People living with HIV who inject or have injected non-prescription drugs: Evidence of substantial differences in health inequalities and experiences of clinical care.

INTRODUCTION: This study investigates differences in health and well-being associated with current, past or no injecting drug use (IDU) among people living with HIV (PLHIV) in Australia, identifying key health care considerations between injecting experiences. METHODS: Data were extracted from the HIV Futures 9 study; a survey of PLHIV conducted in 2018-2019. Chi-square and analysis of variance analyses compared clinical and treatment characteristics, major physical and mental comorbidities, sexually transmitted infection diagnoses, and quality of life for those who reported current (last 12 months), past (12+ months ago) or no IDU. RESULTS: Current IDU (n = 106) was associated with higher rates of sexually transmitted infection testing and diagnoses, higher frequency of self-reported antiretroviral therapy non-adherence due to drug use and greater social quality of life than past (n = 126) or no IDU (n = 508; total N = 740). Past and current IDUs were associated with more mental illness diagnoses and self-reported concern about drug use. Past IDU was associated with more physical comorbidities, lower satisfaction with clinical care and greater difficulty in affording health care than current or no IDU. DISCUSSION AND CONCLUSIONS: Past and current IDUs are associated with unique health concerns. However, past IDU appears to be related to greater dissatisfaction in navigating health care than individuals with current IDU experience. Higher social connection and the types of services being accessed by individuals who currently inject may play a role in shaping service satisfaction. Peer-based interventions to help support individuals in accessing services that are affirming of their needs is an ongoing priority.

Nonlinear optical properties and carrier recombination lifetime of GaN.

Nonlinear optical properties of a selection of gallium nitride samples have been measured using picosecond and nanosecond duration laser pulses at 532 nm. The values of the two-photon absorption coefficient, free carrier absorption cross section, and free carrier refraction cross section are determined along with the recombination lifetime of photogenerated carriers. The effect of hot isostatic pressing on these properties in samples with linear absorption at the band edge due to defects is explored.

Playing at the edges, navigating sexual boundaries, and narrating sexual distress; Practices and perspectives of sexuality and gender diverse people who use GHB.

BACKGROUND: Research addressing sexualised use of GHB to date has largely focussed on gay and bisexual men's GHB use in the context of chemsex, this research has highlighted risks and experiences associated with sexual violence. No studies have included people of diverse sexualities and genders and documented reported practices to ensure mutually gratifying and consensual sex in the context of sexualised drug use (SDU). METHODS: Semi-structured interviews were conducted with 31 people from sexuality and gender diverse communities living in Australia who reported three or more occasions of GHB use in the previous 12 months. Participants were asked about their use of GHB for sex, their experiences of GHB sex and their approaches to negotiating sexual boundaries. Data were analysed thematically. RESULTS: Most participants valued the sexual possibilities enabled by disinhibitory components of GHB and were cognisant of respecting other's sexual boundaries in the context of GHB sex. Participants reported strategies to ensure communication prior to and throughout GHB sex. However, several participants narrated experiences of GHB sex that they felt were distressing and, in some circumstances, sexually violent. In most instances participant's resisted terminology of sexual violence or non-consent as descriptors of their experience and none reported accessing sexual violence services. CONCLUSION: Positive strategies to facilitate sexual communication prior to and throughout GHB sex should be reflected in health promotion and service level responses to promote affirmative and continuous consent among people who use GHB for sex. Education initiatives to help people engaged in SDU to recognise and respond to sexual violence if it occurs ought to be prioritised.

Use of the bacterial reverse mutation assay to predict carcinogenicity of N-nitrosamines.

Under ICH M7, impurities are assessed using the bacterial reverse mutation assay (i.e., Ames test) when predicted positive using in silico methodologies followed by expert review. N-Nitrosamines (NAs) have been of recent concern as impurities in pharmaceuticals, mainly because of their potential to be highly potent mutagenic carcinogens in rodent bioassays. The purpose of this analysis was to determine the sensitivity of the Ames assay to predict the carcinogenic outcome with curated proprietary Vitic (n = 131) and Leadscope (n = 70) databases. NAs were selected if they had corresponding rodent carcinogenicity assays. Overall, the sensitivity/specificity of the Ames assay was 93-97% and 55-86%, respectively. The sensitivity of the Ames assay was not significantly impacted by plate incorporation (84-89%) versus preincubation (82-89%). Sensitivity was not significantly different between use of rat and hamster liver induced S9 (80-93% versus 77-96%). The sensitivity of the Ames is high when using DMSO as a solvent (87-88%). Based on the analysis of these databases, the Ames assay conducted under OECD 471 guidelines is highly sensitive for detecting the carcinogenic hazards of NAs.

Controlling for pleasure and risk: The experiences of sexuality and gender diverse people who use GHB.

BACKGROUND: GHB is used among some sexuality and gender diverse populations at elevated rates, however little qualitative research has explored GHB use among these populations with regards to diverse contexts, settings, practices, and experiences of use. Internationally, harms relating to GHB overdose appear to be increasing. Research outlining consumers' experiences of GHB-related pleasures and their strategies to reduce harms may inform GHB education and intervention responses. METHODS: N = 31 participants reporting three or more occasions of GHB use within the previous 12 months were recruited via digital advertising and snowball methods. Semi-structured interviews were conducted, data were transcribed and analysed in NVivo using a thematic framework analysis. Emergent themes were charted, and divergences and convergences were considered with regards to the sexuality and gender identities of participants. RESULTS: Pleasures associated with GHB were described in relation to the sensation of the GHB high and experiences of intimacy, and connection. GHB was used to enhance socialising and sex in domestic, private, and commercial venues. Participants prioritised terminology of 'control' when describing their practices associated with GHB dosing, measuring, timing and peer moderation. Most participants reported personal experience of GHB overdose with loss of consciousness. CONCLUSION: Participants' near-ubiquitous experience of GHB overdose highlights ongoing education needs around overdose prevention. Efforts must target people new to GHB use who appeared particularly susceptible to overdose. Inconsistencies in understandings around GHB overdose, the perceived severity of overdose and the differences between GHB and its precursors GBL and 1,4-BD, highlight potential focus areas of future education responses. Further research is required to better understand consumers' experiences of sexual violence in the context of GHB use.

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine.

Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some well-validated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta™Mouse lung epithelial cells (FE1 cell assay) and a regulatory-compliant in vivo Big Blue® mouse test. Consistent with previous reports, an additional six-well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.

HCV knowledge, disclosure practices, and risk perceptions among gay and bisexual men who do and do not engage in group sex while using drugs.

ABSTRACT Research suggests that hepatitis C virus (HCV) transmission is more likely among gay and bisexual men (GBM) who engage in sexually adventurous practices, including group sex while using drugs. The current study explored drug use, sexual practices, HCV knowledge, HCV disclosure, and beliefs about HCV transmission among GBM (n = 193) reporting group sex after/while using drugs compared to those who did not. Survey findings indicate that men who participated in group sex while using drugs were more likely to have engaged in other sexually adventurous practices, ever injected drugs, have greater knowledge of HCV, and to be living with HIV. They were also more likely to perceive themselves at risk of acquiring HCV and to know that their sexual activities put them at risk. Interestingly, they had lower expectations of HCV disclosure and were less concerned about the HCV status of their partners. The lower expectations around disclosure and concern about the HCV status of their partners reflect the challenges for GBM in managing HCV transmission where there are limited effective behavioural strategies for reducing sexual transmission, This research also highlights the need to promote HCV testing and treatment to GBM who engage in group sex while using drugs.

Knowledge, attitudes and practices related to hepatitis C among gay and bisexual men in the era of direct-acting antivirals: implications for treatment and prevention.

Increases in hepatitis C (HCV) infections among gay and bisexual men have recently been reported in a number of countries, with sexual transmission being the primary route of infection. Given that in countries such as Australia most gay and bisexual men living with HIV are already engaged in clinical care - as are an increasing number of HIV-negative men - there is potential for reducing onward HCV transmission through proactive testing and treatment. This study explored knowledge, attitudes and practices related to HCV among 194 gay and bisexual men collected through an online survey in Australia. Overall, respondents had high levels of HCV knowledge; however, only 76% knew about the availability of new treatments for HCV. Men's knowledge of their own HCV testing history was uncertain, with one in six unaware if they had ever been tested. Among men who reported recent drug injecting, one-third had been injected by someone else, and two-thirds had injected someone else, indicating a subculture of cross-administering within sexualised drug-use networks. We argue that the robust sexual, socio-cultural and clinical infrastructure that has been developed by - and for - gay and bisexual men around HIV care and prevention creates the potential for reducing HCV in this group.

A regenerative erythropoietic response does not increase the frequency of Pig-a mutant reticulocytes and erythrocytes in Sprague-Dawley rats.

The in vivo rodent Pig-a mutation assay is a sensitive test to identify exposure to mutagenic substances, and has been proposed as an assay for the identification of impurities for pharmaceuticals. Red blood cells (RBCs) and reticulocytes (RETs) are analyzed by flow cytometry after exposure to potentially mutagenic chemicals for cells deficient in the cell surface anchored protein CD59, representing mutation in the X-linked Pig-a gene. The full potential of the assay as well as its limitations are currently being explored. The current study investigated the effects of regenerative erythropoietic bone marrow responses on the frequency of Pig-a mutated reticulocytes (RETCD59- ) and erythrocytes (RBCCD59- ). We hypothesized that a robust regenerative erythropoietic response would not increase the basal frequency of RETCD59- or RBCCD59- cells. Two groups of six male Sprague-Dawley rats either had 2 mL of blood sampled each day via an indwelling catheter over a period of 5 days or were minimally sampled for hematology and used as controls. Blood was also then collected and evaluated 5, 18, and 49 days after the initial bleed period for the number of Pig-a mutant cells in either the RET or RBC population. Despite the expected decrease in hematocrit and the correlative increase in reticulocytes after bleeding, no increase in the number of Pig-a mutant cells was observed in male Sprague-Dawley rats that were bled for five consecutive days. These results indicate that changes in erythropoiesis and hematology parameters in rats appear to have no effect on the background levels of Pig-a mutated RETs and RBCs. Environ. Mol. Mutagen. 59:91-95, 2018. © 2017 Wiley Periodicals, Inc.

Peptide bond-forming reagents HOAt and HATU are not mutagenic in the bacterial reverse mutation test.

The peptide bond-forming reagents 1-hydroxy-7-azabenzotriazole (HOAt, CAS 39968-33-7) and O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, CAS 148893-10-1) either have structural alerts, unclassified features or are considered out of domain when evaluated for potential mutagenicity with in silico programs DEREK and CaseUltra. Since they are commonly used reagents in pharmaceutical drug syntheses, they may become drug substance or drug product impurities and would need to be either controlled to appropriately safe levels or tested for mutagenicity. Both reagents were tested in the bacterial reverse mutation (Ames) test at Covance, under GLP conditions, following the OECD test guideline and ICH S2(R1) recommendations and found to be negative. Our data show that HOAt and HATU-common pharmaceutical synthesis reagents-are not mutagenic, and can be treated as ordinary drug impurities.

Measuring refractive index using the focal displacement method.

A simple technique is introduced for measuring the refractive index of plane-parallel samples having thickness of the order of a millimeter. The refractive index values are reported for six bulk semiconductors, each index measured at two infrared wavelengths using this method. The values are found to be within a few percent of those in literature for four semiconductors. The other two semiconductors were newly grown ternary alloys (CdMgTe and CdMnTe), for which the refractive index values have not been reported previously at the wavelengths studied here.

International Pig-a gene mutation assay trial: evaluation of transferability across 14 laboratories.

A collaborative international trial was conducted to evaluate the reproducibility and transferability of an in vivo mutation assay based on the enumeration of CD59-negative rat erythrocytes, a phenotype that is indicative of Pig-a gene mutation. Fourteen laboratories participated in this study, where anti-CD59-PE, SYTO 13 dye, and flow cytometry were used to determine the frequency of CD59-negative erythrocytes (RBC(CD59-)) and CD59-negative reticulocytes (RET(CD59-)). To provide samples with a range of mutant phenotype cell frequencies, male rats were exposed to N-ethyl-N-nitrosourea (ENU) via oral gavage for three consecutive days (Days 1-3). Each laboratory studied 0, 20, and 40 mg ENU/kg/day (n = 5 per group). Three sites also evaluated 4 mg/kg/day. At a minimum, blood samples were collected three times: predosing and on Days 15 and 30. Blood samples were processed according to a standardized sample processing and data acquisition protocol, and three endpoints were measured: %reticulocytes, frequency of RET(CD59-) , and frequency of RBC(CD59-) . The methodology was found to be reproducible, as the analysis of technical replicates resulted in experimental coefficients of variation that approached theoretical values. Good transferability was evident from the similar kinetics and magnitude of the dose-related responses that were observed among different laboratories. Concordance correlation coefficients showed a high level of agreement between the reference site and the test sites (range: 0.87-0.99). Collectively, these data demonstrate that with adequate training of personnel, flow cytometric analysis is capable of reliably enumerating mutant phenotype erythrocytes, thereby providing a robust in vivo mutation assay that is readily transferable across laboratories.

Wavelength dependence of two photon and free carrier absorptions in InP.

Nonlinear absorption at 1.064 and 1.535 microm wavelengths by two photon and free carrier absorption processes in undoped and Fe doped InP has been investigated. Using picosecond and nanosecond duration lasers, a self-consistent set of the two photon and free carrier absorption coefficients are experimentally obtained through nonlinear transmission measurements for the first time. Reduced carrier recombination lifetime caused a decrease in nonlinear absorption of nanosecond duration laser pulses in Fe doped samples.

Metabolism-dependent mutagenicity of a compound containing a piperazinyl indazole motif: Role of a novel p450-mediated metabolic reaction involving a putative oxaziridine intermediate.

Compound 1a (6-chloro-5-{3-[4-(1H-indazol-3-yl)-piperazin-1-yl]-propyl}-3,3-dimethyl-1,3-dihydro-indol-2-one) was mutagenic to Salmonella typhimurium TA98 in the presence of rat liver S9 subcellular fraction. The metabolism of 1a in rat liver S9 or microsomes demonstrated that it underwent a P450-mediated N-deindazolation (loss of indazole ring) as a predominant metabolic pathway. To investigate a possible link between metabolism and mutagenicity, a structural analogue 1b (6-chloro-5-{3-[4-(1H-indazol-3-yl)-piperidin-1-yl]-propyl}-3,3-dimethyl-1,3-dihydro-indol-2-one), the cleaved product 2a (6-chloro-3,3-dimethyl-5-(3-piperazin-1-yl-propyl)-1,3-dihydro-indol-2-one), and the core motif 3a (3-piperazinyl indazole) were evaluated in the Ames assay. It was found that 1b was not mutagenic to Salmonella typhimurium TA98 in the absence or presence of a metabolic activating system. In contrast to 1a, 1b did not undergo the metabolic cleavage (loss of indazole ring). Marginal mutagenicity of 2a to TA98 was observed with rat liver S9, whereas 3a was shown to be a promutagen. It was further demonstrated that 1a inactivated P450 3A, the principle enzyme catalyzing the N-deindazolation reaction, in an NADPH-, time-, and concentration-dependent manner. The kinetics of inactivation was characterized by a K(I) of 8.1 microM and k(inact) of 0.114 min(-1). The differences in mutagenicity between 1a and 1b suggest that a chemical bond extending from the 3-position of the indazole to a heteroatom (as part of another cyclic ring) is a prerequisite for the toxicity. The metabolic process leading to the elimination of the indazole from the rest of the molecule apparently plays a key role in causing mutagenicity. It is postulated that the N-deindazolation of 1a proceeds via an oxaziridine intermediate, the formation of which is indirectly inferred from the presence of benzoic acid in microsomal incubations. Benzoic acid is thought to be derived from the hydrolysis of 3-indazolone, an unstable product generated from the oxaziridine. Evidence suggests that the electrophilic oxaziridine intermediate may be responsible for the mutagenicity and inactivation of P450 3A.