A Prospective Study of Sudden Cardiac Death among Children and Young Adults.

BACKGROUND: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. METHODS: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

Fatal Stroke in Pregnancy and the Puerperium.

Background and Purpose- Fatal stroke during pregnancy and the puerperium is rare. Pregnancy-related hypertension and vascular abnormalities underlie significant proportions of pregnancy-related stroke, but up to one-quarter are of no known cause. Methods- Case series of fatal pregnancy-related stroke. All cases where the cause of death was attributed to stroke during pregnancy/postpartum were retrieved from the National Coronial Information System database (January 1, 2009 to December 31, 2016). Results- Fourteen fatal strokes were identified, all hemorrhagic in origin. Underlying causes included pregnancy-related hypertension, rupture of vascular malformations, vasculitis, and cardiomyopathy. Conclusions- Fatal pregnancy-related stroke occurred secondary to hemorrhages of heterogeneous causes, including pregnancy-related hypertension and previously undiagnosed risk factors.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.

OBJECTIVE: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. METHODS: Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. RESULTS: The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. INTERPRETATION: A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.

Comparison of conventional autopsy and magnetic resonance imaging in determining the cause of sudden death in the young.

BACKGROUND: Sudden death in the young is a tragic complication of a number of medical diseases. There is limited data regarding the utility of post-mortem Magnetic Resonance (MR) imaging and Computer Tomography (CT) scanning in determining the cause of sudden death. This study sought to compare the accuracy of post-mortem cross-sectional imaging (MR and CT) with the conventional autopsy in determining the cause of sudden death in the young. METHODS: Consecutive patients from 2010 to 2012 (aged 1-35 years) who had sudden death were included. Patients were scanned by CT and 1.5 T MR imaging prior to the conventional autopsy being performed. The primary outcome was diagnostic congruence between imaging and conventional autopsy. RESULTS: In 17 patients studied, the mean age at death was 23 ± 11 years, with a male predominance (n = 12; 71%). The most common cause of death was a primary cardiac pathology (n = 8; 47%), including ARVC (24%) and ischemic heart disease (12%). Non-cardiac causes identified included pulmonary embolism (6%), and aortic dissection (6%). MR imaging correctly identified the diagnosis in 12 patients who subsequently had positive findings at conventional autopsy, while the diagnosis in the remaining 5 cases remained unexplained. MR imaging was found to be highly sensitive (100%) with a high negative (100%) and positive (80%) predictive value. CONCLUSIONS: Dedicated post-mortem MR imaging of the heart and brain is a useful modality in determining the cause of sudden death in children and young adults, particularly in situations where a conventional autopsy cannot be performed for logistic, cultural or personal reasons.

Suicide in young adults: psychiatric and socio-economic factors from a case-control study.

BACKGROUND: Suicide in young adults remains an important public health issue in Australia. The attributable risks associated with broader socioeconomic factors, compared to more proximal psychiatric disorders, have not been considered previously in individual-level studies of young adults. This study compared the relative contributions of psychiatric disorder and socio-economic disadvantage associated with suicide in terms of relative and attributable risk in young adults. METHOD: A population-based case-control study of young adults (18-34 years) compared cases of suicide (n = 84) with randomly selected controls (n = 250) from population catchments in New South Wales (Australia), with exposure information collected from key informant interviews (for both cases and controls). The relative and attributable risk of suicide associated with ICD-10 defined substance use, affective, and anxiety disorder was compared with educational achievement and household income, adjusting for key confounders. Prevalence of exposures from the control group was used to estimate population attributable fractions (PAF). RESULTS: Strong associations were evident between mental disorders and suicide for both males and females (ORs 3.1 to 18.7). The strongest association was for anxiety disorders (both males and females), followed by affective disorders and substance use disorders. Associations for socio-economic status were smaller in magnitude than for mental disorders for both males and females (ORs 1.1 to 4.8 for lower compared to high SES groups). The combined PAF% for all mental disorders (48% for males and 52% for females) was similar in magnitude to socio-economic status (46% for males and 58% for females). CONCLUSION: Socio-economic status had a similar magnitude of population attributable risk for suicide as mental disorders. Public health interventions to reduce suicide should incorporate socio-economic disadvantage in addition to mental illness as a potential target for intervention.

The effects of involuntary job loss on suicide and suicide attempts among young adults: evidence from a matched case-control study.

OBJECTIVE: To assess the influence of involuntary job loss on suicide and attempted suicide in young adults. METHOD: A population-based case-control study of young adults (18-34 years) was conducted in New South Wales, Australia. Cases included both suicides (n=84) and attempts (n=101). A structured interview was conducted with next of kin (for suicide cases) and suicide attempters admitted to hospital. Controls selected from the general population were matched to cases by age and sex. Job dismissal or redundancy (involuntary job loss) in the 12 months before suicide or attempt was the main study variable of interest. Suicide and attempts were modelled separately and in combination as outcomes using conditional logistic regression modelling. The analysis was also adjusted for marital status, socio-economic status and diagnosis of an affective or anxiety disorder. RESULTS: Following adjustment for other variables, involuntary job loss was associated with an odds ratio of 1.82 for suicide and attempted suicide (combined) (95% CI 0.98 to 3.37; p=0.058). Low socio-economic status was associated with an odds ratio of 3.80 for suicide and attempted suicide (95% CI 2.16 to 6.67; p<0.001) compared to high socio-economic status (after adjustment). Diagnosis of a mental disorder was associated with a 7.87 (95% CI 5.16 to 12.01; p<0.001) odds ratio of suicide and attempted suicide compared to no diagnosis (after adjustment). Involuntary job loss was associated with increased odds of suicide and attempts when these were modelled separately, but results did not reach statistical significance. CONCLUSIONS: Involuntary job loss was associated with increased odds of suicide and attempted suicide. The strength of this relationship was attenuated after adjustment for socio-economic status and mental disorders, which indicates that these may have a stronger influence on suicide than job loss.

A descriptive coronial study of heroin toxicity deaths in Australia, 2020-2022: Characteristics, toxicology and survival times.

BACKGROUND AND AIMS: Mortality rates among people who use heroin are estimated to be 15 times that of the general population. The study aimed to determine (1) the case characteristics and circumstances of death of heroin-related toxicity deaths in Australia, 2020-2022; (2) their toxicological profile and major autopsy findings; (3) the proportion of cases in which blood 6-acetyl morphine (6AM) was detected, as a proxy measure of survival times; and (4) compare 6AM positive and negative cases on toxicology, circumstances of death and acute clinical presentation. DESIGN: Retrospective study of heroin toxicity deaths in Australia, 2020-2022, retrieved from the National Coronial Information System. SETTING: This study was conducted Australia-wide. CASES: There were 610 cases of fatal heroin-related drug toxicity. MEASUREMENTS: Information was collected on characteristics, manner of death, toxicology and autopsy results. FINDINGS: The mean age was 42.6 years (range 18-73 years), 80.5% were male and 7.5% were enrolled in a drug treatment programme. The circumstances of death were as follows: unintentional drug toxicity (86.2%), combined unintentional drug toxicity/disease (11.3%) and intentional drug toxicity (2.5%). The median free morphine concentration was 0.17 mg/L (range 0.00-4.20 mg/L). Psychoactive drugs other than heroin were present in 95.2% (Confidence Interval 93.1%-96.8%), most commonly hypnosedatives (62.3%, 58.2%-66.4%) and psychostimulants (44.8%, 40.7%-49.1%). Major autopsy findings of clinical significance included acute bronchopneumonia (14.8%, 11.3%-18.8%), emphysema (16.9%, 13.2%-21.1%), cardiomegaly (30.1%, 12.7%-28.2%), coronary artery disease (27.4%, 23.0%-32.3%), coronary replacement fibrosis (13.4%, 10.1%-17.3%), hepatic cirrhosis (8.8%, 6.6%-12.2%) and renal fibrosis (10.3%, 7.3%-14.0%). In 47.0% (42.3%-51.2%), 6AM was present in blood. CONCLUSIONS: The 'typical' heroin overdose case in Australia from 2020 to 2022 was a male who injected heroin, aged in the 40s, not enrolled in a treatment programme and had used multiple drugs. In over half of cases, there had been a sufficient survival time for 6-acetyl morphine to have been metabolised, which may indicate times in excess of 20-30 min.

A retrospective study of the characteristics and toxicology of cases of lysergic acid diethylamide (LSD)- and psilocybin-related death in Australia.

BACKGROUND AND AIMS: Lysergic acid diethylamide (LSD) and psilocybin are used as recreational drugs, and there is renewed interest in their clinical use. The current study aimed to (1) determine the circumstances of death and case characteristics of LSD- and psilocybin-related death in Australia, 2000-23; and (2) determine the toxicological profile and major autopsy findings of these cases. METHODS: This was a retrospective exploratory study of all cases of LSD- and psilocybin-related death in Australia, 2000-23, retrieved from the National Coronial Information System. RESULTS: A total of 43 cases were identified: 33 LSD and 10 psilocybin. The median ages were 24 years [interquartile range (IQR) = 13, range = 16-53] (LSD) and 26 years (IQR = 18.5, range = 20-58) (psilocybin), and fewer than five cases were female. The most common circumstance of death among both groups was traumatic accident (LSD 36.4%, psilocybin 40.0%). There were 12 cases of self-harm, all of which involved LSD, all by physical means. In a fifth, death was attributed to multiple drug toxicity (LSD 18.2%, psilocybin 20.0%). In one case, death was attributed solely to LSD toxicity, while in a further two cases death was attributed to a cardiovascular event following LSD consumption (one LSD only, one multiple drug toxicity). In four psilocybin cases, the cause of death was undetermined. The most common clinical presentation was severe agitation (LSD 27.3%, psilocybin 20.0%). Median blood concentrations were LSD 0.8 µg/l (IQR = 1.7, range = 0.1-3), psilocin 20 µg/l (IQR = 53.5, range = 6-83). LSD was the only drug present in 25.0% of LSD cases and psilocybin in 20.0% of psilocybin cases. Pre-existing organ pathology was uncommon. CONCLUSIONS: Lysergic acid diethylamide (LSD)- and psilocybin-related death in Australia from 2000 to 2023 was primarily due to traumatic injury, whether through accident or self-harm. Cases of acute toxic reactions that were attributed solely to LSD were rare.

Differences in heroin overdose deaths in Australia by age, 2020-2022: Disease and estimated survival times.

Background: The age of people who use illicit opioids has increased, with a clinical picture of accelerated ageing. The study aimed to determine, stratified by age: 1. The circumstances and characteristics of heroin-related toxicity deaths in Australia, 2020-2022; 2. The toxicological profile and autopsy findings; 3. The proportion of cases in which blood 6-acetyl morphine (6AM) was detected, as a measure of survival time. Methods: Retrospective study of 610 cases of fatal heroin-related drug toxicity in Australia, 2020-2022. Cases were stratified as: <30 years, 30-39 years, 40-49 years, ≥50 years. Results: Compared to the youngest group, those aged ≥50 years were more likely to have a history of chronic pain (12.4 v 3.3 %), to have their death attributed to combined drug toxicity/disease (20.1 v 3.3 %), and to have evidence of a sudden collapse (21.3 v 11.1 %). There were no differences in free morphine concentrations or glucuronide concentrations. Compared to the youngest group, however, the two older groups were significantly more likely to have 6AM present in blood, a proxy measure of a shorter survival time (52.0, 55.2 v 34.5 %). Compared to the youngest group, cases aged ≥50 years were more likely to be diagnosed with cardiomegaly (44.0 v 16.7 %), coronary artery disease (46.0 v 15.0 %), emphysema (35.0 v 5.1 %), hepatic steatosis (15.4 v 3.4 %), hepatic fibrosis (17.6 v 3.4 %), and cirrhosis (19.8 v 0.0 %). Conclusions: Older cases of heroin overdose had more extensive heart, lung, and liver disease, and appeared more likely to have shorter survival times.

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.

Characteristics and circumstances of volatile solvent misuse-related death in Australia, 2000-2021.

INTRODUCTION: Volatile solvent misuse-related death is associated with neuropsychiatric, cardiovascular, respiratory and renal pathology, as well as sudden death. The study aimed to determine: (1) the circumstances of death and case characteristics of volatile solvent misuse-related death in Australia, 2000-2021; (2) the toxicological profile of cases; and (3) the major autopsy findings. METHODS: Retrospective study of volatile solvent misuse-related death in Australia, 2000-2021 retrieved from the National Coronial Information System. FINDINGS: One hundred and sixty-four cases were identified, 79.9% male, mean age 26.5 years (8.5% aged 40 years or older). Circumstances of death were unintentional toxicity (61.0%), unintentional asphyxia (20.1%), intentional self-harm (12.2%) and traumatic accident (6.7%). The most commonly reported acute presentation prior to death was sudden collapse (22 of 47 witnessed events). The most frequently used solvents at the fatal incident were gas fuels (35.4%), gasoline (petrol) (19.5%) adhesives/paints (19.5%), aerosol propellants (12.8%), and volatile anaesthetics (12.8%). The most commonly detected volatile substances were butane (40.7%), toluene (29.6%), and propane (25.9%). Cannabis was present in 27.6% and alcohol in 24.6%. The prevalence of acute pneumonia amongst autopsied cases was low (5.8%) which, together with reports of sudden collapse, suggests that in many cases, death was extremely rapid. There were low levels of major organ pathology. CONCLUSIONS: While the average age of volatile solvent misuse-related death was in the mid-twenties, a substantial proportion occurred amongst people aged 40 years or older. Reflecting availability, gas fuels predominated. In many cases, death appeared to have been rapid.

Characteristics and circumstances of cocaine-related completed suicide in Australia, 2000-2021.

BACKGROUND: There has been a substantial global increase in cocaine use and associated harms. The current study aimed to: 1. Determine the case characteristics and circumstances of death of cocaine-related suicide in Australia 2000-2021; and 2. Determine the toxicological profiles of cases. METHODS: Retrospective study of cocaine-related death in Australia, 2000-2021, retrieved from the National Coronial Information System (NCIS). Suicide intent was based upon the NCIS code for "Intentional Self-harm", derived from case circumstances and coroners' conclusions. Sex comparisons were made for all major variables. RESULTS: A total of 157 cases were identified, 82.2% male, 79.5% employed, with a mean age of 32.3 years. Concerns for mental health were documented in 65.6%, a previous suicide attempt in 21.0%, a history of substance use treatment and/or negative consequences of substance use in 45.9% and injecting drug use in 14.6%. Manner of death amongst both sexes was predominantly by physical means (82.8%). Written intent was documented in 29.3%. Intense agitation prior to the incident was noted in 28.0% and conflict in 24.8%. The median blood cocaine concentration was 0.060 mg/L (range 0.007-5.500). Other drugs were present in 95.5%, most commonly alcohol (63.1%) with a median concentration of 0.140 g/100 ml. Psychostimulants other than cocaine were present in 31.2%. CONCLUSIONS: The 'typical' cocaine-related suicide case was a male, aged in their early thirties, who was highly likely to be employed. The majority of cases used physical means, and a substantial minority were highly agitated and engaged in conflict prior to the fatal incident.

A case series of patients with filamin-C truncating variants attending a specialized cardiac genetic clinic.

Background: FLNC encodes for filamin-C, a protein expressed in Z-discs of cardiac and skeletal muscle, involved in intracellular signalling and mechanical stabilization. Variants can cause diverse phenotypes with skeletal (myofibrillar or distal myopathy) and/or cardiac (hypertrophic, restrictive, and arrhythmogenic cardiomyopathies) manifestations. Truncating variants have recently been implicated in arrhythmogenic cardiomyopathy (ACM) without skeletal disease. Case summary: Retrospective review of medical records, including cardiac investigations, was performed for families attending a specialized clinic with a FLNC truncating variant (FLNCtv). Variants were classified according to accepted variant interpretation criteria. Of seven families identified, six had primary cardiac phenotypes with one nonsense and five frameshift variants (nonsense-mediated decay competent) identified. One family had no cardiac phenotype, with a pathogenic variant (p.Arg2467Alafs*62) identified as secondary genetic finding. Of the six with cardiac phenotypes, proband age at diagnosis ranged 27-35 years (four females). Five families experienced sudden cardiac death (SCD) of a young relative (age range: 30-43 years), and one patient listed for cardiac transplant. Left ventricular (LV) ejection fraction ranged from 13 to 46%, with LV fibrosis (late gadolinium enhancement) on cardiac imaging or on postmortem histology seen in three families. Two families had one genotype-positive/phenotype-negative relative. Discussion: The FLNCtv causes a left-sided ACM phenotype with a high risk of severe cardiac outcomes including end-stage heart failure and SCD. Incomplete penetrance is observed with implications for reporting secondary genetic findings.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Characteristics of fatal 'novel' synthetic opioid toxicity in Australia.

BACKGROUND: Aims: To determine 1. The characteristics of all recorded cases of fatal drug poisoning involving novel synthetic opioids (NSOs) in Australia; 2. The toxicology of cases; and 3. The major autopsy findings. METHODS: Review of all fatal poisonings related to NSOs in Australia 2000-2021 identified in the National Coronial Information System. RESULTS: Thirty-one cases were identified, 96.8% due to unintentional drug toxicity. The mean age was 31.9 years and 87.1% were male. Only six were aged over forty. A history of substance use problems was documented in 80.6% and 58.1% had a history of injecting drug use. In 32.3% the final route of administration of a NSO was by non-injecting routes of administration. Ten NSOs were identified. Fentanyl analogues were present in 67.2%, most commonly furanylfenatyl (19.4%). Other NSO types were present in 39.7%, most commonly U-47700 (35.5%). Substances other than NSOs were present in 90.3%, most commonly benzodiazepines (67.7%) and other opioids (51.6%). A CNS depressant in addition to NSOs was present in 90.3%, and a new psychoactive substance other than a NSO in 25.8%. Pulmonary oedema was diagnosed in 82.6%, aspiration of vomitus in 30.4%, and acute bronchopneumonia in 17.4%. CONCLUSIONS: Ten NSOs were identified. Case characteristics suggest a younger cohort whose profile is more typical of use of other NPS than of the established opioids. A large proportion used NSOs by non-injecting routes of administration.

Characteristics of fatal tapentadol-related toxicity in Australia.

INTRODUCTION: Tapentadol is a centrally acting opioid analgesic prescribed for the treatment of moderate to severe pain. The study aimed to determine the characteristics of Australian toxicity deaths related to tapentadol. METHODS: All cases in which tapentadol use was coded contributory to death (n = 159) were retrieved from the National Coronial Information System (1 July 2000-31 December 2020). RESULTS: The mean age was 48.5 (18-81) and 56% were female. Documented histories of problems with chronic pain (66%), mental health (60.4%), substance use (44%) and injecting drug use (23.3%) were common. The majority of deaths were deemed unintentional (76.1%) and in 18.9% pre-existing disease was co-contributory. The median peripheral blood tapentadol concentration was 1.00 mg L-1 (0.02-47.00), and the median aortic concentration was 2.05 mg L-1 (0.10-30.00). In all cases, psychoactive drugs other than tapentadol were also detected, most commonly antidepressants (72.3%), opioids (66.7%), hypnosedatives (64.2%) and gabapentinoids (43.4%). Of cases where autopsies were conducted, 27.7% were diagnosed with cardiomegaly and 18.5% with severe coronary artery stenosis. Pulmonary oedema (68.1%), aspiration of vomitus (39.5%) and acute pneumonia (26.9%) were common. DISCUSSION AND CONCLUSIONS: The typical tapentadol-related toxicity death involved unintentional death in the presence of multiple drugs, although a notable minority were intentional self-harm. Multiple morbidities were common. The identification and characteristics of these cases indicate that the adverse event profile of tapentadol needs to be considered in the setting of polypharmacy.

Characteristics of fatal gabapentinoid-related poisoning in Australia, 2000-2020.

INTRODUCTION: Gabapentinoids are centrally active GABA agonists whose use has increased substantially in the past decade. The current study aimed to provide a comprehensive clinical profile of a national case series of fatal poisonings related to gabapentinoids. METHODS: Retrospective study of all deaths due to drug toxicity in Australia in which gabapentinoids were a contributory mechanism, retrieved from the National Coronial Information System (2000-2020). Information was collected on case characteristics, toxicology and major organ pathology. RESULTS: A total of 887 cases were identified, with a mean age of 45.7 years and 55.2% being male. Death was due to accidental toxicity in 81.3% of cases and intentional in 18.7%. Pre-existing disease was co-contributory to drug toxicity in 19.5%. Pregabalin was present in 92.9% of cases, with a median blood concentration of 7.6 mg/L (range 0.1-850.0 mg/L). Gabapentin was present in 7.2%, with a median blood concentration of 9.5 mg/L (range 0.5-1940.0 mg/L). Both pregabalin and gabapentin were present in five cases. No other gabapentinoids were detected. Drugs other than gabapentinoids were present in 99.8%, most frequently opioids (90.1%), hypnosedatives (76.9%) and antidepressants (60.5%). A body mass index in the obese range was seen in 45.4%. Clinically significant pre-existing disease was common, notably cardiomegaly (24.9%), emphysema (20.2%), nephrosclerosis (18.7%) and severe hepatic steatosis (11.7%). CONCLUSIONS: The concomitant use of other drugs was close to universal, with CNS depressants predominating. Mental health problems, chronic pain and substance misuse were prominent.

Characteristics of fatal 'novel' benzodiazepine toxicity in Australia.

INTRODUCTION: The study aimed to determine: 1. The characteristics of all recorded cases of fatal drug poisoning involving 'novel' benzodiazepines (NBZDs) in Australia; 2. The toxicology of cases; and 3. The major autopsy findings. METHODS: Retrospective study of all deaths due to drug toxicity in Australia in which NBZDs were present in blood toxicology, retrieved from the National Coronial Information System (2000-2021). Information was collected on case characteristics, toxicology and major organ pathology. RESULTS: A total of 40 cases were identified, the first occurring in 2015, with a median age of 26.5 years and 87.5% being male. Death was due to accidental toxicity in 92.5% of cases. There were extensive histories of substance use problems (80.0%) and mental health problems (32.5%). Etizolam was the most common NBZD (87.5%), followed by flubromazolam (15.0%), with other NBZDs detected in 20.0% (delorazepam, diclazepam, flualprazolam, flubromazepam, lormetazepam). Multiple NBZDs were present in 27.5%. Other drugs were present in 97.5%, most commonly opioids (70.0%), registered benzodiazepines (62.5%), psychostimulants (45.0%) and gabapentinoids (32.5%). A CNS depressant other than a NBZD was detected in 95.0% (n = 38). Autopsies were conducted and available for 30 cases, with pulmonary oedema (76.7%, n = 23), aspiration of vomitus (46.7%, n = 14) and acute bronchopneumonia (36.7%, n = 11) the most common diagnoses. CONCLUSIONS: The 'typical' NBZD-related death was a young male who died due to accidental toxicity. Deaths most frequently involved etizolam and multiple substances, particularly depressants.