed in the TICs compared with normal neural crest-like cells and unrelated cancer tissues. We used gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry to confirm the presence of proteins corresponding to the most abundant TIC-enriched transcripts, thereby providing validation to the gene expression result. RESULTS: Our study revealed that genes in the BRCA1 signaling pathway are frequently misexpressed in NB TICs and implicated Aurora B kinase as a potential drug target for NB therapy. Treatment with a selective AURKB inhibitor was cytotoxic to NB TICs but not to the normal neural crest-like cells. CONCLUSION: This work provides the first high-resolution system-level analysis of the transcriptomes of 11 primary human NB TICs and identifies a set of candidate NB TIC-enriched transcripts for further development as therapeutic targets.

Substance abuse and psychiatric disorders in HIV-positive patients: epidemiology and impact on antiretroviral therapy.

There is a high prevalence of substance abuse and psychiatric disorders among HIV-infected individuals. Importantly, drug and alcohol-use disorders are frequently co-morbid with depression, anxiety and severe mental illness. Not only do these disorders increase the risk of contracting HIV, they have also been associated with decreased highly active antiretroviral therapy (HAART) utilisation, adherence and virological suppression. The literature evaluating the relationship between substance abuse and HIV outcomes has primarily focused on injection drug users, although there has been increasing interest in alcohol, cocaine and marijuana. Similarly, the mental health literature has focused largely on depression, with a lesser focus on severe mental illness or anxiety. To date, there is little literature evaluating the association between co-occurring HIV, substance abuse and mental illness on HAART uptake, adherence and virological suppression. Adherence interventions in these populations have demonstrated mixed efficacy. Both directly observed therapy and pharmacist-assisted interventions appear promising, as do integrated behavioural interventions. However, the current intervention literature has several limitations: few of these studies are randomised, controlled trials; the sample sizes have generally been small; and co-occurring substance abuse and mental illness has not specifically been targeted in these studies. Future studies examining individual substances of abuse, psychiatric disorders and co-occurring substance abuse and psychiatric disorders on HIV outcomes will inform targeted adherence interventions.

Darwinian selection on a selfing locus.

The shift to self-pollination is one of the most prevalent evolutionary transitions in flowering plants. In the selfing plant Arabidopsis thaliana, pseudogenes at the SCR and SRK self-incompatibility loci are believed to underlie the evolution of self-fertilization. Positive directional selection has driven the evolutionary fixation of pseudogene alleles of SCR, leading to substantially reduced nucleotide variation. Coalescent simulations indicate that this adaptive event may have occurred very recently and is possibly associated with the post-Pleistocene expansion of A. thaliana from glacial refugia. This suggests that ancillary morphological innovations associated with self-pollination can evolve rapidly after the inactivation of the self-incompatibility response.