Proceedings of the toxicology and Poisons Network Australasia (TAPNA) 2022 Annual Scientific Meeting

A 19-year-old male prisoner attended a medical appointment, during which he was observed inhaling or ingesting a clear liquid. Following this, he became agitated, requiring mechanical and chemical restraint. Extreme agitation persisted despite intramuscular midazolam (10 mg). On arrival to ED he appeared flushed with dry skin, mydriasis, severe tachycardia (130 bpm), and hypertension (180/110 mmHg). He was subsequently intubated for agitation and behavioural control. His admission was complicated by mild rhabdomyolysis and five generalised tonic-clonic seizures over 2 d, with persistent mydriasis and sinus tachycardia. Peak temperature was 39 °C. The Victorian Poisons Information Centre was contacted. Given the limited exposure history, ongoing seizure activity, and general anaesthetic control of agitation, physostigmine was not recommended despite evidence of a possible anticholinergic toxidrome. The patient was extubated uneventfully on day three and made a full recovery. Total length of hospital stay was 67 h, Intensive Care Unit length of stay was 44 h. Whole blood was analysed for atropine using high-performance liquid chromatography with tandem mass spectrometry. Atropine concentration was 0.01 mg/L (10 ng/mL). This sample was analysed as part of the Emerging Drugs of Australia VIC project – a Health. vic supported, multi-institutional initiative providing intelligence on Victorian ED illicit drug presentations.


Introduction
Although atropine poisoning is historically well described, acute presentations to the Emergency Department (ED) are less commonly encountered.

Case summary
A 19-year-old male prisoner attended a medical appointment, during which he was observed inhaling or ingesting a clear liquid. Following this, he became agitated, requiring mechanical and chemical restraint. Extreme agitation persisted despite intramuscular midazolam (10 mg). On arrival to ED he appeared flushed with dry skin, mydriasis, severe tachycardia (130 bpm), and hypertension (180/110 mmHg). He was subsequently intubated for agitation and behavioural control. His admission was complicated by mild rhabdomyolysis and five generalised tonic-clonic seizures over 2 d, with persistent mydriasis and sinus tachycardia. Peak temperature was 39 °C. The Victorian Poisons Information Centre was contacted. Given the limited exposure history, ongoing seizure activity, and general anaesthetic control of agitation, physostigmine was not recommended despite evidence of a possible anticholinergic toxidrome.
The patient was extubated uneventfully on day three and made a full recovery. Total length of hospital stay was 67 h, Intensive Care Unit length of stay was 44 h.
Whole blood was analysed for atropine using high-performance liquid chromatography with tandem mass spectrometry. Atropine concentration was 0.01 mg/L (10 ng/mL). This sample was analysed as part of the Emerging Drugs of Australia VIC project -a Health. vic supported, multi-institutional initiative providing intelligence on Victorian ED illicit drug presentations.

Discussion
We present a case of severe atropine toxicity. The detected atropine concentration is relatively low compared with published toxic concentration ranges; 30-100 ng/mL [1]. This may be a reflection of timing/ degradation of the sample. Unfortunately, no further information could be obtained from the patient nor corrections service regarding access to atropine preparations. We suspect the likely source to be an ophthalmological atropine preparation. Physostigmine adequately reverses the agitated delirium and central nervous system depression associated with atropine poisoning [2]. Physostigmine has been used as a rescue strategy to avoid intubation, particularly where the exposure history is known [3].

Background
Since late 2020, grain-growing regions of western NSW experienced a rodent plague. This accompanied by increased rodenticide use and subsequent stock shortages of long-acting anticoagulant (LAAC) products prompted use of zinc phosphide-based products in domestic and other unapproved settings. We reviewed the impact of these events on human rodenticide exposures.

Methods
We searched the NSWPIC database for rodenticide exposures between January 2019 and June 2021. Calls were categorised by rodenticide type, reason for exposure, exposure route, disposition, and clinical sequelae. Factors contributing to the exposure were explored during the call, or with active case follow up. Where possible, outcomes for hospitalised cases were obtained.

Results
Call volume of human rodenticide exposures in NSW increased from approximately 25 calls/months prior to November 2020 to 80 calls/month by June 2021. The increase was seen with all types of rodenticides, but the proportion of calls due to zinc phosphide increased from generally <1% prior to up to 13-15% of all cases each month after November 2020. This change coincided with the approval of a higher-strength zinc phosphide product. Exposures were mostly accidental (275) and a small number (7) were occupational. Between January and May 2021, 15 cases were referred to hospital, including 9 zinc phosphide exposures. No serious outcomes were observed. Some hospital referrals were based on limited experience with zinc phosphide exposures and the non-specific manifestations of phosphine poisoning. Symptomatic exposures were mostly adults using zinc phosphide products inappropriately with inadequate PPE, and developed non-specific poisoning manifestations. In all but one case patients' reflected awareness of potential dangers and attempted to minimise these, but felt severity of the plague justified a considered practical approach outweighing the risk. Each person reporting adjusting their practices following symptomatic exposure.

Implications
Environmental events impact on pesticide use and subsequently human exposures and health outcomes. Complications should be monitored to better define the risk-benefit of these products. Lack of access to and cost of alternative rodenticides as well as superior efficacy of zinc phosphide were factors leading to off label zinc phosphide use. Provision of PPE with the sale of zinc phosphide could minimise risk.

Background
Internet publications and social media promoting the use of sodium nitrite for suicide and euthanasia began in 2017, increases in self-poisoning followed. We aimed to investigate time trends and demographic characteristics of deliberate self-poisonings with sodium nitrite in Australia and report on public health responses.

Methods
Retrospective observational study of the National Coronial Information System (July 2000-June 2020), Poisons Information Centres, toxicology services (June 2004-2020). We examined survival, date, gender, age, setting, geographical location, history of a terminal or psychiatric illness, product, and toxicology results. We reviewed public health activities led by NSW Health.
A sudden and sustained step-increase in poisonings was seen from September 2017 (and the first death). Most cases (83%) had a psychiatric illness and no terminal illness (91%). Only one forensic toxicology lab in Queensland was identified to report testing for nitrite/nitrate in post-mortem toxicology on stomach contents and blood. Methaemoglobinaemia was identified as a possible signal for case identification but blood methaemoglobin levels are not routinely performed and are difficult to interpret postmortem. All cases with product information available reported use of pure compounds and purchased online. Many cases had incorrect documentation of sodium nitrate. A rescheduling proposal to make pure sodium nitrite listed in Schedule 10 was submitted. Surveillance of online retailers and reporting to regulators and online marketplaces. A directive was issued to increase antidote stocking of methylene blue across NSW hospitals and to store in the Emergency Department (ED) and issuing of clinical guidelines. Submission to NSW Ambulance to stock methylene blue and to update protocols for toxic cardiac arrest.

Conclusions
The promotion of suicide methodology was associated with a dramatic change in harms from sodium nitrite. State public health actions to date have focused on enhanced surveillance, means restriction, improved antidote stocking, and clinical education. National and international collaboration is needed for monitoring promoted lethal substances.

Background
Serious adverse events can occur in children who are overdosed with clonidine, either when receiving treatment for behavioural disorders or accessing a family member's medication. The NSW Poisons Information Centre previously reported increasing clonidine exposures in children between 2004 and 2017. The Australian Therapeutic Goods Administration (TGA) published a Medicines Safety Update in April 2021, warning health professionals about risks associated with clonidine.

Aim
To explore recent trends in clonidine exposures in children and adolescents at the Victorian Poisons Information Centre (VPIC).

Methods
A retrospective audit of clonidine exposure cases reported to VPIC between 2018 and 2021 was undertaken. Exposures in children and adolescents up to the age of 19 years were included. Calls that did not include an exposure, and recalls, were excluded. Cases were analysed by type of exposure and age categories.

Results
The number of exposure cases reported to the VPIC was relatively stable from 2018 to 2020 (107, 104, and 98 in each year, respectively). In 2021, there was a large increase (155 cases). As a percentage of VPIC exposure calls, this was an increase from around 0.30 to 0.43%. Deliberate self-poisoning cases increased from 21 in 2018, 29 in both 2019 and 2020, to 44 in 2021. The largest increase was in adolescents (from a low of 14 in 2018 to 31 in 2021). Therapeutic error cases ranged from 53 to 35 in 2018-2020 and jumped to 66 in 2021 (mostly in children). The number of accidental exposures was 25-26 in 2018-2020, and increased to 34 in 2021 (mostly in toddlers).

Conclusions
There was an increase in all types of clonidine exposure cases in children and adolescents in 2021 compared to the previous three years. Further research is required to explore the reasons and whether it was a once-off increase, potentially related to COVID-19 pandemic lockdowns, or whether it represents the start of a sustained increase.

Background
In response to rising rates of overdose with modified release (MR) paracetamol, Australia's Therapeutic Goods Administration (TGA) up-scheduled MR paracetamol from Schedule 2 to Schedule 3 in June 2020. This study aimed to evaluate the impact of this on poisonings with over-the-counter analgesics.

Methods
We conducted a retrospective study of exposure calls to the New South Wales Poisons Information Centre (NSWPIC), from 1 February 2017 to 31 January 2022. Intentional exposures to paracetamol, ibuprofen, diclofenac, mefenamic acid, naproxen, and aspirin were analysed. Mean monthly calls were compared before and after the intervention.

Discussion
Poisonings with over-the-counter analgesics increased over the five-year study period. The increase in poisonings with MR Paracetamol does not appear to have been attenuated by re-scheduling. A similar result was seen when codeine was made Schedule 3 in 2010, with pharmacist only dispensing failing to curb the rising overdose rates. Codeine was made Schedule 4 in 2018 and this was followed by a significant decline in poisonings. MR Paracetamol is more toxic in overdose than IR paracetamol, and further up-scheduling to Schedule 4 could be considered. The trends seen in this study are potentially impacted by the COVID-19 pandemic which has increased self-harm in Australia. Future work includes an interrupted time-series analysis to further examine the changes observed here. Background COVID-19 rapid antigen tests (RATs) have been available for use in Australia since 1/11/2021. This study aimed to describe the frequency and clinical characteristics of RAT exposures reported to the New South Wales Poisons Information Centre (NSWPIC). Unknown ingredients of RAT buffer solutions, and inclusion of sodium azide in some brands, prompted a prospective review to assess whether toxicity is a concern.
Methods This is a prospective study conducted at the NSWPIC. From 22 January 2022 to 14 March 2022, RAT buffer solution exposure calls were followed-up to obtain outcome information. Data collected include: brand name, route of exposure, demographics, symptoms, and product safety suggestions.

Results
There were 63 RAT exposure calls to NSWPIC over the 7 weeks study period. The majority were oral exposures (65%, n = 41), followed by nasal (16%, n = 10), dermal (11%, n = 7), and ocular (10%, n = 6; one caller was exposed via ocular and dermal routes). The majority (48%, n = 30) were toddlers, followed by adults (33%, n = 21), children (14%, n = 9), and infants (5%, n = 3). The majority were female (59%, n = 37). Follow-up information was obtained in 27 cases (43%). For oral ingestions, all 18 cases with follow-up data reported no symptoms. For ocular exposure, 3 out of 4 cases with outcome data reported minor symptoms, with the remainder asymptomatic. Three dermal cases with follow-up information all reported no symptoms. Two nasal exposures with outcome data, both reported minor symptoms that may have been unrelated. One patient was assessed in the Emergency Department (ED; following an ocular exposure). Thematic analysis of product safety suggestions revealed improved labelling and enclosures for buffer solutions as the most frequently identified strategies.

Discussion
RAT exposures have been a common call to NSWPIC since being introduced to the market. RAT buffer solutions contain a variety of ingredients, some containing small amounts of sodium azide. Reassuringly, thus far no adverse effects have been reported following ingestion, and only minor effects following ocular and nasal exposures. This study demonstrates the key role for PICs in toxicovigilance and product safety for new products. NSWPIC will continue to monitor RAT exposures, particularly with any new entries on the Australian Register of Therapeutic Goods.

Introduction
Amphetamine-induced PRES syndrome is rarely described. Early recognition and treatment are essential to prevent permanent neurological sequelae [1].

Case report
A 23-year-old male with no-comorbidities was brought into Emergency Department (ED) from a correctional facility after a first episode of witnessed, self-terminating generalised tonic-clonic seizure. He had intravenously injected an unknown quantity of methamphetamine and buprenorphine 2 h prior. On initial assessment, he was hypertensive with a BP 157/67 mmHg, HR 60 bpm, respiratory rate 20/min, and oxygen saturation 99% on room air. He had a severe occipital headache, nausea, and intermittent bilateral visual loss. Neurological examination of the cranial nerves, upper and lower limbs, visual, and cerebellar examination did not reveal any abnormality. He was persistently hypertensive with a blood pressure of up to 180/96 mmHg. He did not have a history of previous seizures or hypertension. A CT brain with angiogram was suggestive of Reversible Cerebral Vasoconstriction Syndrome (RCVS). A nimodipine infusion was commenced with resolution of headaches and hypertension within 36 h. Brain MRI performed 48 h later was consistent with PRES, with oedema of bilateral parietal and occipital lobes. The patient was discharged clinically well 4 d later. It was strongly advised that he avoided all sympathomimetic agents due to risk of recurrence of PRES.

Conclusions
Poisoned patients may have a lower threshold for developing PRES due to the drug effect on endothelial d y s f u n c t i on , s y mp at h e t i c s y s t e m , a n d hypothalamic-pituitary-adrenal axis [2]. Untreated PRES can cause permanent neurologic deficits due to cerebral ischemia, haemorrhage, and herniation [3]. The neuroimaging study of choice is the MRI due to its high sensitivity [1]. It is possible that there is a higher prevalence of PRES associated with drug use than currently documented. Early recognition and meticulous treatment are important to prevent permanent neurological sequelae and to advise the patient of risk of recurrence.

Introduction
Carbon monoxide poisoning can cause delayed neurological sequelae (DNS), a potentially permanent encephalopathy in the form of cognitive impairment and movement disorders [1]. Death secondary to DNS is rarely reported.

Case report
A previously healthy 59-year-old man presented to a regional Emergency Department (ED) after he was found obtunded at a house, where he was exposed to carbon monoxide from a wood burning heater. He was last seen well 8 h prior. On initial assessment, vital signs were GCS 3, BP 110/60 mmHg, HR 120bpm, oxygen saturation 80% on room air. Venous blood gas showed pH 7.39, pCO2 30 mmHg, lactate 7 mmol/L, bicarbonate 15 mmol/L, and carboxyhaemoglobin 19.8%. ECG demonstrated sinus tachycardia. Troponin was elevated at 670 ng/L. He had been treated with 4 h of high flow oxygen, 15 L/min, via a non-rebreather prior to this level. He was intubated and ventilated with FiO 2 100%. Serial carboxyhaemoglobin levels declined to 12.4%, 1.5 h after positive pressure ventilation, and 7.7% 3 h later. Hyperbaric oxygen therapy was discussed but not commenced. Neuroimaging with a CT brain was normal. He recovered well and was successfully extubated 24 h later. He was discharged home 3 d later with a documented normal neurological examination.
Following a lucid interval of 1 week, the patient represented to a tertiary hospital 3 weeks later with a 2-week history of decline in motor and cognitive function, with slow movements, slurred speech, and progressive confusion. Brain MRI demonstrated areas of gliosis in bilateral globus pallidi with non-specific diffuse white matter changes within supratentorial compartment, consistent with neurological sequelae of carbon monoxide poisoning. There was gradual functional decline. The patient was transferred to a nursing home facility, requiring high level of care, 8 weeks later.

Conclusions
DNS sequelae may develop 2-40 days in up to 40% of survivors of acute carbon monoxide poisoning [2]. The most common feature on MRI is symmetrical bilateral basal ganglia abnormality [2]. There is currently no optimal evidence-based treatment for carbon monoxide-associated DNS [1,2]. Prompt treatment of carbon monoxide toxicity may reduce its occurrence.

Introduction
Wound botulism is rarely encountered in developed countries. We report a case of wound botulism in an intravenous drug user. Early clinical recognition and treatment with antitoxin is essential to reducing morbidity and mortality [1,2].

Case report
A 35-year-old male presented to a tertiary Emergency Department with a 2-d history of nonspecific neurological symptoms. He complained of lethargy, difficulty swallowing, increased salivation, and numbness to his mouth. He last injected methamphetamine intravenously 2 d previously, after which his symptoms began. On initial assessment, he was afebrile, blood pressure 130/70 mmHg, oxygen saturation 100% on room air. A neurological examination demonstrated cranial nerve deficits with ptosis, abnormal gag reflex, with difficulty swallowing. He was alert with a GCS 15. There was superficial thrombophlebitis of the left antecubital fossa, where the amphetamines were injected 2 d ago. A blood culture was obtained. Neuroimaging was normal.
The following day, the patient developed progressive neurological features with bilateral tongue weakness, absent gag reflex, bilateral ophthalmoplegia with gaze paresis, increasing drowsiness and respiratory failure requiring intubation and ventilation. The blood culture demonstrated growth of Clostridium botulinum on day 4. The patient was treated with penicillin and botulinum antitoxin. There was gradual improvement in his neurological status. He was extubated after 14 d and was discharged clinically well 26 d later. Clostridium botulinum Type B was detected by public health on the drug paraphernalia.

Conclusions
Wound botulism is most commonly implicated with black tar heroin [3,4]. Botulinum toxin type A is the most common toxin type in wound botulism [3]. Neurological signs of botulism, such as ptosis and altered phonation might be interpreted as mental status changes associated with drug use. Botulism needs to be considered in intravenous drug users with focal neurological signs.

Background
Methylene blue has been advocated for the management of vasoplegic shock due to poisoning in cases refractory to conventional treatments. We describe the experience of Hunter Area Toxicology Service (HATS) in management of 3 vasoplegic shock cases requiring methylene blue.

Case 1
A 57-year-old male presented to ED hypotensive and clinically underperfused having earlier ingested 6 x Diltiazem 180 mg controlled release tablets. Following initial resuscitation he was transferred to ICU. A pulmonary artery catheter was inserted to evaluate haemodynamic status revealing low systemic vascular resistance (SVR) consistent with vasoplegic shock. Despite treatment with noradrenaline, calcium chloride, and vasopressin his SVR remained low. Following HATS consultation a bolus of methylene blue 2 mg/ kg followed by an infusion of 0.5 mg/kg/h was commenced leading to improvement in SVR. Overall, clinical course remained stormy due to other complications and he was discharged 24 d post presentation.

Case 2
A 68-year-old female presented to ED with a GCS of 3 following ingestion of 9 g of Quetiapine. She was intubated for airway protection shortly after becoming hypotensive requiring a Noradrenaline infusion for presumed vasoplegia. Noradrenaline requirements escalated in ICU and vasopressin infusion was commenced. Serum lactate climbed to 12.8 mmol/L over a 6.5 h timeframe. A 1 mg/kg methylene blue bolus was administered. Within 7 h vasopressin was discontinued, noradrenaline had significantly reduced and lactate had returned to reference range. Other complications resulted in a hospital stay of 19 d.

Case 3
A 52-year-old male presented to ED following unquantified ingestion of perindopril, amlodipine, metformin, and sertraline. He became hypotensive requiring noradrenaline/vasopressin infusions and ICU transfer. A methylene blue bolus of 1 mg was administered 5 h post presentation. Clinical review 10 h later reported noradrenaline and vasopressin discontinued, however, cyproheptadine had been commenced on HATS advice for suspected methylene blue-induced serotonin toxicity. He was discharged 48 h post presentation.

Conclusions
This, small, case series supports a role for methylene blue in refractory, toxic, vasoplegia. However, it also highlights the potential for serotonin toxicity in this population of whom many will be taking serotonin-based anti-depressants.

Introduction
Gamma-hydroxybutyrate (GHB) is a popular illicit drug. First synthesised in the 1960s, GHB emerged as a recreational drug of abuse in the early 1980s [1,2]. Exogenous GHB acts as a GABA-B and GHB receptor agonist; mild toxicity manifests as amnesia, hypotonia, and euphoria. Severe toxicity results in coma, bradycardia, hypothermia, and respiratory depression [2].
The Emerging Drug Network Australia (Victoria) (EDNAV) is a collaborative project to detect illicit novel drug exposures in patients presenting to Victorian Emergency Department (ED). It was designed to facilitate the release of early warnings to the general public. Whole blood samples are analysed for GHB using liquid-liquid extraction followed by d e r i v at i s at i o n a n d d e t e c t i o n by g a s chromatography-mass spectrometry (GC-MS) in Selected Ion Monitoring mode.

Case 1
A 35-year-old female patient presented to a metropolitan ED via ambulance after being found unconscious. She had a GCS 3/15, and was hypotensive and hypothermic. The patient was intubated and required ventilatory support for 44 h. Her total length of stay was 69.7 h. GHB concentration 771 mg/L.

Case 2
A 34-year-old male patient presented to a metropolitan ED. On arrival of Ambulance Victoria (AV) the patient was found to be in cardiac arrest. The patient had return of spontaneous circulation after 10 min of CPR and was intubated on scene. His recovery was complicated by an acute kidney injury (AKI; peak creatinine 145 micromol/L), aspiration pneumonitis, and delirium post-extubation. His total length of stay was 252 h. GHB concentration 712 mg/L.

Discussion
Since commencement in 2020, EDNAV has analysed 333 cases for the presence of GHB. GHB was detected in 104 cases (range 6 − 771 mg/L [mean GHB concentration 117 mg/L]). These two cases represent some of the highest GHB concentrations in ante-mortem samples seen in the literature to date [3,4,5]. Although GHB has a short half-life of 30-60 min [1,2], these two cases highlight that in massive overdose with suicidal intent, coma can be protracted requiring prolonged periods of mechanical ventilation.
If GHB quantification becomes routine, timely GHB concentrations could potentially guide management, need for intensive supportive care, and estimate likely period of observation required.

Introduction
Vanilla essence/extract may be deliberately consumed for its high ethanol content. New "alcohol-free" vanilla extracts contain glycerol as an alternative to ethanol. We report a case of life-threatening toxicity after consuming vanilla extract resulting in status epilepticus, severe anion gap metabolic acidosis, pseudohypertriglyceridaemia, and hyperosmolar, non-ketotic coma.

Case summary
A 42-year-old male was admitted to the Emergency Department (ED) with coma, refractory seizures, and faecal incontinence after ingesting 600 mL vanilla extract. Bloods showed pH 6.6, lactate 21 mmol/L, bicarbonate 8 mmol/L, pCO2 84, blood sugar 12.4 mmol/L, ethanol 0.02%, and serum osmolality 456 mOsm/L with anion gap 31 and osmolal gap 151. A presumptive diagnosis of toxic alcohol ingestion was made; the patient was loaded with ethanol and admitted to ICU for haemodialysis. CT head was normal; ketones, urinary crystals, and methanol were negative. Urine organic acid testing was performed as part of a standard method for urine organic acid screening by gas chromatography-mass spectrometry (GCMS); this detected glycerol 84,838 micromol/ mmol creatinine and vanillate, reflecting exogenous glycerol ingestion. Serum triglyceride was measured at 96.4 mmol/L, equivalent to serum glycerol 8977 mg/L. Dialysis continued until anion gap, osmolal gap, and pseudohypertriglyceridaemia resolved. He remained intubated for 4 d due to agitation but discharged neurologically intact on day 6.

Summary of discussion
Standard vanilla essence/extract contains 35-40% ethanol. Recently, vanilla essences using vegetable glycerine (glycerol) as an alcohol replacement have become available, containing ethanol levels of ~1% but high glycerol levels.
Glycerol is a vital component of lipid metabolism. Exogenous glycerol is considered non-toxic and is used as an osmotic laxative or in diagnosis of Meniere's disease. Mild neurological symptoms, such as confusion are reported after therapeutic use or ingestion in the context of renal failure. Seizures and coma have not previously been documented after ingestion but may occur in children with glycerol kinase deficiency. In this case, seizures and coma are presumed due to acutely elevated osmolality.
Laboratory assays for serum triglyceride form glycerol by lipolysis, proportional to the triglyceride concentration. Elevated triglyceride levels therefore represent a surrogate marker to diagnose glycerol poisoning and monitor elimination.
We believe this is the first reported case of glycerol poisoning from ingestion of vanilla essence. This case may herald an emerging cause of accidental poisoning amongst people who consume vanilla essence for its ethanol content.

Background
Patients intoxicated with methamphetamine generally present to Emergency Departments (EDs) with acute behavioural disturbance, acute psychotic symptoms, sympathomimetic toxicity, or seeking help. The aim of our study is to characterise psychosis associated with acute methamphetamine intoxication and its treatment.

Methods
This retrospective case series includes all adult (>15 years) patients who presented with methamphetamine intoxication to the Princess Alexandra Hospital Emergency Department between January and April 2020. All patients identified experiencing psychotic symptoms on arrival were included in this study. Data were supplemented by a manual search of patients' integrated electronic Medical Records (ieMR) and Consumer Integrated Mental Health and Addiction (CIMHA) notes.

Discussion
Almost three-quarters of patients presenting with methamphetamine intoxication suffered from psychotic symptoms, however, these resolved in the majority after a short period of observation. In this study, more than two-thirds of presentations were cleared without a formal Mental Health review and only small proportion were admitted to an inpatient Mental Health ward.

Introduction
Prazosin and Propranolol are cardiac agents which have found increasing use in the treatment of psychiatric conditions, in particular post-traumatic stress disorder (PTSD) and anxiety.

Objective
This study aimed to investigate the incidence of intentional poisonings using prazosin or propranolol in a tertiary toxicology unit.

Methods
All presentations of prazosin and propranolol overdose to a tertiary toxicology service, Hunter Area Toxicology Service (HATS), from 1987 to 2021 were identified from prospective databases, and call records retrieved and reviewed. Demographics, dose, co-ingestants, and complications (ICU admission, LOS, and death) were extracted. Medical records were reviewed for psychiatric diagnosis and indications for prescription for cases from 2015 to 2021. National PBS data was obtained for annual number of prescriptions for prazosin and propranolol.

Results
From 2001-02 to 2021, the number of prescriptions of prazosin and propranolol have increased from 569,884 − 636,903 to 504,121 − 810,223, respectively. Between 1987 and 2021, 64 prazosin and 213 propranolol poisons presented to the toxicology unit, with a significant yearly increase from 2015. Common co-ingestants include benzodiazepines, paracetamol, neuroleptics, and selective serotonin reuptake inhibitors. In the prazosin group, eight patients were admitted to ICU, median LOS 19.5 h, and no deaths. In the propranolol group, 53 patients were admitted to ICU, LOS 17.6 h, and 1 death. Only five patients had concurrent exposures to both prazosin and propranolol. Most patients were prescribed prazosin for PTSD (27/42), and propranolol for anxiety (51/94).

Conclusions
Presentations per year of prazosin and propranolol have increased significantly since 2015. There is/is not a correlation with PTSD and anxiety with overdose using these medications. Patients poisoned with these agents tend to have mild symptoms, and occasionally require intensive care support.

Background
There is little research to characterise plant poisoning in Australia. The aim of this project is to investigate plant exposure calls to a state-based Poisons Information Centre, with a particular focus on symptomology and referral advice.

Methods
This is a retrospective review of plant-related calls to the Queensland Poison Information Centre (QPIC) via the Queensland Health CHIRPs Dashboard and the Pharmhos database from January 2019 to December 2021. The data included patient demographics, plant exposure details, symptomology, and management advice.

Results
There were 3155 plant exposure calls over the study period, including 389 recalls. Children aged 1-4 years were the commonest group exposed, accounting for 1295 (46.8%) unique exposures.

Plant exposures are a common call to a Poisons
Centre. Most exposures are unintentional and occur in children. The majority are asymptomatic or have mild toxicity although medical attention is more common following Euphorbiaceae and gastrointestinal irritants. Significant toxicity was rare and seen in adults with recreational or deliberate self-poisonings.

Aims
With rising therapeutic use worldwide, prescription stimulants are increasingly implicated in poisonings. There is limited research investigating clinical toxicity, mostly extrapolated from illicit amphetamine data. We aimed to investigate the clinical effects of prescription stimulant poisoning.

Methods
This is a retrospective review of hospitalised patients referred to the Queensland Poisons Information Centre (QPIC) and a local toxicology unit following intentional exposures to dexamphetamine, lisdexamfetamine, and methylphenidate between 1 February 2015 and 31 December 2021. Patients were identified from both databases and data extracted from medical records. To facilitate comparison, methylphenidate, and lisdexamfetamine doses were converted to a dexamphetamine-equivalent dose.

Discussion
Prescription stimulant poisoning commonly results in tachycardia, hypertension, and agitation. Severe toxicity is uncommon and mostly manifests as severe agitation.

Introduction
We present an unusual and rare case of Gram-negative cavitating pneumonia with bilateral complex parapneumonic effusions secondary to Fusobacterium necrophorum, in the context of nitrous oxide (NO) inhalation without antecedent or associated pharyngeal infection.

Case
A previously healthy 18-year-old female presented to our Emergency Department (ED) unwell with a fever, rigors, jitteriness, myalgias, unsteady gait, chest discomfort, and shortness of breath, in the absence of cough or other localising symptoms. Her symptoms coincided with several "end-of-lockdown" parties, during which she inhaled NO bulbs; generally 150-200 bulbs 1-2 times a week over 4 weeks. She described using several bulbs together and breath-holding during use. She did not use any other substances regularly. She did not take any regular medications, and specifically no serotonergic agents.
On examination, she was significantly tachycardic and tachypnoeic with normal oxygen saturations, and febrile at 41 °C. She was vague with rapid speech, in the context of rigors, but had full cognition. On initial review, she was noted to have markedly increased tone, particularly in her lower limbs, brisk reflexes, and sustained ankle clonus of >10 beats without ocular clonus. Apart from bibasilar reduced air entry, she had an otherwise normal clinical examination with no obvious infective focus. Her neurological symptoms resolved markedly as her fever resolved. She had normal sensation and gait, and specifically no evidence of disruption of proprioception or other column function.
Investigations revealed marked thrombocytopaenia (platelets 15) with normal haemoglobin and a neutrophilic leucocytosis, procalcitonin of 75.4, and C-reactive protein of 300. She had a mild euvolaemic hyponatraemia (attributed to sepsis) but otherwise a normal renal profile and liver function. Her COVID-19 PCR was negative, and her chest x-ray did not demonstrate any acute pathology. She was commenced on empiric antimicrobials, methionine, and B12 supplementation. She was admitted to the high dependency unit (HDU) and underwent a platelet transfusion.
Her clinical condition progressively deteriorated, where she developed further fevers, rigors, tachycardia, and neurologic findings, and she developed a significant oxygen requirement necessitating high-flow nasal cannulae. Her blood cultures identified a gram-negative organism, identified as Fusobacterium necrophorum. CT chest performed on day 2 of hospital admission demonstrated extensive bilateral pleural effusions, bibasilar collapse, and significant irregular patches of consolidation consistent with necrotising cavitating pneumonia. Extensive investigations were undertaken including autoimmune screening, infective endocarditis screening, and blood-borne virus screening which were all non-contributory. There was no evidence of jugular thrombophlebitis or bacterial seeding secondary to embolic cause.
She was treated with IV Tazocin followed by 6 weeks of oral Co-amoxiclav and made a full recovery. Her bone marrow indices improved and were attributed predominantly to profound sepsis. She was reviewed by the drug and alcohol team during her admission.

Discussion
We present a case of significant necrotising cavitating pneumonia secondary to Fusobacterium necrophorum, in a previously healthy 18-year-old female. F. necrophorum is an anaerobic bacteria found in the nasopharynx, most frequently associated with tonsillitis and Lemmiere's Syndrome, severe septic thrombophlebitis of the internal jugular vein (IJV) related to acute tonsillitis and pharyngitis. Complications of Lemmiere's syndrome include parapneumonic effusions, lung abscesses, sepsis, and cavitating pneumonia. Our patient did not have any evidence or history of pharyngitis or features or IJV thrombosis, nor did she have features of bacterial seeding from another source. There are rare reports in the literature of necrotising pneumonia occurring without IJV thrombosis; however, most cases describe preceding pharyngitis. We were unable to find any case reports of similar events associated with NO use although one published case highlighted a patient with F. necrophorum necrotising pneumonia and severe sepsis in the context of e-cigarette vaping without upper respiratory antecedent.
We hypothesise that our patient underwent bacterial seeding from her upper respiratory tract via the following potential mechanisms.
• Occult bacterial seeding and bacteraemia without obvious thrombosis. • Chronic throat inflammation and chronic airway irritation from her NO inhalation may impair host defence mechanisms, including mucociliary clearance or direct phagocytic function. • Direct inoculation of bacteria from the nasopharynx to the lung from gas insufflation and breath-holding.
This may have been compounded by either a contaminant or pulmonary irritant within the NO bulb. She did not have any evidence of NO-associated neurotoxicity and her bone marrow suppression was attributed predominantly to sepsis. Her clonus and neurological features coincided with episodes of high fever, rigors, and tachypnoea and in this context were attributed to neuroexcitability.
This case represents another complication of NO misuse that has not been previously described in the literature.

The rise of the machines: using artificial intelligence to scale the reach of toxicologists
Moore N. a,b,c , Ionmhain U. N. a,b,c , Ramanathan J. d,e  and Middleton P. M. a,b,

Background
Using machines to automate the jobs that humans find difficult or tedious has been one of the fundamental drivers of all human technology. Artificial intelligence (AI) is a branch of computer science which uses computers to perform tasks associated with intelligent beings. We present the findings of a toxicology centre's one-year experience in using AI to assist in populating a toxicological database.

Methods
We implemented an automated data extraction and screening process from the electronic medical record. This automated extraction was screened using a variety of techniques including keyword search, triage note natural language processing (NLP) and ensemble deep learning models. Final inclusion in the database was confirmed using expert toxicologist opinion. For any missing cases, these were able to be manually added to the database by an expert toxicologist.

Results
In the 12-month period from 1 February 2021 there were a total of 85,120 emergency presentations of which 1078 were included as part of the toxicology registry (1.27%). Overall, an ensemble technique showed best performance characteristics and was thus implemented. Over the 12-month period, there was one miss of major poisonings by the model which was known to the toxicology service. We did note however significant model drift over the period.

Conclusions
NLP can be successfully implemented to screen large amounts of data. Whilst the promise of AI is great, the widespread implementation and evaluation are complex. With ever increasing volume of data, the use of AI techniques is only going to grow, and it is imperative that clinicians lead the development and application of these technologies.

Acute metonitazene toxicity associated with severe respiratory failure
White A. a , Seah V. a , Brown J. b,c , Mcdonald C.

Introduction
Metonitazene is a synthetic mu-opioid agonist described in 1950s that is 30-200x the potency of morphine, in particular for respiratory depression. Clinical data are limited.

Case summary
A man sourced "Spray Oxycontin" online from an overseas supplier. With his first use, he was witnessed to administer 3 sprays intranasally then rapidly become unresponsive and cyanotic. Paramedics arrived 10 min later, noting him to be apnoeic with a weak pulse and pinpoint pupils requiring hand ventilation. He was administered naloxone 400 mcg intravenously and his level of consciousness rapidly resolved but he remained hypoxaemic despite high flow oxygen. In the Emergency Department (ED), non-invasive ventilation was trialled but he was subsequently intubated for a type 2 respiratory failure. He was transferred to the Intensive Care Unit but remained difficult to ventilate despite nitric oxide so was commenced on veno-venous Extracorporeal Membrane Oxygenation. The aetiology of the respiratory failure is not confirmed but may have related to aspiration pneumonitis. His oxygenation slowly improved allowing decannulation 3 d later. He was extubated on day 5 and discharged home without medical sequelae on day 8. LC-QTOF-MS analysis of the product and admission blood and urine sample identified metonitazene.

Discussion
Despite its potency, the effect of metonitazene was readily reversed by a single standard dose of naloxone in this case, without subsequent re-sedation. This may indicate that a small dose was inhaled, and that metonitazene has a short elimination half-life. There is little data on metonitazene misuse in Australia and currently it is not specifically a controlled substance (although ambiguity remains if legally it is considered an analogue/derivative to the prohibited substance etonitazene). In the US, metonitazene is increasingly identified in forensic analyses. A 2021 study identified 20 accidental deaths involving metonitazene (in 30% it was the sole opioid), the majority in individuals with opiate use disorder seeking heroin or fentanyl prior to their death. This case illustrates severe toxicity from an uncommon synthetic opioid that would not be detected on standard opioid screening tests. Poisoning was naloxone-responsive reinforcing the role for take-home naloxone. This highlights the dangers of online purchases of high-risk substances.

Background
Rising case numbers, hospitalisations and deaths from COVID-19 has created concern in the community. Conflicting information about proposed treatments for COVID-19 added to uncertainty for the population. The NSW Poisons Information Centre (NSWPIC) noted an increase in calls relating to home remedies for COVID-19 as the population self-managed the risk. We summarise the remedies used to inform training of staff and advice to callers.

Methods
In the absence of a predefined field to code in the database, COVID-19 home remedies relevant to NSWPIC were identified by surveying staff regarding scenarios they were consulted on. We reviewed Google to identify other trending home remedies for COVID-19. A search of standard toxicology databases and PubMed determined the potential toxicity of these home remedies. Data are presented qualitatively.

Results
Calls to NSWPIC were prompted by adverse effects or out of concern. Most callers were not aware of the potential harms of the home remedy. The duration of exposures was extremely variable. The more common exposures are summarised. (1) Hydrogen peroxide: when nebulised this can cause inflammation to the respiratory system resulting in cough, dyspnoea, and pneumonitis depending on the concentration and duration. Nausea and vomiting are also reported. Mouthwashes 1-1.5% are low risk. (2) Antiseptics: gargling or swallowing strong antiseptics can cause oropharyngeal inflammation, vomiting, diarrhoea, and abdominal pain; corrosive injury occurs with some products. Povidone-iodine (0.5-1%) can be gargled or used as a nasal spray, but there are limited data for prolonged use of higher concentrations. Ingestion or intravenous administration is potentially hazardous. (3) Dermal application of household cleaning products: mild to moderate dermatitis, with burns from stronger products. (4) Spraying surface disinfectants into face masks: oropharyngeal irritation, dizziness, headache, and nausea. (5) High doses of supplements for a prolonged period: can cause kidney stones (Vitamin C), anosmia (Zinc), hypercalcaemia (vitamin D).

Implications
There is a lack of information regarding the potential harms from home remedies for consumers, prompting more open discussion. These results framed the training of staff at NSWPIC.

Background
Olanzapine pamoate is a long-acting salt-based intra-muscular depot injection for the treatment of schizophrenia since 2009. Approximately, 1.4% of patients develop a serious adverse event called Post injection delirium/sedation syndrome (PDSS) [1]. PDSS is characterised by excessive sedation, anticholinergic symptoms, extrapyramidal symptoms, dysarthria, or ataxia (2). The theorised pathophysiology is partial intravascular inoculation, because of the syndrome's presentation similarities to oral Olanzapine overdose and high serum Olanzapine levels in those who develop it [2].

Objectives
To determine the presentation characteristics and onset time of Olanzapine PDSS to formulate a novel treatment approach.

Methods
This is a retrospective review of patients who had the diagnosis of Olanzapine PDSS from two toxicology units and the New South Wales Poisons Information data between January 2017 and February 2022. Adult patients were included if they had been given intramuscular Olanzapine and developed and fulfilled PDSS criteria1. Clinical symptoms, time to symptoms, length of symptomology, and treatment were extracted and entered into a preformatted Excel database.

Results
There were 12 patients, with a median age of 48 years (IQR: 33-49) and male predominance (85%). Dose ranged from 210 to 405 mg. Median onset time to PDSS symptoms was 15 min (IQR: 10-45), with the most frequent first symptom being drowsiness and confusion. PDSS symptoms predominate with drowsiness, confusion, slurred speech, ataxia, and agitation as highlighted by Figure 1. Median length of symptoms was 19 h (IQR: 14-20). In one case, we proposed a novel treatment approach with bromocriptine and physostigmine followed by rivastigmine to manage anti-dopaminergic and anti-cholinergic symptoms respectively, which appeared to lessen symptoms.

Conclusion
This case series supports Detke et al. [1] characterisations of PDSS symptomology predominantly being those of anti-cholinergic syndrome with similar onset (<1 h) and duration times (<72 h). A novel treatment is proposed for the management of PDSS.

Background
Pesticide self-poisonings account for a significant proportion of suicides around the world, primarily in agricultural countries throughout Asia [1]. Risk factors include socioeconomic status, occupation, and substance accessibility. As such, bans on highly poisonous pesticides have proven to be highly effective in reducing the incidence of fatal pesticide self-poisonings [2]. Pesticide self-poisonings also occur in high-income countries such as Australia, albeit in fewer numbers. The aim of this study is to provide an overview of pesticide self-poisonings in S o u t h Au s t r a l i a ( S A ) o v e r 2 0 y e a r s (2000-2019).

Methods
Post-mortem pesticide detections were identified from the Toxicology Database at Forensic Science SA (FSSA). Positive detections were then cross-referenced against autopsy reports to identify fatal cases of fatal pesticide self-poisoning. Recorded variables included age, sex, date of death, intent, scene, toxicology, and autopsy findings. Statistical analyses were performed using R. A linear regression was utilised to characterise trends in the time series, with a Chi-squared test verified with Fisher's exact test and a two-sample t-test to identify significance in the proportion and distribution of age and sex groups within the cohort.

Results
Between 2000 and 2019, 41 cases of fatal pesticide self-poisoning were identified in SA. The decedents included 10 females and 31 males (76%), with more than 50% of the cohort comprised elderly persons. Thirty-nine cases were found to be suicides and the remaining two cases were of undetermined intent. Three deaths were attributed to mixed substance toxicity (i.e. a pesticide in conjunction with a pharmaceutical substance) with the remaining cases attributed to pesticide-only toxicity. Toxicological analysis of post-mortem blood samples revealed that products containing methomyl (n = 10) and diquat/paraquat (n = 10) were the most frequently ingested.

Implications
The findings of this study demonstrate that there has been a consistent, yet low number of pesticide self-poisonings in SA. It appears to be a suicide method used particularly among males and elderly persons, potentially due to ease of access in the absence of alternative means. It is unclear whether accessibility-limiting interventions would be successful in reducing the numbers of pesticide self-poisonings in high-income countries, such as Australia.

Accidental carbon monoxide poisonings reported to the NSWPIC 2018-2022: sources, trends, and populations affected
Turner C. a,b , Wright N. a , Adamo G. a , Roberts D

Background
Carbon monoxide (CO) poisoning continues to contribute to preventable morbidity and mortality. Understanding trends, major causes, and affected populations can inform harm minimisation approaches.

Methods
We searched the NSWPIC database for CO exposures from 01/01/2018 to 28/02/2022. Over one-third of calls were deliberate self-poisonings and excluded from further analysis. NSWPIC call records were manually reviewed, plus the eMR if required and available. Poisonings were categorised by the source of CO, patient(s) age, time (year and season), location (state, and NSW local health district), and Poisoning Severity Score (PSS). Additionally, information on the victim's country of origin, preferred language, symptoms, and treatment was sought from the eMR for NSW poisonings related to use of charcoal heaters or BBQs indoors.

Results
A total of 318 accidental CO poisonings were identified in this period. Of 123 were caused by heating exposures, primarily faulty gas heaters, or using charcoal heaters indoors. These poisonings tended to occur in groups, including children, and pregnant women. They also tended towards more severe poisonings, with a moderate or severe PSS in 45% of poisonings caused by charcoal heating. Poisonings caused by charcoal heating in NSW disproportionately affected the culturally and linguistically diverse community. Vehicle engines resulted in 79 poisonings. Tools with small gasoline engines were the source for 47 poisonings; these were individual exposures and almost exclusively adult males. Total carbon monoxide poisonings have increased from 55 in 2018 to 94 in 2021. As expected, CO poisonings are markedly increased in winter months, with triple the number of poisonings compared to the other seasons.

Conclusions
Accidental CO poisonings have continued to increase over the past 4 years, with preventable poisonings of vulnerable groups (pregnant women and children) continuing. This data supports education and harm minimisation approaches addressing the risks of using charcoal heaters inside, and highlights the need for this to be accessible in a range of languages.

Background
The New South Wales Poisons Information Centre (NSWPIC) has received calls regarding accidental and intentional ingestion of the desiccant component of home pregnancy tests (HPTs). There is a concerning internet trend that promotes ingestion of HPT desiccant as emergency contraception.

Methods
This is a retrospective study of calls to the NSWPIC. The NSWPIC database was searched from 05/01/14 to 17/03/22 for exposure calls where "pregnancy test" appeared in the substance free-text field. Records were hand-searched and included if ingestion of desiccant tablets from HPTs were involved. Characteristics and demographics were described. A review of products available on the Australian market and social media trends was also conducted.

Results
The NSWPIC received 14 exposure calls about HPT desiccants over the study period, all since 2019. There were seven accidental exposures in toddlers. In addition, intentional ingestion by adolescent females have also been reported to NSWPIC (n = 7). Social media posts on TikTok have popularised the myth that the tablet acts as emergency contraception. The myth first appeared in 2019, however NSWPIC continues to receive calls indicating that the trend persists. There are a variety of products available on the Australian market. The desiccant component in some HPTs is tablet-shaped and housed within the test casing. The casing must be deliberately opened to access the tablet. The tablet ingredients are not readily available for many of the tests. Although desiccants are generally considered non-toxic, the desiccant tablet in the Clearblue ® brand contains aluminium oxide and sodium oxide and is classified by the National Poisons Register as corrosive.

Discussion
HPT desiccant exposures can occur even though the device casing must be tampered with to access the tablet. This unusual exposure presents a variety of potential hazards. The desiccant tablet is a choking hazard in young children. In addition, digital pregnancy tests contain a button battery which is hazardous for young children. Furthermore, some brands contain corrosive ingredients. The urban myth relating to emergency contraception could lead to unintended pregnancy. Clearblue ® have refuted the myth in social media posts and on their website and recommend seeking medical advice if the tablet is ingested.

A four-year follow up of methanol-related visual defects: initial severity predicts longterm outcome
Gheslaghi F. a , Wong A. b,c , Firouzfar R.

Introduction
Methanol toxicity can lead to severe and persistent visual defects. Few studies have examined long-term outcomes.

Methods
This was a retrospective cohort study conducted in the poisoning referral centres -Khoorshid and Alzahra University Hospitals, affiliated with the Isfahan University of Medical Sciences from March 2015 to October 2020. Patients hospitalised secondary to methanol poisoning were included in this study and had follow up ophthalmology exams (up to 4 years).

Results
Thirty-nine patients were included in the study. Most patients (95%) were male, with a mean age of 34 years. Treatment modalities used on admission were haemodialysis in 36 (92%) cases and bicarbonate therapy in 38 (97%). All patients who had decreased visual acuity on admission had sustained defects (acuity/ visual fields) on follow up (n = 13). All patients who had visual field defects on admission had bilateral optic disc atrophy on follow up (n = 13). No patients who complained of blurred vision and photophobia on admission had any persisting visual field, visual acuity, or optic disc abnormality on follow up. Of the 36 patients who underwent dialysis, 22 (61%) had a normal follow-up examination and 14 (39%) suffered from impaired visual acuity, visual field, and ocular fundoscopy. Out of 38 patients who received bicarbonate, 24 (63%) patients had no visual complication and 14 (64%) patients had ocular complications. There was no significant relationship between ocular complications and treatment of patients (p > 0.05).

Discussion
Patients who had evidence of visual acuity defects on admission post methanol toxicity were highly likely to have long-term visual acuity, visual field defects, and optic disc atrophy. Patients who complained of blurred vision were less likely to have long-term visual defect sequelae. There was no association between use of bicarbonate or haemodialysis and improvement in long-term outcomes.

Introduction
Guanfacine, a centrally acting alpha-2 adrenergic receptor agonist, historically used as an antihypertensive in adults, has recently seen a resurgence as an alternative treatment for attention deficit hyperactivity disorder largely in children and adolescents. Both immediate and extended-release formulations exist. We report an unusual case of significant guanfacine-induced QT prolongation with an extended-release ingestion.

Case summary
A 22 female with a complex psychiatric history including attention deficit hyperactivity disorder, post-traumatic stress disorder (PTSD), and borderline personality disorder ingested 140 mg guanfacine extended release and zopiclone 52.5 mg in context of escalating suicidal ideation. This was her third presentation to Emergency within 2 d and the implications of this ingestion were not initially appreciated. She was admitted directly to a psychiatric ward. Twelve hours post-ingestion she had an ICU assist for reduced consciousness (GCS 14). She was moved to an acute medical ward, where she developed symptomatic hypotension (90/62 mmHg) and bradycardia to 38 beats per minute. Her ECG demonstrated sinus rhythm with QRS/QT intervals within normal limits. On day 3 she had an arrest call after being found unresponsive on the floor. Her uncorrected QT interval was 730 ms. She was managed with supportive care. Her QT returned to baseline in the subsequent 5 d. Polymorphic ventricular tachycardia was not observed. Her transthoracic echocardiography did not demonstrate any abnormalities.

Discussion
Previous literature on guanfacine-induced long QT is sparse and conflicting. Studies in paediatric populations report no QT prolonging with guanfacine extended-release use. There is only a single case series reporting minor QT prolongation with supratherapeutic doses of 8 mg. Large ingestions are rare with only one other case of a large overdose (189 mg) previously published. There was no QT prolongation noted in this case, implying a lack of a dose-response correlation. As guanfacine extended-release use becomes more prevalent, further cases of significant QT prolongation may be observed, requiring close monitoring. Further surveillance is required to elucidate the mechanism and clinical significance of these findings.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.