Statistics

Supporting children after sexual abuse is also essential for the adults they become

Nina Papalia · Benjamin L Spivak · Linda Ashford · Ahona Guha · Stefan Luebbers · James RP Ogloff · Nina Papalia · Benjamin L Spivak · Linda Ashford · Ahona Guha · Stefan Luebbers · James RP Ogloff

More effective care strategies are required to reduce the burden of TBI, particularly among younger men

Gerard M O'Reilly · Kate Curtis · Biswadev Mitra · Yesul Kim · Afsana Afroz · Kate Hunter · Courtney Ryder · Delia V Hendrie · Nick Rushworth · Jin Tee · Shane D'Angelo · Emma Solly · Oashe Bhattacharya · Mark C Fitzgerald · Gerard M O'Reilly · Kate Curtis · Biswadev Mitra · Yesul Kim · Afsana Afroz · Kate Hunter · Courtney Ryder · Delia V Hendrie · Nick Rushworth · Jin Tee · Shane D'Angelo · Emma Solly · Oashe Bhattacharya · Mark C Fitzgerald

Selecting a suitable CVD risk equation for the Australian population

Sinan Brown · Emily Banks · Mark Woodward · Natalie Raffoul · Garry Jennings · Ellie Paige

Australia has a vibrant and changing clinical trials landscape, but there are areas requiring improvement

Anna Lene Seidler · Melina L Willson · Mason Aberoumand · Jonathan G Williams · Kylie E Hunter · Angie Barba · R John Simes · Angela Webster

The NCSR improves health care provider engagement in cancer screening through better access to patient screening records and by facilitating safety net follow up of screen-detected abnormalities, which could influence better health outcomes through early detection and treatment

Dorota Gertig · John Lee

To the Editor: The flavivirus Murray Valley encephalitis virus (MVEV) was isolated in 1951 from the brain tissue of fatal cases of encephalitis.1 Subsequent work by Australian investigators established MVEV as the likely aetiological pathogen of the severe encephalitis “Australian X disease”.1 MVEV is enzootic in northern Western Australia and the Northern Territory, resulting in sporadic human cases.2 In south‐east Australia, however, MVEV activity can be absent for decades only to reappear with significant human outbreaks. The three most recent outbreaks in Australia were in 1951 (45 cases), 1974 (58 cases) and 2011 (17 cases).1,2,3 The case fatality rate is about 18% in hospitalised patients, reflecting the severity of disease.4 Since 1974, Victoria has employed vertebrate and invertebrate surveillance methods to detect MVEV activity before human cases.5 Until 2021, sentinel chicken flocks were placed along the Murray River and tested weekly for MVEV seroconversion during the mosquito season, which runs from November to April. The most recent seroconversions were in 2011, along the Murray River, in Greater Bendigo, and in Greater Shepparton.6 This testing strategy was limited by biological and logistic delays, diminishing the system as an early warning tool. In 2021, sentinel chickens were retired, with flavivirus testing combined into the long‐standing alphavirus mosquito trapping program when polymerase chain reaction (PCR) assays replaced labour‐intensive and insensitive cell culture methods.7 For the 2022–2023 mosquito season, in the setting of Japanese encephalitis virus activity and historic floods, the Victorian Department of Health supported 15 councils to trap mosquitoes as part of the Victorian Arbovirus Disease Control Program (VADCP). Trapped mosquitoes were pooled and submitted for PCR testing. The size and composition of these varied depending on the number of collected mosquitoes, with a preference for analysis of speciated mosquitoes if possible. Detections were confirmed with sequencing at a reference laboratory. As of 23 January 2023, we have detected MVEV in 14 mosquito traps across four local government areas (Box). The positioning and density of the traps are influenced by proximity to population centres and resource considerations, which may influence the likelihood of virus detection in different localities. The first detection was in mosquitoes collected on 4 January 2023. New South Wales and South Australia have also reported MVEV detections in multiple locations. Subsequently, on 17 February 2023 the first human case of MVEV infection in Victoria since 1974 was confirmed after lengthy investigation of a person with illness onset on 16 January 2023. This represents the first detections of MVEV in south‐east Australia in the 2022–2023 mosquito season, the first surveillance detections in Victoria since 2011, and the first confirmed human case in Victoria since 1974. The timing of these signals is notably earlier in the season than previous sentinel chicken seroconversions, which occurred in February 2011, supporting mosquito PCR testing as a rapid surveillance tool. This difference in timing may, however, be explained by inter‐year environmental or sampling factors, and a controlled comparison between mosquito and sentinel chicken surveillance, in the context of subsequent human cases, is required to demonstrate the most useful surveillance tool. Nonetheless, the presence of virus and capable vectors suggests the risk for human infection is present, and, importantly, informs public health actions. MVEV in south‐east Australia is rare and the time between outbreaks is measured in decades. These early mosquito surveillance signals have preceded a human health event which has not occurred in Victoria since 1974. In the absence of an effective vaccine, prevention relies on vector control and health promotion, while case detection requires clinician awareness. Retrospectively, a serosurvey will be essential to measure the extent of human exposure during this period of MVEV activity. Finally, given our understanding of MVEV in Victoria is limited by a paucity of historical events to analyse, researchers should engage in this rare opportunity to study MVEV epidemiology and ecology. Box – Victorian local government areas (LGA) with the first 14 polymerase chain reaction (PCR) detections of Murray Valley encephalitis virus in trapped mosquitoes in 2023 (shaded in red). LGAs where surveillance was undertaken are outlined. The inset shows the Australian state of Victoria shaded‐in and the dates of mosquito collection and notification to the Department of Health * Greater Bendigo LGA.

Maxwell Braddick · Aidan Yuen · Rebecca Feldman · N Deborah Friedman

Flexibility of design is not a panacea, but adaptive clinical trial designs offer the potential for more efficient research

Elizabeth G Holliday · Natasha Weaver · Daniel Barker · Christopher Oldmeadow

Increased in-hospital mortality may reflect changes in care across the Australian health system that need to be rectified

Sing Chee Tan · Tess Evans · Matthew L Durie · Paul J Secombe · David Pilcher

In-hospital mortality was not higher for transferred patients, confirming careful case selection and sustained commitment to care by hospitals

the SPRINT‐SARI Australia investigators

Most incident melanomas are managed by primary care practitioners, underscoring the need for specific training

Nirmala Pandeya · Catherine M Olsen · Maja M Shalit · Jean Claude Dusingize · Rachel E Neale · David C Whiteman

We need to design data systems that hold social and health equity as a core value and desired outcome of data integration

Catherine Smith · Claire M Vajdic · Niamh Stephenson

Pioneering cancer epidemiologist and champion of women in science

Karen Canfell · Bette Liu · Emily Banks

Improving mental health outcomes requires both direct access and accelerated specialist services growth

Catherine Vacher · Adam Skinner · Jo‐An Occhipinti · Sebastian Rosenberg · Nicholas Ho · Yun Ju Christine Song · Ian B Hickie

Not all placebo interventions control for the placebo effect, potentially producing misleading results Placebo‐controlled trials have traditionally been considered the gold standard when comparing the effect of an intervention with no intervention, as they allow the opportunity to differentiate between the therapeutic and placebo effects. However, the results are only valid if appropriate placebo controls are used; otherwise, the placebo control may be a “wolf in sheep's clothing”. The placebo effect is present in all experiences of interventions, with the magnitude of the effect potentially influenced by several factors.1 The observed summary measure of the primary outcome (eg, mean/median) in each treatment arm or intervention is thus a combination of the real therapeutic effect, the placebo effect, and the natural progression of the condition since treatment initiation (Box 1). The magnitude of each of these components may vary within both person and group. Placebo controls are intended to control for the placebo effect, but where the placebo effect is not equal across interventions, this is unlikely the case and the magnitude of the therapeutic effect remains unknown. To control for the placebo effect, a placebo control should have no specific therapeutic effect on outcomes of interest and be perceived as real and identical to the primary intervention.2 These placebo criteria are often not possible to achieve for all interventions (eg, lifestyle interventions). Despite this, several studies have compared such interventions with so‐called placebo controls that do not meet these criteria, potentially producing misleading results. In this Perspective, we discuss three possible problems with so‐called placebo controls that potentially result in failure to control for the placebo effect: the placebo control having a specific, therapeutic effect on outcomes of interest; the placebo control being distinguishable from the intervention of interest; and an emerging issue of open‐label placebos being used to supposedly control for the placebo effect. Specific therapeutic effects Placebo controls should have no specific therapeutic effect on outcomes of interest, to control for the placebo effect. However, there are several examples of so‐called placebo controls that contravene these criteria. For example, although saline injections are pharmacologically inert and, therefore, often thought of as having no specific effects, saline injections may improve symptoms3,4 and may have specific physical and chemical effects that could improve outcomes of interest,5 and hence do not necessarily control for the placebo effect. Importantly, the potential negative effects of so‐called placebo controls should also be considered. Recently, the REDUCE‐IT trial compared the effect of icosapent ethyl with a placebo control (a mineral oil) on cardiovascular disease, concluding that the drug improved cardiovascular outcomes.6 However, further analyses revealed that this difference was not likely due to the effectiveness of the icosapent ethyl but rather to the harm caused by the placebo control, which may have interacted with other medications being taken by the participants.7 It is thus crucial to ensure that the placebo control does not have specific therapeutic effects, even if pharmacologically inert, because such effects may lead to misinterpretation of the therapeutic effects of the drug being tested. Distinguishable from the intervention of interest A placebo control must be indistinguishable from the primary intervention. This point not only facilitates blinding of the participant (and potentially outcome assessors) thus reducing bias, but also allows for control of the magnitude of the placebo effect. There is a large body of evidence indicating that not all placebo interventions have the same effect, with the level of invasiveness, dosage and brand differentially affecting individual expectations around intervention outcomes.1 For example, a 2022 study compared an education and exercise program for people with knee osteoarthritis with a so‐called placebo control, where the placebo was a saline injection with arthrocentesis (where required) — two very distinct treatments.8 Having so‐called placebo controls that are distinguishable from the primary intervention does not necessarily control for the placebo effect because the magnitude of the placebo effect may differ from that of the primary intervention. Open‐label placebos A new suggested approach to allow for comparison of distinguishable interventions while apparently controlling for the placebo effect is the use of an open‐label placebo — an inert intervention where the participant is made aware of the inert status of the intervention. Open‐label placebos have gained increasing attention, with evidence indicating they are more effective than no treatment in some contexts.9,10,11 However, these findings do not indicate that open‐label placebos control for the placebo effect, and the manner in which they are delivered may also have an impact on the outcomes for the intervention group. An open‐label placebo was employed in the abovementioned study regarding knee osteoarthritis. In that study, all participants had the candidate interventions described, with statements that the saline injections were “inert, yet with potential beneficial effects that may compare to those of exercise and education” and that “investigators had no treatment preference,“8 presumably in an attempt to make the placebo effect comparable. However, both statements mean the intervention is no longer perceived to be real and may negatively affect the outcomes of the education and exercise intervention. It is critical to appreciate that the participants’ expectations, particularly when manipulated by investigators, may not only increase the expectations of benefits but also reduce them and, therefore, affect measured outcomes. For instance, in a recent study, the same active medication was provided to all participants, but one group was told they had the real medication (the truth) and the other group that they had an “active placebo” (deception), resulting in statistically significant differences in measured effect between the groups, despite the therapeutic effect per se being identical in both groups.12 In the same way, in the 2022 knee osteoarthritis trial, the explanations to participants regarding the potential comparative effectiveness of the saline injection versus the exercise and education intervention may have influenced the measured effect by manipulating the participants’ expectations.8 Open‐label placebos do not typically control for the placebo effect adequately, as the magnitude of the placebo effect is still likely to differ between groups as well as at the individual level. Implications and recommendations For interventions involving lifestyle and psychosocial components, we do not and cannot know the mean/median magnitude of the placebo effect for each group. Based on the 2022 trial,8 we provide two hypothetical scenarios (Box 2). For simplicity of comparison, each scenario assumes that the measured mean/median effect of the two interventions is equal. The identical outcome scores may lead one to conclude that combined education and exercise programs have no real therapeutic value. Where the placebo effect is adequately controlled (Box 2, A), this conclusion would be correct. However, where the placebo effect is not equal across the two groups (Box 2, B), this conclusion would be misleading; the education and exercise intervention in fact has a greater therapeutic effect. We have no way of knowing the true magnitude of the placebo effect and, therefore, we are unable to assess the real therapeutic effect of the intervention. As such, we cannot make assumptions about the appropriateness of these interventions as placebo controls. While placebo‐controlled trials may have value in differentiating the relative real and placebo effects of an intervention, we must accept that they are not possible for many interventions, including lifestyle and psychosocial interventions. It is not always possible to have a control intervention with no specific therapeutic effects that is perceived to be real and appears identical to the primary intervention, which are the requirements of a placebo control.2 Importantly, the impossibility of undertaking placebo‐controlled trials for some interventions does not diminish their potential role as part of the management of chronic conditions, nor the need for and value of pragmatic randomised controlled trials that compare such interventions with, for instance, usual treatment. Although these studies may be criticised for the potential benefits being driven by the placebo effect, we argue that the placebo effect is now an accepted part of any intervention. Indeed, prescribing placebos is common among medical professionals,13,14,15 despite knowing that the treatments they are administering have no therapeutic effect per se. The ethical implications of such practice are beyond the scope of this Perspective, but the practice highlights a willingness to accept that the placebo effect contributes to the effectiveness of therapies. If we remain focused on placebo‐controlled trials as the gold standard, researchers may feel pressured to conduct trials that are no longer consistent with an acceptance in current practice that placebo effects are an integral part of effective therapy and/or trials that might not necessarily control for the placebo effect. There must be a clear rationale for conducting placebo‐controlled trials, and the limitations of this approach for guiding a necessary evidence base for clinical practice should be acknowledged.16,17,18 We must accept that we cannot have appropriate placebo controls for many interventions, and that calling comparison interventions “placebo controls”, when they do not necessarily control for the placebo effect, is misleading and may result in inappropriate recommendations from health professionals as well as false perceptions of treatment effectiveness by the general public. We should focus on the best available evidence that may also be the best possible evidence, even if that evidence does not consist of placebo‐controlled trials. Box 1 – A hypothetical example comparing the difference in treatment outcome between three interventions: (1) no intervention, (2) a placebo intervention, and (3) an intervention of interest* * Where appropriate, placebo interventions have been used, assuming no impact of treatment on the placebo effect. Box 2 – Hypothetical examples comparing the pain reduction from saline injections with a combined education and exercise program, with both interventions having the same measured effect but different magnitudes of placebo effect* * (A) The placebo effect is adequately controlled. (B) The placebo effect is not equal across the two groups.

Jessica Stanhope · Amy Salter · Philip Weinstein

Clinical trials improve care and save lives but need more clinician and consumer engagement

Angela L Todd · Don Nutbeam

People who attend reproductive health or alcohol and drug services should be routinely screened for syphilis

Allison Carter · Hamish McManus · James S Ward · Tobias Vickers · Jason Asselin · Greta Baillie · Eric PF Chow · Marcus Y Chen · Christopher K Fairley · Christopher Bourne · Anna McNulty · Phillip Read · Kevin Heath · Nathan Ryder · Jenny McCloskey · Christopher Carmody · Heather McCormack · Kate Alexander · Dawn Casey · Mark Stoove · Margaret E Hellard · Basil Donovan · Rebecca J Guy

The range of prevalence estimates suggests that re-assessing future demand may be appropriate

Annette J Dobson · Leon Flicker · Osvaldo P Almeida · Michael Waller · Kaarin Anstey

Improving the collection of neurosyphilis surveillance data and integrating neurosyphilis incidence data into syphilis reports may enhance our understanding of the epidemiology of neurosyphilis

Ei T Aung · Marcus Y Chen · Christopher K Fairley · Jason J Ong · Eric PF Chow

Data on the expected effectiveness of a formal cardiovascular risk screening are needed

Ellie Paige · Natalie Raffoul · Emma Lonsdale · Emily Banks

To the Editor: Lord and colleagues’ article1 provides a much‐needed snapshot of breast cancer distant recurrence and metastatic survival. As one of Australia's leading breast cancer advocacy organisations, Breast Cancer Network Australia (BCNA) has long been calling for reporting of recurrence data. Although we can justifiably celebrate a 5‐year survival rate of 92%,2 the long term data on distant recurrence reported by Lord and colleagues demonstrate the importance of looking beyond 5 years to understand the full burden of disease. In addition, Lord and colleagues’ survival data after distant recurrence is a critical first step in understanding the survival experience of this important but neglected group. In the associated Editorial, Redfern and Martin3 highlight that Australia's cancer registries do not systematically collect or report recurrence. The same applies for stage at diagnosis. Consequently, the number of Australians living with metastatic breast cancer is unknown. This is a fundamental problem. Without information to quantify this group of people we cannot adequately plan or deliver services. The problem extends beyond breast cancer to cancers such as prostate, melanoma, colorectal and lung, where targeted therapies, immunotherapies, and antibody drug conjugates are driving improvements in survival for patients with metastatic disease.4 These patients often have long term, complex supportive care needs yet have little visibility in our health care system. BCNA's 2017 national survey of 10318 people with breast cancer identified higher information and support needs among patients with metastatic compared with non‐metastatic breast cancer.5 These information and support needs were also less likely to be met by services for people with metastatic compared with non‐metastatic breast cancer.5 On 13 October 2022, which was Metastatic Breast Cancer Awareness Day, BCNA launched its Making metastatic breast cancer count Issues Paper to draw much‐needed attention to these issues.6 In the absence of cancer registry data, we applied Australian modelling from 2008 to current breast cancer mortality data.2,7 We estimate that in 2020 there were at least 10553 Australians living with metastatic breast cancer. Data from the United States suggest this number will continue to grow.8 Collection of recurrence and stage at diagnosis data will require national leadership and accountability, including continued investment in Cancer Australia's Stage, Treatment and Recurrence Project. Critically, it will also require input from key stakeholders including data‐management experts, cancer epidemiologists, cancer registries, clinicians and consumers. The time for action is now.

Andrea Smith · Vicki Durston · Sam Mills

When will we see Indigenous Australians move from being the examined to being the examiners?

Candice McKenzie · Lilon G Bandler

Having received three COVID-19 vaccine doses was associated with much lower likelihood of hospitalisation or death

Robert J Ellis · Cameron RM Moffatt · Luke T Aaron · Greta Beaverson · Khin Chaw · Corinne Curtis · Rhett Freeman‐Lamb · Deborah Judd · Khadija Khatry · Yee Sum Li · Terry Nash · Bonnie Macfarlane · Karen Slater · Yudish Soonarane · Mark Stickley · Satyamurthy Anuradha

Restrictions should be accompanied by advice about appropriate locations for seeking medical care, by condition severity and type

Amy L Sweeny · Gerben Keijzers · Andrea Marshall · Emma J Hall · Jamie Ranse · Ping Zhang · Gary Grant · Ya‐Ling Huang · Dinesh Palipana · Yang D Teng · Benjamin Gerhardy · Jaimi H Greenslade · Philip Jones · Julia L Crilly

CF diagnosed in adults can manifest with milder symptoms across a range of organ systems than classical CF

Amelia Lin · Keith Wong · Simone K Visser · Helen Jo · Yasmeen Al‐Hindawi · Katrin Kosbab‐Jackson · Molly Cocks · Anastasia Volovets · Paul Haber · Kirsten Hammond · Nicole Taylor · Veronica Yozghatlian · Edmund MT Lau · Nathaniel S Marshall · Tara Aquino‐Salomon · Sheila Sivam

SARS-CoV-2 infection is associated with higher incidence of hospitalisation with several respiratory and non-respiratory conditions

Stacey L Rowe · Karin Leder · Kylie Dyson · Lalitha Sundaresan · Dennis Wollersheim · Brigid Lynch · Ifrah Abdullahi · Benjamin C Cowie · Nicola Stephens · Terence M Nolan · Sheena G Sullivan · Brett Sutton · Allen C Cheng