Characteristics, toxicology and major organ pathology of deaths due to acute alcohol toxicity in Australia, 2011-2022.

INTRODUCTION: Acute alcohol toxicity is a significant component of alcohol-related mortality. The study aimed to: (i) determine the circumstances of death and characteristics of fatal alcohol toxicity cases, 2011-2022; (ii) determine their toxicological profile and major autopsy findings; and (iii) determine trends in population mortality rates. METHODS: Retrospective study of acute alcohol toxicity deaths in Australia, 2011-2022, retrieved from the National Coronial Information System. RESULTS: A total of 891 cases were identified, with a mean age of 49.2 years, 71.0% being male. Alcohol use problems were noted in 71.3%. In 57.5% death was attributed solely to acute alcohol toxicity, and combined acute alcohol toxicity/disease in 42.5%. There was evidence of sudden collapse in 24.9% of cases. The mean BAC was 0.331 g/100 mL (range 0.107-0.936), and spirits were the most commonly reported beverages (35.8%). Cases of combined toxicity/disease had significantly lower BACs than those attributed solely to alcohol toxicity (0.296 vs. 0.358 g/100 mL). Cardiomegaly was diagnosed in 32.5%, and severe coronary artery disease in 22.1%. Aspiration of vomitus was noted in 18.0%, and chronic obstructive pulmonary disease in 19.6%. Severe liver steatosis was present in 33.4% and 13.6% had cirrhosis. There was an average annual percentage increase in deaths of 7.90. DISCUSSION AND CONCLUSIONS: The 'typical' case was a long-standing, heavy spirits drinker. BACs showed enormous variation and no arbitrary concentration may be deemed lethal. Clinically significant disease was associated with death at a lower BAC and people with such disease may be at increased risk of alcohol poisoning.

Clinical characteristics of fatal cocaine toxicity in Australia, 2000-2021.

INTRODUCTION: With increased use, the number of cocaine-related deaths has increased. We aimed to determine: (i) the toxicological profile of cocaine, metabolites and adulterants amongst three groups of cocaine-related fatalities in which cocaine and/or metabolites were present in blood: (a) fatal toxicity, where cocaine only (CO) was present (n = 48), (b) multiple drug toxicity (MDT) where other drugs were present (n = 604), and (c) a comparison group of death from traumatic injury (TI, n = 232); (ii) the acute clinical presentation by group; and (iii) cardiovascular disease by group. METHODS: Retrospective study of cocaine-related deaths in Australia, 2000-2021, from the National Coronial Information System. RESULTS: The parent drug cocaine was significantly more common, and had a higher median concentration, amongst the CO group (97.9%, 1.550 mg/L) than the MDT (68.9%, 0.09 mg/L) and TI (70.7%, 0.05 mg/L) groups respectively. Similarly large ratios between CO, MDT and TI were seen for benzoylecgonine (2.100, 0.510, 0.240 mg/L), methylecgonine (1.350, 0.140, 0.070 mg/L), lignocaine (1.200, 0.200, 0.150 mg/L) and levamisole (0.230, 0.045, 0.025 mg/L). The two toxicity groups had significantly higher proportions than the TI group for reports of sudden collapse, seizure, acute psychosis, hyperthermia and vomiting. In addition, CO had higher proportions than MDT and TI of sudden collapse. CO had significantly higher proportions of cardiomegaly and coronary artery disease than the TI group. DISCUSSION AND CONCLUSIONS: Compared to MDT and TI cases, CO cases had higher cocaine concentrations, higher concentrations of adulterants, higher levels of cardiovascular disease and were more likely to suddenly collapse.

Rates, characteristics and toxicology of cocaine-related deaths in Australia, 2000-2021.

AIMS: To (i) assess the population mortality rates of cocaine-related deaths in Australia, 2000 to 2021; (ii) determine the circumstances of death and case characteristics; and (iii) determine their toxicological profile. DESIGN: Retrospective study of cocaine-related deaths in Australia, 2000 to 2021, retrieved from the National Coronial Information System. SETTING: Australia-wide. CASES: A total of 884 cases, mean age = 33.8 (SD, 10.0) years and 86.5% (n = 765) male. MEASUREMENTS: Information was collected on characteristics, manner of death and toxicology. Only cases in which the presence of blood cocaine and/or metabolites were included. FINDINGS: Population rates did not significantly increase during 2001-2011 (annual percentage change [APC] = 1.5; CI, -3.2, 6.5), but from 2012, there was a marked acceleration (APC = 20.0, 95% CI, 15.5, 25.3). Circumstances of death were unintentional drug toxicity (70.7%, n = 625), intentional self-harm (17.8%, n = 157), traumatic accident (11.5%, n = 102). The proportion of cases constituted by unintentional toxicity declined across the study period (APC = -2.6; CI, -3.1, -2.1). There was a substantial decline in the proportion of cases with a history of injecting drug use (APC = -5.7; CI, -6.5, -4.9) and with a history of substance use problems (APC = -3.2; CI, -3.9, -2.5). Both cocaine (0.100 vs 0.050 mg/L, P < 0.001) and benzoylecgonine (0.590 vs 0.240 mg/L, P < 0.001) concentrations were higher amongst toxicity cases than in cases of death from traumatic injury. Cocaethylene was present in 26.4% (n = 233), levamisole in 18.6% (n = 164) and lignocaine in 11.5% (n = 102). Psychoactive drugs in addition to cocaine were present in 92.9% (n = 821), most commonly opioids (50.5%, n = 446), alcohol (47.1%, n = 416), hypnosedatives (43.2%, n = 382) and psychostimulants (30.3%, n = 268). There was a steady decline in the proportion of opioid positive cases (APC = -5.4; CI, -6.3, -4.5). CONCLUSIONS: There was a large increase in cocaine-related deaths across Australia from 2000 to 2021. This was accompanied by changes in case profiles, with histories of injecting drug use and substance use problems, as well as recent opioid use, becoming less prominent.

Trends in methamphetamine use, markets and harms in Australia, 2003-2019.

INTRODUCTION: To describe trends in methamphetamine use, markets and harms in Australia from 2003 to 2019. METHODS: Data comprised patterns of use and price from sentinel samples of people who inject drugs and who use MDMA/other illicit stimulants and population-level amphetamine-related police seizures, arrests, hospitalisations, treatment episodes and deaths from approximately 2003 to 2019. Bayesian autoregressive time-series models were analysed for: no change; constant rate of change; and change over time differing in rate after one to three changepoints. Related indicators were analysed post hoc with identical changepoints. RESULTS: The percentage of people who inject drugs reporting weekly use increased from 2010 to 2013 onwards, while use among samples of people who regularly use ecstasy and other illicit stimulants decreased. Seizures and arrests rose steeply from around 2009/10 to 2014/15 and subsequently plateaued. Price increased ($15.9 [95% credible interval, CrI $9.9, $28.9] per point of crystal per year) from around 2009 to 2011, plateauing and then declining from around 2017. Hospitalisation rates increased steeply from around 2009/10 until 2015/16, with a small subsequent decline. Treatment also increased (19.8 episodes [95% CrI 13.2, 27.6] with amphetamines as the principal drug of concern per 100 000 persons per year) from 2010/11 onwards. Deaths involving amphetamines increased (0.285 per 100 000 persons per year) from 2012 until 2016. DISCUSSION AND CONCLUSIONS: These findings suggest that problematic methamphetamine use and harms escalated from 2010 to 2012 onwards in Australia, with continued demand and a sustained market for methamphetamine. [Correction added on 30 May 2022, after first online publication: In the Abstract under 'Discussion and Conclusions' 'onwards' has been added after … 2010 to 2012].

Asbestos-related lung cancer: Clinical characteristics and survival outcomes in an Australian cohort seeking workers compensation.

BACKGROUND AND OBJECTIVES: Due to difficulties in identifying sufficient-sized cohorts there remains uncertainty about prognostic and clinical differences that may be unique to asbestos-related lung cancer (ARLC). In this study, we use the Helsinki Criteria to define a group of ex-workers with lung cancer attributable to asbestos exposure and investigate differences that may exist. METHODS: A total of 529 patients seeking workers' compensation for their lung cancer were assigned to either ARLC or the non-ARLC based on parameters defined in the Helsinki Criteria. Clinical and survival details were collected and analyzed. RESULTS: In our study population, ARLC patients were on average older (72.1 ± 7.8) than non-ARLC patients (66.5 ± 10.2, P < 0.001) and were more likely to be diagnosed as a result of incidental findings or screening program (P < 0.001). The groups were similar in terms of clinical characteristics with the only difference being that plaques were more prevalent among ARLC patients (P < 0.001). Differences were observed for median overall survival (OS), ARLC (9 months) and non-ARLC (13 months, P = 0.005), as well for treatment (P = 0.01). After adjusting for age, however, these differences disappeared. CONCLUSIONS: Age at diagnosis, pleural plaques, and asymptomatic presentation were the attributes that we identified as significantly different between asbestos-related cancer and other lung cancers. In this cohort, ARLC patients were older diagnosis and with worse overall survival.

Barbiturate-related hospitalisations, drug treatment episodes, and deaths in Australia, 2000-2018.

OBJECTIVES: To determine the characteristics and population rates of barbiturate-related hospitalisations, treatment episodes, and deaths in Australia, 2000-2018. DESIGN, SETTING: Analysis of national data on barbiturate-related hospitalisations (National Hospital Morbidity Database, 1999-2000 to 2017-18), drug treatment episodes (Alcohol and Other Drug Treatment Services National Minimum Data Set, 2002-03 to 2017-18), and deaths (National Coronial Information System, 2000-01 to 2016-17). MAIN OUTCOME MEASURES: Population rates directly age-standardised to the 2001 Australian standard population; average annual percentage change (AAPC) in rates estimated by Joinpoint regression. RESULTS: We identified 1250 barbiturate-related hospitalisations (791 cases of deliberate self-harm [63%]), 993 drug treatment episodes (195 cases with barbiturates as the principal drug of concern [20%]), and 511 deaths during the respective analysis periods. The barbiturate-related hospitalisation rate declined from 0.56 in 1999-2000 to 0.14 per 100 000 population in 2017-18 (AAPC, -6.0%; 95% CI, -7.2% to -4.8%); the declines in hospitalisations related to accidental poisoning (AAPC, -5.8%; 95% CI, -9.1% to -2.4%) and intentional self-harm (AAPC, -5.6%; 95% CI, -6.9% to -4.2%) were each statistically significant. Despite a drop from 0.67 in 2002-03 to 0.23 per 100 000 in 2003-04, the drug treatment episode rate did not decline significantly (AAPC, -6.7%; 95% CI, -16% to +4.0%). The population rate of barbiturate-related deaths increased from 0.07 in 2000-01 to 0.19 per 100 000 population in 2016-17 (AAPC, +9.3%; 95% CI, +6.2-12%); the rate of intentional self-harm deaths increased (AAPC, +11%; 95% CI, +7.4-15%), but not that of accidental deaths (AAPC, -0.3%; 95% CI, -4.1% to +3.8%). CONCLUSIONS: While prescribing and community use of barbiturates has declined, the population rate of intentional self-harm using barbiturates has increased. The major harm associated with these drugs is now suicide.

Associations Between Ambient Particulate Air Pollution and Cognitive Function in Indonesian Children Living in Forest Fire-Prone Provinces.

Smoke from forest fires can reach hazardous levels for extended periods of time. We aimed to determine if there is an association between particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) and living in a forest fire-prone province and cognitive function. We used data from the Indonesian Family and Life Survey. Cognitive function was assessed by the Ravens Colored Progressive Matrices (RCPM). We used regression models to estimate associations between PM2.5 and living in a forest fire-prone province and cognitive function. In multivariable models, we found very small positive relationships between PM2.5 levels and RCPM scores (PM2.5 level at year of survey: ß = 0.1%; 95% confidence interval (CI) [0.01, 0.19%]). There were no differences in RCPM scores for children living in forest fire-prone provinces compared with children living in non-forest fire-prone provinces (mean difference = -1.16%, 95% CI [-2.53, 0.21]). RCPM scores were lower for children who had lived in a forest fire-prone province all their lives compared with children who lived in a non-forest fire-prone province all their life (ß = -1.50%; 95% CI [-2.94, -0.07]). Living in a forest fire-prone province for a prolonged period of time negatively affected cognitive scores after adjusting for individual factors.

Unintentional and intentional drug poisoning deaths, Australia, 2012-2016: Drug pattern profile and demographic characteristics.

BACKGROUND: Identifying differences in unintentional versus intentional drug poisoning deaths can inform targeted prevention. This study aimed to: compare unintentional versus intentional drug poisoning deaths by drug involvement, age and sex; describe patterns of drug involvement by intent; and describe common drug patterns by age and sex. METHODS: Cases comprised deaths among Australians aged ≥15 where drug poisoning was the underlying cause (Cause of Death Unit Record File 2012-2016). Sex, age, and drug involvement were analysed by intent using logistic regression. RESULTS: Of 7994 deaths, 71% were unintentional and 24% intentional. Compared with unintentional deaths, intentional deaths were more likely among females (OR 1.31 [95% CI 1.16-1.48]) and those aged 55+ (1.50 [1.25-1.81] for 55-64 years; 3.79 [3.07-4.66] for 65+ years, compared to 35-44 years), and were more likely to involve hypnosedatives (2.11 [1.87-2.39]), other psychotropic medicines (1.58 [1.39-1.78]), non-opioid analgesics and anaesthetics (1.48 [1.25-1.73]). Common unintentional profiles comprised: opioids (excluding heroin); heroin; alcohol; opioids with hypnosedatives; opioids with hypnosedatives and other psychotropic medicines; stimulants; other psychotropic medicines; and opioids with other psychotropic medicines. Unintentional deaths involving heroin or stimulants only had a greater proportion of males (79.0% and 83.4%, respectively) and younger individuals aged 15-34 (30.3% and 39.5%, respectively). Common intentional profiles comprised: hypnosedatives; other psychotropic medicines; opioids (excluding heroin); hypnosedatives with other psychotropic medicines; opioids with hypnosedatives; and opioids with hypnosedatives and other psychotropic medicines. CONCLUSION: The demographic and drug involvement profile of intentional and unintentional deaths were distinct, suggesting different approaches to prevention are necessary.

Trends in cocaine use, markets and harms in Australia, 2003-2019.

INTRODUCTION: This paper aims to describe cocaine use, markets and harms in Australia from 2003 to 2019. METHODS: Outcome indicators comprised prevalence of use from triennial household surveys; patterns of use from annual surveys of sentinel samples who use stimulants; and cocaine-related seizures, arrests, hospitalisations, deaths and treatment episodes. Bayesian autoregressive time-series analyses were conducted to estimate trend over time: Model 1, no change; Model 2, constant rate of change; and Model 3, change over time differing in rate after one change point. RESULTS: Past-year population prevalence of use increased over time. The percentage reporting recent use in sentinel samples increased by 6.1% (95% credible interval [CrI95% ] 1.2%,16.9%; Model 3) per year from around 2017 (48%) until the end of the series (2019: 67%). There was a constant annual increase in number of seizures (count ratio: 1.1, CrI95% 1.1,1.2) and arrests (1.2, CrI95% 1.1,1.2), and percentage reporting cocaine as easy to obtain in the sentinel samples (percent increase 1.2%, CrI95% 0.5%,1.8%; Model 2). Cocaine-related hospitalisation rate increased from 5.1 to 15.6 per 100 000 people from around 2011-2012 to 2017-2018: an annual increase of 1.3 per 100 000 people (CrI95% 0.8,1.8; Model 3). While the death rate was low (0.23 cocaine-related deaths per 100 000 people in 2018; Model 2), treatment episodes increased from 3.2 to 5.9 per 100 000 people from around 2016-2017 to 2017-2018: an annual increase of 2.9 per 100 000 people (CrI95% 1.6,3.7; Model 3). DISCUSSION AND CONCLUSIONS: Cocaine use, availability and harm have increased, concentrated in recent years, and accompanied by increased treatment engagement.

Trends in treatment episodes for methamphetamine smoking and injecting in Australia, 2003-2019.

INTRODUCTION: We examined trends in Australian treatment episodes for smoking and injecting methamphetamine from 2003 to 2019. METHODS: Data from the Alcohol and Other Drug Treatment National Minimum Data Set, where amphetamines were the principal drug of concern, were analysed from 2003 to 2019. Rates were calculated per 100 000 population aged 10-100 years. Joinpoint software was used to identify changepoints and estimate the annual percentage change (APC) in the rate of treatment episodes. Treatment episode characteristics were compared for smoking versus injecting in 2019. RESULTS: The rate of treatment episodes for methamphetamine increased from 77 to 262 per 100 000 population between 2003 and 2019 (average APC 8%, P < 0.001), this being due to treatment episodes for smoking methamphetamine (average APC 32%, P < 0.001) with no significant increase in treatment episodes for injecting methamphetamine (average APC 3%). Treatment episodes for smoking increased sharply from 2003 to 2008 (APC 72%, P < 0.001) and again from 2010 to 2016 (APC 46%, P < 0.001), this upward trend being attenuated between 2016 and 2019 (APC 7%, P = 0.012). Treatment episodes for methamphetamine smoking (cf. injecting) involved younger clients (median age 30 vs. 35 years, P < 0.001) who were more likely to receive assessment or case management only (37% vs. 29%, P < 0.001). DISCUSSION AND CONCLUSIONS: Increased methamphetamine treatment episodes in Australia since 2003 are due mostly to smoking the drug, this occurring among younger cohort who receive less substantive treatment than clients who inject methamphetamine.

Associations between sun sensitive pigmentary genes and serum prostate specific antigen levels.

BACKGROUND: Melanoma and prostate cancer may share risk factors. This study examined the association between serum PSA levels, which is a risk factor for prostate cancer, and variants in some melanoma-associated pigmentary genes. METHODS: We studied participants, all aged 70+ years, in the Concord Health and Ageing in Men Project who had no history of prostatitis or received treatment for prostate disease (n = 1033). We genotyped variants in MC1R (rs1805007, rs1805008), ASIP (rs4911414, rs1015362), SLC45A2 (rs28777, rs16891982), IRF4 (rs12203592), TYRP1 (rs1408799), TYR (rs1126809, rs1042602), SLC24A2 (rs12896399), and OCA2 (rs7495174). Generalised linear dominant models with Poisson distribution, log link functions and robust variance estimators estimated adjusted percentage differences (%PSA) in mean serum PSA levels (ng/mL) between variant and wildtype (0%PSA = reference) genotypes, adjusting for age, body mass index, serum 25OHD levels and birth regions (Australia or New Zealand (ANZ), Europe or elsewhere). RESULTS: Serum PSA levels were strongly associated with advancing age and birth regions: mean PSA levels were lower in Europe-born (-29.7%) and elsewhere-born (-11.7%) men than ANZ-born men (reference). Lower %PSA was observed in men with variants in SLC45A2: rs28777 (-19.6;95%CI: -33.5, -2.7), rs16891982 (-17.3;95%CI:-30.4,-1.7) than in wildtype men (reference). There were significant interactions between birth regions and PSA levels in men with variants in MC1R (rs1805007; p-interaction = 0.0001) and ASIP (rs4911414; p-interaction = 0.007). For these genes %PSA was greater in ANZ-born men and lower in Europe- and elsewhere-born men with the variant than it was in wildtype men. In a post hoc analysis, serum testosterone levels were increased in men with MC1R rs1805007 and serum dihydrotestosterone in men with ASIP rs1015362. CONCLUSION: Men with SNPs in SLC45A2, who have less sun sensitive skin, have lower PSA levels. Men with SNPs in MC1R and ASIP, who have more sun sensitive skin, and were born in ANZ, have higher PSA levels. Androgens may modify these apparent associations of pigmentary genes and sun exposure with PSA levels. IMPACT: PSA levels and possibly prostate cancer risk may vary with sun sensitivity and sun exposure, the effects of which might be modified by androgen levels.

Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study.

BACKGROUND: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. METHODS: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 109, 7 × 109, and 9 × 109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. FINDINGS: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 109 TargomiRs once weekly. We established that 5 × 109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. INTERPRETATION: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. FUNDING: Asbestos Diseases Research Foundation.