Letters

To the Editor: Uncontrolled before‐and‐after studies are highly prone to bias. Wabe and colleagues report on the impact of rapid influenza testing on outcomes for emergency department (ED) patients.1 They compared outcomes across four hospitals between the 2016 influenza season, when standard testing was used, and 2017, when rapid testing was used. Rapid testing was associated with shorter test turnaround times, more patients receiving results, and lower admission rates. Before‐and‐after studies use historical controls, in this case the prior influenza season, to evaluate the impact of interventions. This may be adequate for comparing simple indicators, such as test turnaround time, or for generating hypotheses. However, uncontrolled before‐and‐after studies are not useful for assessing more complex outcomes, such as admission rates, which are highly vulnerable to bias from other factors that may impact the observed results. For this reason, they are discouraged by some publishing groups.2 Frequent genetic drift in influenza virus strains causes variations in the burden and severity of illness each year, which influences ED presentations, testing and admission rates. The 2017 influenza season saw unprecedented numbers of influenza cases and ED presentations in NSW,3 which likely influenced admission practices. Teasing out the effect of rapid testing on admission rates is therefore not possible using an uncontrolled comparison between two disparate influenza seasons, in the manner of Wabe and colleagues. The steps taken to attempt to reduce seasonal effects cannot address this. It is also not possible to determine the net direction of biases in this study. Given the higher cost of rapid tests, it is important to have good estimates of their impact to inform economic evaluations. There are stronger methodologies that still allow timely evaluation using routinely collected data. At minimum, a comparison could be made to hospitals that did not implement rapid testing. When data from more seasons are available, an interrupted time series analysis may be appropriate.4 Interventions that mitigate the burden of seasonal influenza on health services are critical. Rapid testing is likely one such intervention, and therefore warrants careful evaluation with robust methodologies to inform its use.

Anthea L Katelaris · Ross M Andrews · Jeremy McAnulty

To the Editor: Currie and colleagues highlight the important topic of animal vaccines as occupational hazards and the need for improved clinician advice to manage patients safely.1 The article title describes “high pressure” injections, yet the oil emulsion vaccine of most concern, against ovine Johne's disease, is delivered via a standard needle injection. All accidental mineral oil injections are of concern (as are all high pressure injections). Appropriate identification and advice can be obtained by contacting a Poisons Information Centre (PIC). This was not discussed by Currie and colleagues, although it was recommended in a reference they cited.2 Unlike some vaccine manufacturers, the publicly funded PIC service provides 24‐hour emergency medical advice (131 126) for the public and health professionals. PICs access the Australian National Poisons Register, which allows rapid identification of the dozens of oil‐containing vaccines. Currently in Australia, oil adjuvant vaccines lack clear labelling to identify the presence of oil on the front packaging. Increased prominence would aid recognition, similar to initiatives for active ingredients within human therapeutic products. Indeed, review of the unscheduled status of most animal vaccines is required as they possess a risk assessment profile at odds with the Scheduling Policy Framework.3 Improved pharmacovigilance of veterinary products (and agrochemicals) is urgently required, particularly regarding the risks posed to human health. Unpublished analysis of data from Australian PIC annual reports identified about 2000 cases annually of human exposures to veterinary pharmaceuticals. We recently reported on human exposures to veterinary pharmaceuticals from New South Wales PIC calls from 2014 to 2016, with 30 exposures to Johne's disease vaccine alone.4 Collectively, PICs have over 20 times the number of reports to the designated authority for post‐market surveillance; the Australian Adverse Experience Reporting Program run by the Australian Pesticides and Veterinary Medicines Authority received 91 reports for human effects from registered veterinary medicines and agricultural chemical products combined in 2015.5 There is an opportunity for PICs to be engaged more efficiently in surveillance, which would allow the collection of additional information through follow‐up calls to understand risk factors, evaluate outcomes and recommend interventions to prevent future injuries. This would facilitate improvements in management of human exposures to veterinary pharmaceuticals to protect occupational health.

Jared A Brown · Nicholas A Buckley · Rose Cairns · Claire E Wylie

To the Editor: We thoroughly enjoyed the insightful review on erectile dysfunction by McMahon.1 We offer some observations, as most of the abnormalities described in erectile dysfunction are also associated with obstructive sleep apnoea (OSA). Fortunately, OSA can be reliably diagnosed in 80% of cases by bilateral, simultaneous, lateral, passive, anterosuperior, paramarginal distraction of a patient's upper eyelids.2 Finding lax (floppy) lids clearly has a positive association with OSA. Clinical examination of patients with lax eyelids — and in their extreme manifestation, floppy eyelid syndrome — can elucidate a patient's preferred sleeping laterality. Moreover, the presence of OSA can be imputed if the lid laxity is moderate to severe.2 We were concerned that there was no mention of the pathogenetic association of OSA with erectile dysfunction; it may be prudent to exclude OSA in patients diagnosed with erectile dysfunction. As management of floppy eyelid syndrome includes weight loss, it was gratifying to see McMahon emphasising lifestyle modification to reduce the impact of vascular risk factors. Similarly, upper eyelid laxity can also be improved with weight loss.3 This also benefits the OSA‐related complications of hypertension, diabetes, myocardial infarction, stroke and depression, and the ophthalmological complications of floppy eyelid syndrome. It was pleasing to note that McMahon referred to non‐arteritic ischaemic optic neuropathy. However, this condition occurs not only in the context of utilisation of phosphodiesterase type 5 inhibitors but also as a consequence of OSA.4 We suggest that clinicians carry out lid distraction to screen for OSA and assist in the diagnosis and management of erectile dysfunction.

Kriti Agnihotri · Eugene Ting · Ian C Francis

To the Editor: Over the past decades, the incidence of type 2 diabetes, rarely diagnosed in children and adolescents before the 1990s,1 has been increasing in young people in several populations, including Australia.2,3,4 Early onset type 2 diabetes appears to have a more severe phenotype compared with adult onset type 2 diabetes, and has a high prevalence of complications already present at the time of diagnosis despite the patients’ young age and short duration of the disease.5 We aimed to describe the characteristics of Western Australian children aged less than 10 years diagnosed with type 2 diabetes between June 2000 and June 2017. Demographic and clinical data for children diagnosed with type 2 diabetes during the study period were extracted from the population‐based WA Children's Diabetes Database and via manual review of hospital clinical files. Of the 193 children aged less than 16 years diagnosed with type 2 diabetes in WA during the study period, 12 children were diagnosed at less than 10 years of age, with the youngest aged 6 years and 11 months. These 12 patients had one or both parents diagnosed with type 2 diabetes, 11 children were Aboriginal Australians, one was Māori, 11 were obese (mean body mass index z‐score, 2.38; standard deviation [SD], 0.64); nine were female, and seven had one or more comorbidities. Of the 11 children examined, ten had acanthosis nigricans present on their skin. Three children presented with polyuria and polydipsia, six were unwell with other illnesses and three were asymptomatic. Type 1 diabetes antibodies were negative in seven of eight of the children tested, and the mean glycated haemoglobin level at diagnosis was 75 mmol/mol (mean, 9.0%; SD, 2.4%). Nine patients had one or more diabetes complications present at the time of diagnosis; seven had dyslipidaemia, two had an elevated albumin creatinine ratio, and three had hypertension. Our study describes the common clinical features of early onset type 2 diabetes in young children in WA, such as history of parental type 2 diabetes, Aboriginal heritage, obesity, and female sex, and provides strong evidence for the need to screen children with these risk factors for type 2 diabetes, irrespective of their age. Moreover, the high prevalence of diabetes complications present strongly supports the need for complications screening at the time of diagnosis.

Jacqueline A Curran · Aveni Haynes · Elizabeth A Davis

To the Editor: In July 2019, sarcopenia — a progressive and generalised skeletal muscle condition involving loss of skeletal muscle mass and function1 — was awarded a code in the International Classification of Diseases, tenth revision, Australian modification (ICD‐10‐AM). This recognition has arrived 30 years after Irwin Rosenberg first described the condition in 1989.2 Sarcopenia is independently associated with poor quality of life, falls, fractures, institutionalisation and mortality.1 About 13–19% of community‐dwelling older adults may have this condition, and prevalence is highest among those living in residential care.1 All individuals experience declines in muscle mass and function during ageing, but only those who meet the criteria described in the Box are considered to have sarcopenia. The definition currently promoted by the Australian and New Zealand Society for Sarcopenia and Frailty Research is the initial European Working Group on Sarcopenia in Older People definition,3 which was adopted after a Delphi consensus.5 Measures of muscle strength and physical performance such as grip strength, chair stands and gait speed are cost‐effective and easy to perform in clinical practice. Obtaining measures of muscle and lean mass may be challenging outside of the research setting. Therefore, in individuals with low muscle strength or physical performance, in the absence of other potential causes (eg, osteoarthritis), sarcopenia should be suspected and safe and effective interventions can be offered. Patients with, or at risk of, sarcopenia should be recommended exercise therapy, in particular, progressive resistance training.1 This type of training prescribed by treating clinicians can be implemented by allied health professionals, including exercise physiologists and physiotherapists. Protein supplementation can prevent loss of muscle, but this is most beneficial when combined with progressive resistance training.1 A number of randomised controlled trials are underway examining different therapeutics for the treatment of sarcopenia.1 With the advent of the ICD‐10‐AM code, primary care clinicians, allied health staff, and members of the public will begin observing sarcopenia diagnoses on medical correspondence. Hospital funding models may adjust in line with the ICD‐10‐AM code and in recognition of the increased complexity and risk of complications that comes with caring for patients with sarcopenia. An understanding of this condition, its implications and treatment is key in providing evidence‐based care to patients living with sarcopenia. Box – Diagnostic tools and measurements to diagnose sarcopenia* using the initial European Working Group on Sarcopenia in Older People (EWGSOP) definition†3 Component Thresholds and equipment Low muscle strength Hand grip strength using dynamometer: Men: < 30 kg Women: < 20 kg Low physical performance Men and women over 4 m course: Gait speed: ≤ 0.8 m/s Low lean mass ALM using whole‐body DXA (adjusted for height, m2): Men: < 7.26 kg/m2 Women: < 5.50 kg/m2 ALM = appendicular lean mass; DXA = dual x‐ray absorptiometry. * Diagnosis of sarcopenia is based on low lean mass and low physical performance or muscle strength. † The EWGSOP have developed a revised definition for sarcopenia (known as EWGSOP2);4 however, this has not yet been recommended for use in Australia.

Jesse Zanker · David Scott · Sharon L Brennan‐Olsen · Gustavo Duque

To the Editor: As reported by Rowe and colleagues1 in their retrospective analysis of maternal immunisation, uptake of influenza and acellular pertussis vaccines among pregnant women remains unacceptably low. One contributing factor may be inconsistent messaging. Historically, vaccine manufacturers have included precautions about the lack of data on use in pregnancy in their product information sheets. Such precautions have been shown to lead to vaccination hesitancy and refusal among pregnant women.2,3 In contrast, the current edition of the Australian Immunisation Handbook states: “Pregnant women are routinely recommended to receive influenza vaccine … and pertussis‐containing vaccine”.4 In 2018, the Therapeutic Goods Administration asked its Advisory Committee on Vaccines to provide independent expert advice on the available safety data on influenza vaccination in pregnancy with regards to the pregnancy category of influenza vaccines. The Advisory Committee on Vaccines advised that “adoption of Australian Pregnancy Category A should be considered by sponsors for certain inactivated influenza vaccines”.5 Pregnancy Category A signals to doctors and the public that the vaccine has been used by large numbers of expectant mothers with no evidence of harm to their babies. This is in line with the Australian Immunisation Handbook: “Clinical trial data and observational studies show no increased risk of congenital defects or adverse effects in the fetuses of women who received influenza vaccine during pregnancy”.4 Following the publication of the Advisory Committee on Vaccines statement, two of the four adult influenza vaccines and one of the two acellular pertussis vaccines used to vaccinate pregnant women in Australia have changed their pregnancy category to Category A. These changes show that the Australian regulator is receptive to feedback from the medical community on how to improve immunisation rates. Hopefully, the reclassification of the pregnancy category of these vaccines will translate into increased maternal uptake and better outcomes for Australian mothers and babies.

Heidi Shukralla · Michael Coory

Christmas is known for festive decorations

Paul Heyworth · Ryan Shulman

To the Editor: The editorial by Murnion and Conigrave1 and the article by Crossin and colleagues2 on the dangers of misuse of pregabalin are a timely warning to all prescribers. The black market utility (based on testimonies) and frequent misuse of pregabalin is well known both academically and to prescribers in prison environments.3,4 Harm relating to gabapentinoid use is noted to be increasing globally. A 2017 case–control study showed a dramatic increase in relative risk of death with opioid and gabapentinoid versus opioid alone.5 People leaving prison are at a higher risk of opioid overdose death, partly because of loss of tolerance.6,7 This will likely be compounded by inappropriate gabapentinoid prescribing. In New South Wales prisons, the Justice Health and Forensic Mental Health Network sees many patients who present seeking pregabalin and other prescription drugs in our health clinics. Patients often enter custody using high doses of medications prescribed in the community, including gabapentinoids, benzodiazepines and opiates. The Network applies a multidisciplinary team approach between primary care, pharmacy, and drug, alcohol and mental health services for these complex patients. Furthermore, clinicians undertake regular medication reviews of patients; medications that are not indicated are deprescribed to reduce potential harm to patients.8,9 The Network has developed management guidelines around gabapentinoid use, including regular review of prescriptions by general practitioners and the clinical director. Off‐label use is discouraged. Pregabalin is always a supervised medication, and dose limits and deprescribing programs are in place to limit availability if not indicated. Alternate medications for the management of diagnosed neuropathic pain are effective and may pose less risk in prison environments.8,9 Gabapentinoid drugs are not used as an alternative to opiate pain medications in NSW prisons. Patients are assessed and given appropriate medications according to the quality and safe use of medicines approach, and medication charts are regularly audited to ensure safe prescription of medications. There has been an overall reduction in actual gabapentinoid prescribing in NSW prisons in recent years. We encourage all Australian prescribers to ensure care around prescribing of gabapentinoid and other medications, especially for complex patients with drug and alcohol misuse and polypharmacy issues.

Gary Nicholls · Peter Samios · Stephen Hampton

To the Editor: We read with interest the recent publication by Rowe and colleagues.1 The authors reported low influenza vaccine coverage (39%) among pregnant women in Victoria from 2015 to 2017. Individual‐level factors associated with this finding included greater maternal age, primigravidity, early antenatal care and GP‐led antenatal care.1 As the authors accurately concluded, integrating vaccine delivery into antenatal care pathways is important to improve pregnant women's vaccination coverage.1 Our team reported on this previously, with coverage approximating 90% achieved by introducing standing orders for midwives.2 In collaboration with key stakeholders from six Victorian maternity services, a Monash University‐led project funded by Better Care Victoria is currently underway to implement integrated vaccination strategies and measure the cost and magnitude of improvement in maternal immunisation coverage in Victoria,3 the results of which will be available by the end of 2019. One of the key findings in the article by Rowe and colleagues1 is higher odds of influenza vaccination in women who gave birth after 37 weeks' gestation compared with women who gave birth before 28 weeks (adjusted odds ratio [aOR], 4.74; 95% CI, 3.54–6.35). A similar finding was reported for women who gave birth between 28 and 36 weeks gestation (aOR, 4.13; 95% CI, 3.07–5.56).1 This finding has two important implications. Firstly, it may indicate a potential beneficial effect of influenza vaccine received by pregnant women in reducing pre‐term birth (< 37 weeks' gestation). This is consistent with a recent systematic review and meta‐analysis that reported inactivated influenza vaccine to have a protective effect against pre‐term birth and low birth weight.4 Secondly, this finding may serve as an opportunity to emphasise the safety and benefits of influenza vaccines on perinatal outcomes. As the authors alluded to in their discussion, pregnant women tend to view influenza as primarily a health risk for themselves rather than for their infants.1 Given the importance of health care providers' recommendations in encouraging influenza vaccination among pregnant women, timely dissemination of the potential benefit in lowering the chance of pre‐term birth could further empower health care providers to recommend influenza vaccines to pregnant women.5

Khai Lin Kong · Michelle L Giles · Euan M Wallace

To the Editor: Last month, the Medical Journal of Australia called for manuscript submissions on the topic of “Women in medicine and medical leadership in Australia — is there gender equity?” We answer with a resounding no. Indeed, we believe the question itself perpetuates gender disparity by suggesting that the answer is up for debate. There is overwhelming evidence to demonstrate that gender equity in medicine and medical leadership in Australia has not been achieved. Women have had gender parity in Australian medical schools for decades; however, they represent only 28% of medical deans and 12.5% of hospital chief executive officers.1 In February 2019, The Lancet dedicated an entire issue on advancing women in science, medicine and global health.2 The MJA has also reported on capacity, capability and credibility barriers for women in health leadership.3 These disparities are even greater for Aboriginal and Torres Strait Islander women, women of colour and women with disabilities. There is an urgent need to shift our focus from asking whether gender inequity exists to implementing and evaluating sustainable strategies to change the status quo. This year, the Australian Medical Association of Victoria changed its constitution to include a 40% gender quota for its board.4 The Royal Australasian College of Surgeons has established a business plan with tangible indicators to promote leadership and flexible training for its female surgeons.5 Both the Women in Tropical Health Catalyse Program6 in Australia and Wāhine Connect (www.wahineconnect.nz) in New Zealand offer mentoring for women in medicine and medical leadership. We need to bolster current strategies aimed at improving the number of women in medical leadership. Moreover, we need to keep our workplaces, colleges, committees, professional associations and academic journals accountable for the role they play in the persistent gender inequities in medicine and medical leadership in Australia. We invite the MJA to follow The Lancet's example and dedicate an entire issue to strategies that advance women in medicine and medical leadership. We implore it not to ask “is there gender equity?” when the answer to this question is patently clear. The answer is no.

Allison Hempenstall · Jillian Tomlinson · Marie M Bismark

To the Editor: I thank Whitfield and colleagues for their article about hyperemesis gravidarum and abnormal liver function in pregnancy.1 In a 15‐month prospective study in South West Wales, abnormalities of liver function were present in 3% of pregnancies.2 In managing pregnant women with hepatic dysfunction, it is important to consider uncommon causes of liver disease that may be associated with serious maternal and fetal morbidity and mortality if untreated. Addison disease is a rare but potentially life‐threatening condition that may imitate hyperemesis gravidarum in presenting with vomiting, weight loss, postural hypotension and hyponatraemia.3,4 Addison disease has also been associated with elevated hepatic transaminases in 16 published cases, reversing with glucocorticoid replacement.5 In excluding Addison disease, the physiological rise in cortisol during pregnancy must be considered using trimester‐specific reference ranges for short synacthen testing.6 In the pregnant woman with unexplained liver disease and fever, acyclovir should be administered empirically, given the absence of cutaneous vesicles in up to 80% of affected patients and the extreme maternal and fetal mortality associated with untreated herpes simplex virus hepatitis.7 Budd–Chiari syndrome should be considered with abnormal liver function in pregnancy with abdominal pain, hepatomegaly and ascites. Additionally, the use of herbal and over‐the‐counter medications should be sought in pregnant women with abnormal liver function, given the high rates of complementary and alternative medicine use in pregnancy and their potential to cause liver injury.8 Investigations need to be interpreted with regard to gestational physiological changes, as copper, ceruloplasmin, α‐1 antitrypsin and alkaline phosphatase levels rise significantly in pregnancy. Serum lipase levels are commonly elevated in hyperemesis gravidarum — levels up to ten times normal have been reported in the absence of pancreatitis.9 Antithrombin III levels may be useful to distinguish acute fatty liver of pregnancy from pre‐eclampsia with haemolysis, elevated liver enzymes and low platelets.10 Bile acid levels are not specific for intrahepatic cholestasis of pregnancy, being elevated in many hepatic disorders including non‐alcoholic fatty liver disease. Twenty per cent of women with pruritus typical of intrahepatic cholestasis of pregnancy have normal bile acids and liver function at presentation, and symptoms may precede abnormal biochemistry by up to 6 weeks.11 In addition to ondansetron and glucocorticoids, mirtazapine has been effective in the management of hyperemesis gravidarum in case reports.12

Adam Morton

To the Editor: In their article, De Costa and colleagues1 clearly demonstrate the importance of making mifepristone freely available for prescription to all registered Australian medical practitioners, and they emphasise that the current need for special registration discourages general practitioners to become involved in medical abortion provision. We conducted a cross‐sectional study of 39 GPs and 30 primary health care nurses from regional or rural Victoria and identified additional uptake barriers.2 Most study participants showed important gaps in medical abortion knowledge, despite their overall positive stance on abortion and extensive experience with women with unplanned pregnancies, and only a few indicated to be current medical abortion providers. Although nearly all health practitioners indicated they would support a colleague in providing abortions, fewer GPs than nurses were interested in medical abortion training. The main reported uptake barriers to medical abortion provision included a lack of training opportunities as well as the absence of local support services required in Australia for the recommended pre‐abortion ultrasound and for surgical back‐up in the case of complications. Participants additionally worried about the legality of providing abortions, and some indicated that their practices would not allow the provision of this service. Abortion access for Australian women in regional and rural regions is still very restricted. By moving early medical abortion provision into the primary health care setting of underserved regions, and particularly in general practice, this situation can be considerably improved. However, the uptake among GPs remains low.3 In addition to addressing uptake barriers, alternative solutions to improve abortion access in underserved areas should be further explored as well, such as the use of telemedicine (until recently provided by the Tabbot Foundation) and the inclusion of primary health care nurses in the abortion provision process — an evidence‐based practice that is already extensively implemented in a range of high income countries.4,5 A nurse‐led model approach not only addresses the shortage of physicians but also the time‐intensive aspect of the medical abortion process, and it provides women with choice and flexibility, which is indispensable to their reproductive autonomy and, thus, to their overall welfare.

Caroline Moel‐Mandel · Melissa Graham

To the Editor: Recreational misuse of nitrous oxide remains a significant public health problem,1 sustained in part by the ready availability online of gas‐containing canisters intended for use in the catering industry. Known as “nangs” or “whippits” and usually purchased in bulk, each canister contains 8 g of nitrous oxide. When inhaled, this gives a seconds‐long “high”, which is typically prolonged by using several “nangs” in a single session. Some individuals can consume hundreds each day. Prolonged exposure to nitrous oxide leads to the oxidisation of vitamin B12, rendering it unusable in key enzymatic reactions necessary for normal myelin synthesis.2 Over time, this leads to a potentially devastating neuropsychiatric syndrome that commonly presents with ataxia.3 Notably, the culprit shortage of vitamin B12 is a qualitative one and can be purely so, meaning that marked clinical deficits emerge in the presence of serum B12 levels that appear normal on standard laboratory assays. Furthermore, with continued exposure to nitrous oxide, these deficits will respond poorly to vitamin B12 supplementation. In a year‐long clinical audit at Royal Prince Alfred Hospital (2017–2018), seven nitrous oxide users, all aged between 20 and 30 years, presented with ataxia that ranged from mild to severe (Box 1). Most patients also had psychiatric symptoms. Nearly every patient estimated using 100 or more canisters of nitrous oxide per day in the months before being seen. Four patients also reported engaging in B12 supplementation (both oral and parenteral), aiming to circumvent the harmful sequelae of prolonged nitrous oxide misuse. Laboratory studies showed that all seven patients had accumulated homocysteine, as is usually seen when vitamin B12 is in short supply in the body.2 Individuals who reported taking supplements had serum B12 levels that were either normal or in excess of normal, implicating a qualitative deficiency of metabolically useful B12. Evidence of demyelination was seen on spinal cord imaging in six patients, including all those who used supplements, with the “inverted V” sign4 visible on T2‐weighted magnetic resonance imaging sequences (Box 2). Despite treatment according to best practice guidelines, all patients left hospital with persistent symptoms, and most were unable to walk or to attend to their bodily needs without the assistance of family members (modified Rankin score, 4). Sadly, one of the least affected individuals re‐presented to hospital with worsened symptoms because of continued nitrous oxide misuse. At every opportunity nitrous oxide users should be reminded of the futility of B12 supplementation, as one of many reasons why they should choose to avoid this profoundly destructive drug. Box 1 – Patients presenting with symptoms due to nitrous oxide misuse Age (years) Sex Canister use Duration of use B12 supplementation Ataxia severity* Psychiatric symptoms† Homocysteine level Serum B12 (active) MRI: “inverted V” sign‡ mRS: Day 1 mRS: discharge 20 Female 250/day 1 year No Severe Yes High Low (low) Yes 4 4 30 Male 60/day 1 year No Moderate Yes High Low (low) Yes 1 1 30 Male 100/day 6 months No Mild No High Low (normal) No 1 1 21 Male 200/day 1 year Yes Severe Yes High Normal (normal) Yes 4 4 23 Female 300/day 2 months Yes Severe Yes High Normal (high) Yes 4 4 23 Female 200/day 2 months Yes Severe Yes High High (high) Yes 4 4 28 Male 300/day 1 year Yes Mild No High Normal (normal) Yes 1 1 MRI = magnetic resonance imaging; mRS = modified Rankin score of neurological disability. * Ataxia: mild = visible gait disturbance; moderate = frequent falls; severe = inability to walk without assistance. † Psychiatric symptoms included mood disturbance, memory impairment and psychosis. ‡ MRI findings: “inverted V” sign on T2‐weighted MRI spinal cord imaging (Box 2). mRS: 0 = no symptoms; 1 = no significant disability despite symptoms; 2 = slight disability; 3 = moderate disability; 4 = moderately severe disability, unable to walk or attend to bodily needs without assistance; 5 = severe disability, bedridden; 6 = dead. Box 2 – T2‐weighted magnetic resonance imaging sequence showing “inverted V” sign, indicating the presence of dorsal column demyelination

Christopher Blair · Chris Tremonti · Leon Edwards · Paul S Haber · G Michael Halmagyi

To the Editor: Recreational use of nitrous oxide is increasing among regular drug users in Australia1 and internationally.2 In a New South Wales survey of participants who had used ecstasy or other stimulants in the past 6 months, 75% of respondents reported recent use of nitrous oxide in 2018, up from 20% in 2013.3 Nitrous oxide use while bingeing on stimulants rose from 4% of respondents in 2013 to 16% in 2017.4,5 Access to nitrous oxide has been facilitated by businesses offering 24/7 delivery of large quantities of canisters, ostensibly for whipping cream.6 We examined presentations to 60 emergency departments (EDs) across NSW from January 2012 to December 2018 (covering about 82% of all NSW ED presentations) in which the patient reported inhaling nitrous oxide outside a therapeutic setting. We extracted records from the Rapid Emergency Department Data for Surveillance (REDDS) dataset in which the person was aged 16 years or over and “nitrous oxide” or related terms were mentioned in the presenting problem, nursing assessment or diagnosis fields. We manually reviewed records for inclusion; this method may underestimate true presentation counts. ED presentations fitting the criteria were infrequent (n = 118) but increased over time, particularly from 2016 to 2018 (Box). Most presentations were in persons aged 16–30 years (n = 98, 83%) and just over half were men (n = 66, 56%). Almost half indicated polydrug use (n = 54, 46%), and one quarter indicated chronic or heavy use of nitrous oxide (n = 28, 24%). Consistent with the case literature,7 presenting problems and diagnoses included injury (n = 15, 13%), neurological symptoms (n = 14, 12%), loss of consciousness or syncope (n = 13, 11%), respiratory arrest (n = 2, 2%), self‐harm or suicidal ideation (n = 16, 14%), or other mental health conditions (n = 28, 24%). This increase in presentations may reflect changes in the underlying population or in data collection, rather than changes in drug use. However, the trend is consistent with drug use survey findings,1,3 suggesting that recreational nitrous oxide use may be an emerging health problem in Australia. Clinicians should include nitrous oxide use as part of a drug history, consider potential use among young patients presenting with neurological symptoms resembling B12 deficiency, and educate users on the health impacts, harm minimisation strategies and available support services. NSW Health is educating at‐risk groups through multilingual fact sheets8 and targeted social media and other messaging. This report is the result of an investigation carried out by the NSW Ministry of Health under the provisions of the NSW Health Administration Act 1982; therefore, specific ethics approval was not required. Data were sourced from the REDDS, which is maintained by the Ministry of Health, and were analysed by Ministry of Health staff for the purpose of the investigation. Box – Emergency department presentations in New South Wales in which the patient reported inhaling nitrous oxide in a non‐therapeutic setting (from January 2012 to December 2018) Data source: Rapid Emergency Department Data for Surveillance (REDDS), held by NSW Ministry of Health.

Anna Bethmont · Claire E Harper · Betty SH Chan · Andrew H Dawson · Jeremy McAnulty

To the Editor: The authors of a recent Guttmacher–Lancet Commission article1 point out that Australia is a signatory to the United Nations Sustainable Development Goals, which nominate sexual and reproductive health as rights. The key focus of the article on the Guttmacher–Lancet Commission is around human immunodeficiency virus and sexually transmitted infections, unintended pregnancy, contraception, abortion, and sexual violence.1 These are all important reproductive health rights to address. While the Guttmacher–Lancet Commission also includes maternal and newborn health, there is no mention of reproductive carrier screening. Reproductive carrier screening involves testing prospective parents — before pregnancy, ideally, or in the early stage of pregnancy — for carrier status for autosomal recessive and X‐linked recessive disorders, and giving reproductive choices to people at increased risk of having an affected child. These choices include pre‐implantation genetic diagnosis, prenatal diagnosis by chorionic villus sampling or amniocentesis, donor gametes or embryos, adoption, having no children, or ignoring the risks. Most couples with or at risk of having an affected child have no family history, which is typical for recessively inherited diseases. Reproductive carrier screening is available in Australia, although only through a fee‐for‐service mechanism, but most couples are unaware of its availability. Currently, screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy is available,2 and in the future we may be able to screen for a vastly expanded number of diseases. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists has recently released a position statement to recommend that all women, either before pregnancy or in the first trimester, should be offered carrier screening for inherited conditions.3 Reproductive carrier screening should be a routine part of pregnancy care and should be considered a health care right.

R John Massie · Martin B Delatycki

To the Editor: We welcome the research letter by Roche and Kostadinov,1 who have reported an increasing trend in risky alcohol consumption among adults aged over 50 years. The Report of the Chief Health Officer Queensland in 20162 presented the trends for lifetime risky drinking3 and found a similar trend of risky drinking for males aged 65 years and older. While agreeing with the authors' overall message, there are concerns on the method used to assess trend, in particular, the highly significant P values for the relatively small change in prevalence. Population‐weighted counts, as presented in the research, are used to ensure that prevalence estimates are representative of the national population, but are inappropriate to use when determining the precision of the estimate. Using the weighted counts to calculate the χ2 statistic for trend effectively assumes that the population is the sample size (ie, 8 015 139 in 2016), when in fact the sample size was 23 772 in 2016.4 The effect of this is an overprecise estimate that results in a highly significant P value. Using the authors' table, a simple linear regression with prevalence as the outcome and year as the predictor can be used as a quick face validity check. This results in non‐significant trends for both risky and high risk groups; however, when these groups are combined a significant result is observed (significance level P < 0.05). My research into lifetime risky drinking also encountered this issue of incorporating population weights into trend analysis and this was resolved by using various regression techniques.5 Another advantage of using regression is the ability to incorporate interactions in models to test differences in trend between subgroups. Using this technique identified a statistical difference in lifetime risky drinking trends between people aged 18–29 years and people aged 65 years and older (P < 0.001) (Box). I believe that the authors' findings are important, but we need to take care that results are not discredited by choice of methodology. Interactive data visualisations of alcohol consumption and other risk factors trends for Queensland can be found at the Queensland health website.6 Box – Trends in prevalence of lifetime risky drinking, by age group, Queensland, 2010–2018* * Reproduced from Queensland Health's website.6

Tim Roselli