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Background: Prolonged diarrhoea is common amongst returning travellers and is often caused by intestinal protozoa. However, the epidemiology of travel-associated illness caused by protozoal pathogens is not well described., Methods: We analysed records of returning international travellers with illness caused by Giardia duodenalis, Cryptosporidium spp., Cyclospora cayetanensis or Cystoisospora belli, reported to the GeoSentinel Network during January 2007-December 2019. We excluded records of travellers migrating, with an unascertainable exposure country, or from GeoSentinel sites that were not located in high-income countries., Results: There were 2517 cases, 82.3% giardiasis (n = 2072), 11.4% cryptosporidiosis (n = 287), 6.0% cyclosporiasis (n = 150) and 0.3% cystoisosporiasis (n = 8). Overall, most travellers were tourists (64.4%) on long trips (median durations: 18-30 days). Cryptosporidiosis more frequently affected people < 18 years (13.9%) and cyclosporiasis affected people ≥ 40 years (59.4%). Giardiasis was most frequently acquired in South Central Asia (45.8%) and sub-Saharan Africa (22.6%), cryptosporidiosis in sub-Saharan Africa (24.7%) and South-Central Asia (19.5%), cyclosporiasis in South East Asia (31.3%) and Central America (27.3%), and cystoisosporiasis in sub-Saharan Africa (62.5%). Cyclosporiasis cases were reported from countries of uncertain endemicity (e.g. Cambodia) or in countries with no previous evidence of this parasite (e.g. French Guiana). The time from symptom onset to presentation at a GeoSentinel site was the longest amongst travellers with giardiasis (median: 30 days). Over 14% of travellers with cryptosporidiosis were hospitalized., Conclusions: This analysis provides new insights into the epidemiology and clinical significance of four intestinal protozoa that can cause morbidity in international travellers. These data might help optimize pretravel advice and post-travel management of patients with travel-associated prolonged gastrointestinal illnesses. This analysis reinforces the importance of international travel-related surveillance to identify sentinel cases and areas where protozoal infections might be undetected or underreported., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The COVID-19 pandemic has profoundly impacted individuals, society, and healthcare organisations worldwide. Recent international research suggests that concerns, needs, and experiences of healthcare workers (HCWs) have evolved throughout the pandemic. This longitudinal qualitative study explored the evolving views and experiences of Victorian healthcare workers (HCWs) and organisational key personnel during the coronavirus disease (COVID-19) pandemic., Methods: We recruited participants from the Coronavirus in Victorian Health and Aged care workers (COVIC-HA) study cohort. We conducted two rounds of semi-structured interviews with HCWs and organisational key personnel from three different healthcare settings (hospital, aged care and primary care) in Victoria, Australia, in May-July 2021 and May-July 2022. Data were analysed thematically using trajectory and recurrent cross-sectional approaches, guided by a temporal change framework., Results: Twelve HCWs and five key personnel from various professional roles participated in interviews at both timepoints. Expected themes derived from mid-2021 interviews (navigating uncertainty, maintaining service delivery, and addressing staff needs) evolved over time. Concerns shifted from personal health and safety to workforce pressures, contributing to HCW burnout and fatigue and ongoing mental health support needs. New themes emerged from mid-2022 interviews, including managing ongoing COVID-19 impacts and supporting the healthcare workforce into the future. Clear and consistent communication, stable guidelines and forward-looking organisational responses were considered crucial., Conclusions: Our longitudinal qualitative study highlighted the evolving impact of the COVID-19 pandemic on HCWs' perceptions, health and wellbeing and uncovered long-term sector vulnerabilities. Analysing HCW experiences and key personnel insights over time and across different pandemic phases provided crucial insights for policymakers to protect the healthcare workforce. Findings emphasise the need for proactive strategies that prioritise HCWs' wellbeing and workforce sustainability. Policy makers must invest in HCW health and wellbeing initiatives alongside healthcare system improvements to ensure resilience and capacity to meet future challenges., Trial Registration: This study was approved through the Victorian Streamlined Ethical Review Process (SERP: Project Number 68,086) and registered with ANZCTR (ACTRN12621000533897) on 6 May 2021., (© 2024. The Author(s).)

Background: Malaria continues to pose a significant burden in endemic countries, many of which lack access to molecular surveillance. Insights from malaria cases in travellers returning to non-endemic areas can provide valuable data to inform endemic country programmes. To evaluate the potential for novel global insights into malaria, we examined epidemiological and molecular data from imported malaria cases to Australia., Methods: We analysed malaria cases reported in Australia from 2012 to 2022 using National Notifiable Disease Surveillance System data. Molecular data on imported malaria cases were obtained from literature searches., Results: Between 2012 and 2022, 3204 malaria cases were reported in Australia. Most cases (69%) were male and 44% occurred in young adults aged 20-39 years. Incidence rates initially declined between 2012 and 2015, then increased until 2019. During 2012-2019, the incidence in travellers ranged from 1.34 to 7.71 per 100 000 trips. Cases were primarily acquired in Sub-Saharan Africa (n = 1433; 45%), Oceania (n = 569; 18%) and Southern and Central Asia (n = 367; 12%). The most common countries of acquisition were Papua New Guinea (n = 474) and India (n = 277). Plasmodium falciparum accounted for 58% (1871/3204) of cases and was predominantly acquired in Sub-Saharan Africa, and Plasmodium vivax accounted for 32% (1016/3204), predominantly from Oceania and Asia. Molecular studies of imported malaria cases to Australia identified genetic mutations and deletions associated with drug resistance and false-negative rapid diagnostic test results, and led to the establishment of reference genomes for P. vivax and Plasmodium malariae., Conclusions: Our analysis highlights the continuing burden of imported malaria into Australia. Molecular studies have offered valuable insights into drug resistance and diagnostic limitations, and established reference genomes. Integrating molecular data into national surveillance systems could provide important infectious disease intelligence to optimize treatment guidelines for returning travellers and support endemic country surveillance programmes., (© International Society of Travel Medicine 2023. Published by Oxford University Press.)

The site frequency spectrum (SFS) is a widely used summary statistic of genomic data. Motivated by recent evidence for the role of neutral evolution in cancer, we investigate the SFS of neutral mutations in an exponentially growing population. Using branching process techniques, we establish (first-order) almost sure convergence results for the SFS of a Galton-Watson process, evaluated either at a fixed time or at the stochastic time at which the population first reaches a certain size. We finally use our results to construct consistent estimators for the extinction probability and the effective mutation rate of a birth-death process.

Tumor heterogeneity is a complex and widely recognized trait that poses significant challenges in developing effective cancer therapies. In particular, many tumors harbor a variety of subpopulations with distinct therapeutic response characteristics. Characterizing this heterogeneity by determining the subpopulation structure within a tumor enables more precise and successful treatment strategies. In our prior work, we developed PhenoPop, a computational framework for unravelling the drug-response subpopulation structure within a tumor from bulk high-throughput drug screening data. However, the deterministic nature of the underlying models driving PhenoPop restricts the model fit and the information it can extract from the data. As an advancement, we propose a stochastic model based on the linear birth-death process to address this limitation. Our model can formulate a dynamic variance along the horizon of the experiment so that the model uses more information from the data to provide a more robust estimation. In addition, the newly proposed model can be readily adapted to situations where the experimental data exhibits a positive time correlation. We test our model on simulated data (in silico) and experimental data (in vitro), which supports our argument about its advantages., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Dengue is the most important arboviral disease globally and poses ongoing challenges for control including in non-endemic countries with competent mosquito vectors at risk of local transmission through imported cases. We examined recent epidemiological trends in imported and locally acquired dengue in Australia, where the Wolbachia mosquito population replacement method was implemented throughout dengue-prone areas of northern Queensland between 2011 and 2019., Methods: We analysed dengue cases reported to the Australian National Notifiable Disease Surveillance System between January 2012 and December 2022, and Australian traveller movement data., Results: Between 2012 and 2022, 13 343 dengue cases were reported in Australia (median 1466 annual cases); 12 568 cases (94.2%) were imported, 584 (4.4%) were locally acquired and 191 (1.4%) had no origin recorded. Locally acquired cases decreased from a peak in 2013 (n = 236) to zero in 2021-22. Annual incidence of imported dengue ranged from 8.29/100 000 (n = 917 cases) to 22.10/100 000 (n = 2203) annual traveller movements between 2012 and 2019, decreased in 2020 (6.74/100 000 traveller movements; n = 191) and 2021 (3.32/100 000 traveller movements; n = 10) during COVID-19-related border closures, then rose to 34.79/100 000 traveller movements (n = 504) in 2022. Imported cases were primarily acquired in Southeast Asia (n = 9323; 74%), Southern and Central Asia (n = 1555; 12%) and Oceania (n = 1341; 11%). Indonesia (n = 5778; 46%) and Thailand (n = 1483; 12%) were top acquisition countries. DENV-2 (n = 2147; 42%) and DENV-1 (n = 1526; 30%) were predominant serotypes., Conclusion: Our analysis highlights Australia's successful control of locally acquired dengue with Wolbachia. Imported dengue trends reflect both Australian travel destinations and patterns and local epidemiology in endemic countries., (© International Society of Travel Medicine 2024. Published by Oxford University Press.)

Background: Chikungunya is an important travel-related disease because of its rapid geographical expansion and potential for prolonged morbidity. Improved understanding of the epidemiology of travel-related chikungunya infections may influence prevention strategies including education and vaccination., Methods: We analysed data from travellers with confirmed or probable chikungunya reported to GeoSentinel sites from 2005 to 2020. Confirmed chikungunya was defined as a compatible clinical history plus either virus isolation, positive nucleic acid test or seroconversion/rising titre in paired sera. Probable chikungunya was defined as a compatible clinical history with a single positive serology result., Results: 1202 travellers (896 confirmed and 306 probable) with chikungunya were included. The median age was 43 years (range 0-91; interquartile range [IQR]: 31-55); 707 (58.8%) travellers were female. Most infections were acquired in the Caribbean (28.8%), Southeast Asia (22.8%), South Central Asia (14.2%) and South America (14.2%). The highest numbers of chikungunya cases reported to GeoSentinel were in 2014 (28.3%), 2015 (14.3%) and 2019 (11.9%). The most frequent reasons for travel were tourism (n = 592; 49.3%) and visiting friends or relatives (n = 334; 27.7%). The median time to presentation to a GeoSentinel site was 23 days (IQR: 7-52) after symptom onset. In travellers with confirmed chikungunya and no other reported illnesses, the most frequently reported symptoms included musculoskeletal symptoms (98.8%), fever/chills/sweats (68.7%) and dermatologic symptoms (35.5%). Among 917 travellers with information available, 296 (32.3%) had a pretravel consultation., Conclusions: Chikungunya was acquired by international travellers in almost 100 destinations globally. Vector precautions and vaccination where recommended should be integrated into pretravel visits for travellers going to areas with chikungunya or areas with the potential for transmission. Continued surveillance of travel-related chikungunya may help public health officials and clinicians limit the transmission of this potentially debilitating disease by defining regions where protective measures (e.g. pretravel vaccination) should be strongly considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Infectious disease surveillance tracks disease epidemiology and informs prevention and control. Public health measures implemented in Australia during the COVID-19 pandemic (2020 to 2022) affected infectious disease epidemiology. We examined notifiable disease epidemiology in Australia from 2012 to 2022, evaluating disease trends and pandemic impacts., Methods: We analysed case notifications supplied to the Australian National Notifiable Disease Surveillance System (NNDSS) from 1 January 2012 to 31 December 2022. The annual incidence and notification incidence trends were calculated and the average changes in annual incidence were investigated by Poisson regression., Results: Over the study period, there were 14,087,045 notifications of 68 diseases. Respiratory diseases were the most commonly notified disease group (83% of all notifications) and vector-borne diseases the least (< 1%). The ten highest-incidence diseases comprised 97% of all notifications over the study period, with COVID-19 alone accounting for 72%. Notifications were most common among the 20-39-year age group (37%). From 2012-2019, notification incidence of gastrointestinal, respiratory and sexually transmissible infections increased, whereas for bloodborne viral hepatitis, vector-borne diseases and imported diseases it decreased. From 2020-2021, average notification incidence of most non-COVID-19 respiratory diseases decreased compared to the 2012-2019 period; sexually transmissible infections notification incidence remained fairly stable; notification incidence of some gastrointestinal diseases increased while others decreased; and notification of imported diseases markedly decreased. A rebound in notification incidence was seen for most diseases in 2022., Conclusions: Prior to the COVID-19 pandemic, most notifiable diseases had increasing notification incidence, except for bloodborne viral hepatitis, vector-borne diseases and imported diseases. COVID-19-related public health measures had variable impacts on notifiable diseases., Competing Interests: Declarations. Ethics approval and consent to participate: The project was approved by the Monash University Human Research Ethics Committee (MUHREC; project #28955) and CDNA jurisdictional members. This study was conducted using national notifiable disease surveillance data only. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To identify and characterise COVID-19 workers' compensation claims in healthcare and other industries during the pandemic in Victoria, Australia., Methods: We used workers' compensation claims identified as COVID-19 infection related from 1 January 2020 to 31 July 2022 to compare COVID-19 infection claims and rates of claims by industry and occupation, and in relation to Victorian COVID-19 epidemiology. A Cox proportional hazards model assessed risk factors for extended claim duration., Results: Of the 3313 direct and indirect COVID-19-related claims identified, 1492 (45.0%) were classified as direct COVID-19 infection accepted time-loss claims and were included in analyses. More than half (52.9%) of COVID-19 infection claims were made by healthcare and social assistance industry workers, with claims for this group peaking in July-October 2020. The overall rate of claims was greater in the healthcare and social assistance industry compared with all other industries (16.9 vs 2.4 per 10 000 employed persons) but industry-specific rates were highest in public administration and safety (23.0 per 10 000 employed persons). Workers in healthcare and social assistance were at increased risk of longer incapacity duration (median 26 days, IQR 16-61 days) than in other industries (median 17 days, IQR 11-39.5 days)., Conclusions: COVID-19 infection claims differed by industry, occupational group, severity and timing and changes coincided with different stages of the COVID-19 pandemic. Occupational surveillance for COVID-19 cases is important and monitoring of worker's compensation claims and incapacity duration can contribute to understanding the impacts of COVID-19 on work absence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Climate change presents a major public health concern in Australia, marked by unprecedented wildfires, heatwaves, floods, droughts, and the spread of climate-sensitive infectious diseases. Despite these challenges, Australia's response to the climate crisis has been inadequate and subject to change by politics, public sentiment, and global developments. This study illustrates the spatiotemporal patterns of selected climate-related environmental extremes (heatwaves, wildfires, floods, and droughts) across Australia during the past two decades, and summarizes climate adaptation measures and actions that have been taken by the national, state/territory, and local governments. Our findings reveal significant impacts of climate-related environmental extremes on the health and well-being of Australians. While governments have implemented various adaptation strategies, these plans must be further developed to yield concrete actions. Moreover, Indigenous Australians should not be left out in these adaptation efforts. A collaborative, comprehensive approach involving all levels of government is urgently needed to prevent, mitigate, and adapt to the health impacts of climate change., Competing Interests: JA is a member of World Meteorological Organization Study Group on Integrated Health Services. OJ has contracts from the NSW Health and Victoria Government, Department of Health. OJ is a Management Committee Member of the Global Heat and Health Information Network. OJ has the patent of Environmental Measurement Unit (International Patent Application No: PCT/AU2021/051248)., (© 2023 The Author(s).)

We analysed aggregate work absences during the coronavirus disease 2019 (COVID-19) pandemic from two Victorian hospital sites and corresponding individual-level survey data to understand changes in the rates and types of workplace absence. We found changing reasons for workplace absences as the pandemic progressed and observed higher rates of annual and sick leave during the months coinciding with increased COVID-19 cases and workforce burnout., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Recent evidence suggests that nongenetic (epigenetic) mechanisms play an important role at all stages of cancer evolution. In many cancers, these mechanisms have been observed to induce dynamic switching between two or more cell states, which commonly show differential responses to drug treatments. To understand how these cancers evolve over time, and how they respond to treatment, we need to understand the state-dependent rates of cell proliferation and phenotypic switching. In this work, we propose a rigorous statistical framework for estimating these parameters, using data from commonly performed cell line experiments, where phenotypes are sorted and expanded in culture. The framework explicitly models the stochastic dynamics of cell division, cell death and phenotypic switching, and it provides likelihood-based confidence intervals for the model parameters. The input data can be either the fraction of cells or the number of cells in each state at one or more time points. Through a combination of theoretical analysis and numerical simulations, we show that when cell fraction data is used, the rates of switching may be the only parameters that can be estimated accurately. On the other hand, using cell number data enables accurate estimation of the net division rate for each phenotype, and it can even enable estimation of the state-dependent rates of cell division and cell death. We conclude by applying our framework to a publicly available dataset., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Dengue virus is a flavivirus transmitted by Aedes mosquitoes and is an important cause of illness worldwide. Data on the severity of travel-associated dengue illness are limited., Objective: To describe the epidemiology, clinical characteristics, and outcomes among international travelers with severe dengue or dengue with warning signs as defined by the 2009 World Health Organization classification (that is, complicated dengue)., Design: Retrospective chart review and analysis of travelers with complicated dengue reported to GeoSentinel from January 2007 through July 2022., Setting: 20 of 71 international GeoSentinel sites., Patients: Returning travelers with complicated dengue., Measurements: Routinely collected surveillance data plus chart review with abstraction of clinical information using predefined grading criteria to characterize the manifestations of complicated dengue., Results: Of 5958 patients with dengue, 95 (2%) had complicated dengue. Eighty-six (91%) patients had a supplemental questionnaire completed. Eighty-five of 86 (99%) patients had warning signs, and 27 (31%) were classified as severe. Median age was 34 years (range, 8 to 91 years); 48 (56%) were female. Patients acquired dengue most frequently in the Caribbean ( n  = 27 [31%]) and Southeast Asia ( n  = 21 [24%]). Frequent reasons for travel were tourism (46%) and visiting friends and relatives (32%). Twenty-one of 84 (25%) patients had comorbidities. Seventy-eight (91%) patients were hospitalized. One patient died of nondengue-related illnesses. Common laboratory findings and signs were thrombocytopenia (78%), elevated aminotransferase (62%), bleeding (52%), and plasma leakage (20%). Among severe cases, ophthalmologic pathology ( n  = 3), severe liver disease ( n  = 3), myocarditis ( n  = 2), and neurologic symptoms ( n  = 2) were reported. Of 44 patients with serologic data, 32 confirmed cases were classified as primary dengue (IgM+/IgG-) and 12 as secondary (IgM-/IgG+) dengue., Limitations: Data for some variables could not be retrieved by chart review for some patients. The generalizability of our observations may be limited., Conclusion: Complicated dengue is relatively rare in travelers. Clinicians should monitor patients with dengue closely for warning signs that may indicate progression to severe disease. Risk factors for developing complications of dengue in travelers need further prospective study., Primary Funding Source: Centers for Disease Control and Prevention, International Society of Travel Medicine, Public Health Agency of Canada, and GeoSentinel Foundation., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0721.

Background: Many travellers do not receive vaccines pre-travel. Tools such as vaccine decision aids could support informed vaccine decision-making. We aimed to characterise Australians' pre-travel vaccine attitudes, behaviours and information needs and examine the role for decision aids in travel medicine., Methods: Online cross-sectional survey of Australian adults in December 2022. We included questions on demographics, pre-travel health-seeking behaviour, and information needs. We measured vaccine confidence (Vaccine Confidence Index Index) and used hypothetical disease scenarios to evaluate behavioural and social drivers of vaccination. We used multivariable logistic regression models to identify predictors of vaccine uptake and thematically analysed free-text responses., Results: We received complete survey responses from 1223/1326 Australians (92% response rate). Amongst those reporting previous overseas travel, 67% (778/1161) reported past pre-travel health encounter(s) and 64% (743/1161) reported past pre-travel vaccination. Half (50%) strongly agreed that vaccines were important for their health; fewer strongly agreed that vaccines were safe (37%) and effective (38%). In multivariable analyses, past pre-travel vaccine uptake was associated with increasing age (OR = 1.17 [95% CI 1.08-1.27] p < 0.001 per ten-year increase) and travel to higher-risk destinations (OR = 2.92 [2.17-3.93] p < 0.001); travellers visiting friends and relatives (VFRs) were less likely to have received pre-travel vaccines (OR = 0.74 [0.56-0.97] p = 0.028). Predictors for wanting vaccination against hypothetical diseases included past pre-travel vaccination (Disease X: OR 2.60 [1.91-3.56] p < 0.001) and confidence in vaccine safety (Disease X: OR 7.18 [5.07-10.18], p < 0.001); past VFR travel was predictive of not wanting vaccination (Disease X: OR 0.72 [0.52-1.00], p = 0.049). Most (63%) were interested in using a vaccine decision aid, generally together with a trusted health professional., Conclusions: Health professionals play an important role in supporting pre-travel vaccine decision-making. However, our findings indicate that reliable, accurate and engaging digital resources, such as decision aids, could support travellers to make informed pre-travel vaccine decisions., (© International Society of Travel Medicine 2023. Published by Oxford University Press.)

Background: Understanding mortality burden associated with communicable diseases is key to informing resource allocation, disease prevention and control efforts, and evaluating public health interventions. We quantified excess mortality among people notified with communicable diseases in Victoria, Australia., Methods: Cases of communicable disease notified in Victoria between 1 January 1991 and 31 December 2021 were linked to the death registry. Informational gain obtained through linkage and 30-day case fatality rates were calculated for each disease. Standardised mortality ratios (SMR) and 95% confidence intervals were calculated up to a year following illness onset., Findings: There were 1,032,619 cases and 5985 (0.58%) died ≤30 days of illness onset. Following linkage, the 30-day case fatality rate increased more than 2-fold. Diseases with high 7-day SMR signifying excess mortality included invasive pneumococcal disease (167.7, 95% CI 153.4-182.7); listeriosis (166.2, 95% CI 121.2-218.3); invasive meningococcal disease (145.9, 95% CI 116.7-178.3); legionellosis (43.3, 95% CI 28.0-62.0); and COVID-19 (21.9, 95% CI 19.7-24.3). Most diseases exhibited a strong negative gradient, with high SMRs in the first 7-days of illness onset that reduced over time., Interpretation: We demonstrated that the rate of death in Victoria's notifiable disease surveillance dataset is underestimated. Further, compared to a general population, there is evidence of elevated all-cause mortality among people notified with communicable diseases often up to one year following illness onset. Not all elevated risk is likely directly attributable to the communicable diseases of interest, rather, it may reflect underlying comorbidities or behaviours in these individuals. Regardless of attribution, infection with communicable diseases may represent a marker of mortality. Key to preventing deaths may be through timely and appropriate transition to primary and preventive healthcare following diagnosis., Funding: No funding was provided for this study., Competing Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. TN has clinical trial contracts that provide institutional (not personal) payments to the Murdoch Childrens Research Institute and the University of Melbourne outside submitted work relating to sponsored vaccine trials of several different vaccines by Moderna, Sanofi, Seqirus, Iliad, Dynavax, and GSK. TN is a member of COVID-19, Respiratory Syncytial Virus and influenza vaccines clinical trial committees conducted by Moderna, SKBio Korea, Clover (PRC), and Emergent Biotech, outside submitted work., (© 2023 The Authors.)

Tumor heterogeneity is a complex and widely recognized trait that poses significant challenges in developing effective cancer therapies. In particular, many tumors harbor a variety of subpopulations with distinct therapeutic response characteristics. Characterizing this heterogeneity by determining the subpopulation structure within a tumor enables more precise and successful treatment strategies. In our prior work, we developed PhenoPop, a computational framework for unravelling the drug-response subpopulation structure within a tumor from bulk high-throughput drug screening data. However, the deterministic nature of the underlying models driving PhenoPop restricts the model fit and the information it can extract from the data. As an advancement, we propose a stochastic model based on the linear birth-death process to address this limitation. Our model can formulate a dynamic variance along the horizon of the experiment so that the model uses more information from the data to provide a more robust estimation. In addition, the newly proposed model can be readily adapted to situations where the experimental data exhibits a positive time correlation. We test our model on simulated data ( in silico ) and experimental data ( in vitro ), which supports our argument about its advantages.

Background: International travellers may seek care abroad to address health problems that arise during their trip or plan healthcare outside their country of residence as medical tourists., Methods: Data were collected on travellers evaluated at GeoSentinel Network sites who reported healthcare during travel. Both unplanned and planned healthcare were analysed, including the reason and nature of healthcare sought, characteristics of the treatment provided and outcomes. Travellers that presented for rabies post-exposure prophylaxis were described elsewhere and were excluded from detailed analysis., Results: From May 2017 through June 2020, after excluding travellers obtaining rabies post-exposure prophylaxis (n= 415), 1093 travellers reported care for a medical or dental issue that was an unanticipated part of the travellers' planned itinerary (unplanned healthcare). Travellers who sought unplanned healthcare abroad had frequent diagnoses of acute diarrhoea, dengue, falciparum malaria and unspecified viral syndrome, and obtained care in 131 countries. Thirty-four (3%) reported subsequent deterioration and 230 (21%) reported no change in condition; a third (n = 405; 37%) had a pre-travel health encounter. Forty-one travellers had sufficient data on planned healthcare abroad for analysis. The most common destinations were the US, France, Dominican Republic, Belgium and Mexico. The top reasons for their planned healthcare abroad were unavailability of procedure at home (n = 9; 19%), expertise abroad (n = 9; 19%), lower cost (n = 8; 17%) and convenience (n = 7; 15%); a third (n = 13; 32%) reported cosmetic or surgical procedures. Early and late complications occurred in 14 (33%) and 4 (10%) travellers, respectively. Four travellers (10%) had a pre-travel health encounter., Conclusions: International travellers encounter health problems during travel that often could be prevented by pre-travel consultation. Travellers obtaining planned healthcare abroad can experience negative health consequences associated with treatments abroad, for which pre-travel consultations could provide advice and potentially help to prevent complications., (© International Society of Travel Medicine 2023. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To assess the mental health and wellbeing of health and aged care workers in Australia during the second and third years of the coronavirus disease 2019 (COVID-19) pandemic, overall and by occupation group., Design, Setting, Participants: Longitudinal cohort study of health and aged care workers (ambulance, hospitals, primary care, residential aged care) in Victoria: May-July 2021 (survey 1), October-December 2021 (survey 2), and May-June 2022 (survey 3)., Main Outcome Measures: Proportions of respondents (adjusted for age, gender, socio-economic status) reporting moderate to severe symptoms of depression (Patient Health Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder scale, GAD-7), or post-traumatic stress (Impact of Event Scale-6, IES-6), burnout (abbreviated Maslach Burnout Inventory, aMBI), or high optimism (10-point visual analogue scale); mean scores (adjusted for age, gender, socio-economic status) for wellbeing (Personal Wellbeing Index-Adult, PWI-A) and resilience (Connor Davidson Resilience Scale 2, CD-RISC-2)., Results: A total of 1667 people responded to at least one survey (survey 1, 989; survey 2, 1153; survey 3, 993; response rate, 3.3%). Overall, 1211 survey responses were from women (72.6%); most respondents were hospital workers (1289, 77.3%) or ambulance staff (315, 18.9%). The adjusted proportions of respondents who reported moderate to severe symptoms of depression (survey 1, 16.4%; survey 2, 22.6%; survey 3, 19.2%), anxiety (survey 1, 8.8%; survey 2, 16.0%; survey 3, 11.0%), or post-traumatic stress (survey 1, 14.6%; survey 2, 35.1%; survey 3, 14.9%) were each largest for survey 2. The adjusted proportions of participants who reported moderate to severe symptoms of burnout were higher in surveys 2 and 3 than in survey 1, and the proportions who reported high optimism were smaller in surveys 2 and 3 than in survey 1. Adjusted mean scores for wellbeing and resilience were similar at surveys 2 and 3 and lower than at survey 1. The magnitude but not the patterns of change differed by occupation group., Conclusion: Burnout was more frequently reported and mean wellbeing and resilience scores were lower in mid-2022 than in mid-2021 for Victorian health and aged care workers who participated in our study. Evidence-based mental health and wellbeing programs for workers in health care organisations are needed., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12621000533897 (observational study; retrospective)., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Objective: We sought to examine the extent to which populations experiencing inequities were considered in studies of COVID-19 vaccination in individuals with autoimmune inflammatory rheumatic diseases (AIRDs)., Methods: We included all studies (n = 19) from an ongoing Cochrane living systematic review on COVID-19 vaccination in patients with AIRDs. We used the PROGRESS-Plus framework (place of residence, race/ethnicity, occupation, gender/sex, religion, education, socioeconomic status, and social capital, plus: age, multimorbidity, and health literacy) to identify factors that stratify health outcomes. We assessed equity considerations in relation to differences in COVID-19 baseline risk, eligibility criteria, and description of participant characteristics and attrition, controlling for confounding factors, subgroup analyses, and applicability of findings., Results: All 19 studies were cohort studies that followed individuals with AIRDs after vaccination. Three studies (16%) described differences in baseline risk for COVID-19 across age. Two studies (11%) defined eligibility criteria based on occupation and age. All 19 studies described participant age and sex. Twelve studies (67%) controlled for age and/or sex as confounders. Eight studies (47%) conducted subgroup analyses across at least 1 PROGRESS-Plus factor, most commonly age. Ten studies (53%) interpreted applicability in relation to at least 1 PROGRESS-Plus factor, most commonly age (47%), then ethnicity (16%), sex (16%), and multimorbidity (11%)., Conclusion: Sex and age were the most frequently considered PROGRESS-Plus factors in studies of COVID-19 vaccination in individuals with AIRDs. The generalizability of evidence to populations experiencing inequities is uncertain. Future COVID-19 vaccine studies should report participant characteristics in more detail to inform guideline recommendations., (© 2022 American College of Rheumatology.)

Tumor heterogeneity is an important driver of treatment failure in cancer since therapies often select for drug-tolerant or drug-resistant cellular subpopulations that drive tumor growth and recurrence. Profiling the drug-response heterogeneity of tumor samples using traditional genomic deconvolution methods has yielded limited results, due in part to the imperfect mapping between genomic variation and functional characteristics. Here, we leverage mechanistic population modeling to develop a statistical framework for profiling phenotypic heterogeneity from standard drug-screen data on bulk tumor samples. This method, called PhenoPop, reliably identifies tumor subpopulations exhibiting differential drug responses and estimates their drug sensitivities and frequencies within the bulk population. We apply PhenoPop to synthetically generated cell populations, mixed cell-line experiments, and multiple myeloma patient samples and demonstrate how it can provide individualized predictions of tumor growth under candidate therapies. This methodology can also be applied to deconvolution problems in a variety of biological settings beyond cancer drug response., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background: The impact of the COVID-19 pandemic on travel risk perceptions and pre-travel healthcare attendance is unknown. We aimed to explore barriers and enablers to engagement in and uptake of pre-travel advice (PTA) among university students, a recognised at-risk group for travel-related morbidity and poor PTA uptake. Additionally, we aimed to explore whether the COVID-19 pandemic has influenced attitudes towards future PTA., Methods: Semi-structured interviews were conducted with university students (October-December 2021). Thematic analysis of the data was conducted using the Health Belief Model (HBM) framework., Results: We interviewed 18 students (11 male, median age 24). Students' risk perceptions relating to travel-related illnesses were influenced by past experiences, travel destination, vaccination status and knowledge. Barriers to seeking PTA included a lack of perceived need and concerns about accessibility/availability, whereas potential benefits included reduced health risks, vaccine-induced protection, and knowledge gain. Cues to seeking future PTA were perceived risks of travel-related illness, perceived high-risk destination, itinerary-related vaccine requirements, perceived benefits of advice and concerns about COVID-19 infection. COVID-19 risk perceptions did not consistently align with those of other travel-related illness. We used findings to inform recommendations., Conclusion: The current COVID-19 pandemic offers an opportunity to increase students' risk awareness and promote preventive travel health behaviours. Recommendations to improve students' future engagement in PTA include: 1) increasing awareness of risks associated with travel, 2) emphasising PTA benefits, and 3) ensuring PTA is convenient, accessible and affordable., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess associations between SARS-CoV-2 infection and the incidence of hospitalisation with selected respiratory and non-respiratory conditions in a largely SARS-CoV-2 vaccine-naïve population ., Design, Setting, Participants: Self-control case series; analysis of population-wide surveillance and administrative data for all laboratory-confirmed COVID-19 cases notified to the Victorian Department of Health (onset, 23 January 2020 - 31 May 2021; ie, prior to widespread vaccination rollout) and linked hospital admissions data (admission dates to 30 September 2021)., Main Outcome Measures: Hospitalisation of people with acute COVID-19; incidence rate ratios (IRRs) comparing incidence of hospitalisations with defined conditions (including cardiac, cerebrovascular, venous thrombo-embolic, coagulative, and renal disorders) from three days before to within 89 days of onset of COVID-19 with incidence during baseline period (60-365 days prior to COVID-19 onset)., Results: A total of 20 594 COVID-19 cases were notified; 2992 people (14.5%) were hospitalised with COVID-19. The incidence of hospitalisation within 89 days of onset of COVID-19 was higher than during the baseline period for several conditions, including myocarditis and pericarditis (IRR, 14.8; 95% CI, 3.2-68.3), thrombocytopenia (IRR, 7.4; 95% CI, 4.4-12.5), pulmonary embolism (IRR, 6.4; 95% CI, 3.6-11.4), acute myocardial infarction (IRR, 3.9; 95% CI, 2.6-5.8), and cerebral infarction (IRR, 2.3; 95% CI, 1.4-3.9)., Conclusion: SARS-CoV-2 infection is associated with higher incidence of hospitalisation with several respiratory and non-respiratory conditions. Our findings reinforce the value of COVID-19 mitigation measures such as vaccination, and awareness of these associations should assist the clinical management of people with histories of SARS-CoV-2 infection., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background: Student travellers are recognised as a group at high risk of travel-related morbidity, but few previous studies have evaluated students' perceptions of or willingness to take risks during travel. Individual risk propensities may influence travellers' engagement in pre-travel healthcare and can therefore inform strategies in pre-travel risk communication. This study aimed to describe the factors influencing risk-taking willingness, risk perceptions and future health-seeking intention among student travellers., Method: We conducted a cross-sectional online survey (June-August 2021) among students enrolled at Monash University, Melbourne, Australia. Primary outcomes were travel-related risk-taking willingness and risk perceptions, measured using the health/safety items of the validated Domain-Specific Risk-Taking (DOSPERT) scale., Results: Four hundred and eighteen students completed the survey. The mean age of respondents was 25.61 years, 78% were female and 46% were born outside Australia. Greater willingness to take risks was predicted by younger age (<25 years), being Australian-born, greater travel experience (3+ trips), having previously sought PTA, and perceiving oneself at low risk of severe COVID-19. We found no significant predictors of risk perception. Increased intention to seek pre-travel advice in the future was associated with greater risk perception, younger age, and perceiving oneself at high risk of severe COVID-19., Conclusion: These findings support the rationale for a greater role of risk communication in travel medicine promotion strategies. We recommend that this could be achieved through 1) increasing risk perception by emphasising potential travel-associated risks, 2) personalising information about travel risks, 3) addressing perceived benefits of engaging in risky behaviours, and 4) reinforcing self-efficacy., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Wastewater monitoring as a public health tool is well-established and the SARS-CoV-2 (COVID-19) pandemic has seen its widespread uptake. Given the significant potential of wastewater monitoring as a public health surveillance and decision support tool, it is important to understand what measures are required to allow the long-term benefits of wastewater monitoring to be fully realized, including how to establish and/or maintain public support. The potential for positive SARS-CoV-2 detections to trigger enforced, community-wide public health interventions (e.g., lockdowns and other impacts on civil liberties) further emphasises the need to better understand the role of public engagement in successful wastewater-based monitoring programs. This paper systematically reviews the processes of building and maintaining the social license to operate wastewater monitoring. We specifically explore the relationship between different stakeholder communities and highlight the information and actions that are required to establish a social license to operate and then prevent its loss. The paper adds to the literature on social license to operate by extending its application to new domains and offers a dynamic model of social license to help guide the agenda for researcher and practitioner communities., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Organizational responses that support healthcare workers (HCWs) and mitigate health risks are necessary to offset the impact of the COVID-19 pandemic. We aimed to understand how HCWs and key personnel working in healthcare settings in Melbourne, Australia perceived their employing organizations' responses to the COVID-19 pandemic., Method: In this qualitative study, conducted May-July 2021 as part of the longitudinal Coronavirus in Victorian Healthcare and Aged Care Workers (COVIC-HA) study, we purposively sampled and interviewed HCWs and key personnel from healthcare organizations across hospital, ambulance, aged care and primary care (general practice) settings. We also examined HCWs' free-text responses to a question about organizational resources and/or supports from the COVIC-HA Study's baseline survey. We thematically analyzed data using an iterative process., Results: We analyzed data from interviews with 28 HCWs and 21 key personnel and free-text responses from 365 HCWs, yielding three major themes: navigating a changing and uncertain environment, maintaining service delivery during a pandemic , and meeting the safety and psychological needs of staff . HCWs valued organizational efforts to engage openly and honesty with staff, and proactive responses such as strategies to enhance workplace safety (e.g., personal protective equipment spotters). Suggestions for improvement identified in the themes included streamlined information processes, greater involvement of HCWs in decision-making, increased investment in staff wellbeing initiatives and sustainable approaches to strengthen the healthcare workforce., Conclusions: This study provides in-depth insights into the challenges and successes of organizational responses across four healthcare settings in the uncertain environment of a pandemic. Future efforts to mitigate the impact of acute stressors on HCWs should include a strong focus on bidirectional communication, effective and realistic strategies to strengthen and sustain the healthcare workforce, and greater investment in flexible and meaningful psychological support and wellbeing initiatives for HCWs., Competing Interests: KL (APP115500) and CH (APP1173271) were supported by National Health and Medical Research Fellowships. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McGuinness, Josphin, Eades, Clifford, Fisher, Kirkman, Russell, Hodgson, Kelsall, Lane, Skouteris, Smith and Leder.)

There is a significant challenge in global health and development research that pivots on the difficulties of delivering (cost-)effective treatments or interventions that are scalable andtransferable across settings. That is, how does one deliver "true effects", proven treatments, into new settings? This is often addressed in pragmatic trials or implementation research in which one makes adjustments to the delivery of the treatment to ensure that it works here and there. In this critical analytical review, we argue that the approach mis-characterises the cause-effect relationship and fails to recognise the local, highly contextual nature of what it means to say an intervention "works". We use an ongoing randomised controlled trial (RCT)-an informal settlement redevelopment intervention in Indonesia and Fiji to reduce human exposure to pathogenic faecal contamination-as a vehicle for exploring the ideas and implications of identifying interventions that work in global health and development. We describe the highly contextualised features of the research and the challenges these would pose in attempts to generalise the results. In other words, we detail that which is frequently elided from most RCTs. As our critical lens, we us the work of American philosopher, Nancy Cartwright, who argued that research produces dappled regions of causal insights-lacunae against a backdrop of causal ignorance. Rather than learn about a relationship between a treatment and an outcome, we learn that in the right sort of context, a treatment reliably produces a particular outcome. Moving a treatment from here to there becomes, therefore, something of an engineering exercise to ensure the right factors (or "shields") are in place so the cause-effect is manifest. As a consequence, one cannot assume that comparative effectiveness or cost-effectiveness would be maintained., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: the COVID-19 pandemic has incurred psychological risks for healthcare workers (HCWs). We established a Victorian HCW cohort (the Coronavirus in Victorian Healthcare and Aged-Care Workers (COVIC-HA) cohort study) to examine COVID-19 impacts on HCWs and assess organisational responses over time., Methods: mixed-methods cohort study, with baseline data collected via an online survey (7 May-18 July 2021) across four healthcare settings: ambulance, hospitals, primary care, and residential aged-care. Outcomes included self-reported symptoms of depression, anxiety, post-traumatic stress (PTS), wellbeing, burnout, and resilience, measured using validated tools. Work and home-related COVID-19 impacts and perceptions of workplace responses were also captured., Results: among 984 HCWs, symptoms of clinically significant depression, anxiety, and PTS were reported by 22.5%, 14.0%, and 20.4%, respectively, highest among paramedics and nurses. Emotional exhaustion reflecting moderate-severe burnout was reported by 65.1%. Concerns about contracting COVID-19 at work and transmitting COVID-19 were common, but 91.2% felt well-informed on workplace changes and 78.3% reported that support services were available., Conclusions: Australian HCWs employed during 2021 experienced adverse mental health outcomes, with prevalence differences observed according to occupation. Longitudinal evidence is needed to inform workplace strategies that support the physical and mental wellbeing of HCWs at organisational and state policy levels.

Background: Non-immune international travellers are at risk of acquiring hepatitis A. Although hepatitis A vaccination is recommended for unvaccinated travellers to high or intermediate hepatitis A virus endemicity, compliance with this recommendation is not universal.The main objective was to describe the demographic and travel characteristics of international travellers infected with hepatitis A during travel., Methods: Available data on travellers with confirmed (positive molecular test) or probable (symptomatic individuals with a single positive IgM test) hepatitis A diagnosed during and after travel from January 2008 to December 2020 were obtained from the GeoSentinel Surveillance Network database. We analysed demographic and travel characteristics of infected travellers., Results: Among 254 travellers with hepatitis A (185 confirmed and 69 probable), the median age was 28 years (interquartile range: 19-40), 150 (59%) were male, and among 54 travellers with information available, 53 (98%) were unvaccinated. The most common reasons for travel included tourism (n = 120; 47%) and visiting friends or relatives (VFR; n = 72; 28%). About two-thirds of VFR travellers with hepatitis A (n = 50; 69%) were younger than 20 years old. Hepatitis A was acquired most frequently in South-Central Asia (n = 63; 25%) and sub-Saharan Africa (n = 61; 24%), but 16 travellers (6%) acquired hepatitis A in regions with low endemicity including Western Europe (n = 7; 3%), the Caribbean (n = 6; 2%) and North America (n = 3; 1%). Median duration from illness onset to GeoSentinel site presentation was ~7 days (interquartile range : 4-14 days). Among 88 travellers with information available, 59% were hospitalized., Conclusions: Despite availability of highly effective vaccines, travellers still acquire hepatitis A, even when traveling to low-endemicity destinations. Providing pre-departure hepatitis A vaccine to susceptible travellers is crucial to reducing travel-associated hepatitis A and should be offered to all travellers as part of the pre-travel consultation, regardless of destination., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Outbreaks of influenza in swine can result in potential threats to human public health. A notable occurrence was the emergence of swine-origin H1N1 influenza viruses in 2009. Since then, there have been several documented outbreaks of swine-origin influenza infecting humans in several countries. Sustained events have occurred when H1N1v, H1N2v, and H3N2v swine-origin viruses have infected humans visiting agricultural shows in the US. The predominant H3N2v viruses gained the matrix protein from the A(H1N1)pdm09 viruses, with reported human-to-human transmission raising fears of another pandemic. Current vaccines do not induce secondary cell-mediated immune responses, which may provide cross-protection against novel influenza A subtypes, however, population susceptibility to infection with seasonal influenza is likely to be influenced by cross-reactive CD8+ T-cells directed towards immunogenic peptides derived from viral proteins. This study involved a retrospective review of historical influenza viruses circulating in human populations from 1918 to 2020 to identify evidence of prior circulation of H3N3v immunogenic CD8+ T-cells peptides found in the NP and M1 proteins. We found evidence of prior circulation of H3N2v NP and M1 immunogenic peptides in historical influenza viruses. This provides insight into the population context in which influenza viruses emerge and may help inform immunogenic peptide selection for cytotoxic T-cell lymphocytes (CTL)-inducing influenza vaccines. Next-generation vaccines capable of eliciting CD8+ T-cell-mediated cross-protective immunity may offer a long-term alternative strategy for influenza vaccines., (© 2021 Wiley Periodicals LLC.)

Background: Typhoid fever is a notifiable disease within Australia. Although studies in endemic regions give an indication of acquisition risk, many countries lack reliable data, and little is known of the absolute or relative risk in Australian travellers. By combining notified case data with travel statistics provided by the Australian Bureau of Statistics, the aim of this study was to give an indication of risk for typhoid acquisition among Australian travellers., Methods: Australian typhoid notifications between 1st January 2010 and 30th June 2017 were grouped by country of acquisition and age category (<15 or ≥15 years). Australian travel data were used to inform time at risk and incidence rate of Australian typhoid notifications pertaining to country and region of acquisition. Salmonella Paratyphi infections, though notifiable, were excluded as the focus was vaccine preventable illness. Data from New South Wales and Victoria were used to examine the incidence in those acquiring infection in their country of birth (COB) against travellers who did not., Results: Nine hundred twenty-three cases of typhoid were notified over the period of review, 96% of which were acquired overseas. The greatest determinant of risk was travel destination, with countries in south Asia associated with highest crude incidence rate (252 per 100 000 person-years), particularly Bangladesh. Younger age and immigrants returning to their COB were generally associated with higher risk of acquisition., Conclusions: The risk of typhoid fever in Australian travellers to endemic regions is considerable. Immigrants returning to their COB appear to be at higher risk and it is likely that this risk extends to their traveling dependents. These findings help clinicians and public health officials to plan and advise pre-travel vaccination strategies with at-risk individuals and groups. Additional sociodemographic data collection with Australian typhoid notifications would enhance the surveillance of differing international travel risk groups leaving Australia., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine.)

The site frequency spectrum (SFS) is a popular summary statistic of genomic data. While the SFS of a constant-sized population undergoing neutral mutations has been extensively studied in population genetics, the rapidly growing amount of cancer genomic data has attracted interest in the spectrum of an exponentially growing population. Recent theoretical results have generally dealt with special or limiting cases, such as considering only cells with an infinite line of descent, assuming deterministic tumor growth, or taking large-time or large-population limits. In this work, we derive exact expressions for the expected SFS of a cell population that evolves according to a stochastic branching process, first for cells with an infinite line of descent and then for the total population, evaluated either at a fixed time (fixed-time spectrum) or at the stochastic time at which the population reaches a certain size (fixed-size spectrum). We find that while the rate of mutation scales the SFS of the total population linearly, the rates of cell birth and cell death change the shape of the spectrum at the small-frequency end, inducing a transition between a 1/j 2 power-law spectrum and a 1/j spectrum as cell viability decreases. We show that this insight can in principle be used to estimate the ratio between the rate of cell death and cell birth, as well as the mutation rate, using the site frequency spectrum alone. Although the discussion is framed in terms of tumor dynamics, our results apply to any exponentially growing population of individuals undergoing neutral mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There has been immense interest and debate regarding the effectiveness of antibiotic treatment for chronic low back pain. Two randomised controlled trials have examined the efficacy of antibiotics for chronic low back pain with disc herniation and Modic changes, but have reported conflicting results. The aim of this double-blind, randomised, placebo-controlled trial is to determine the efficacy of antibiotic treatment in a broader patient subgroup of chronic low back pain with disc herniation and investigate whether the presence of Modic changes predicts response to antibiotic therapy., Methods: One hundred and seventy individuals with chronic low back pain will be recruited through hospital and private medical and allied health clinics; advertising in national, community and social media; and posting of flyers in community locations. They will be randomly allocated to receive either amoxicillin-clavulanate (500 mg/125 mg) twice per day for 90 days or placebo. The primary outcome measure of pain intensity will be assessed using the Low Back Pain Rating scale and a 100-mm visual analogue scale at 12 months. Secondary measures of self-reported low back disability and work absence and hindrance will also be examined, and an economic analysis will be conducted. Intention-to-treat analyses will be performed., Discussion: There is uncertainty about whether antibiotic treatment is effective for chronic low back pain and, if effective, which patient subgroup is most likely to respond. We will conduct a clinical trial to investigate the efficacy of antibiotics compared with placebo in individuals with chronic low back pain and a disc herniation. Our findings will provide high-quality evidence to assist in answering these questions., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12615000958583 . Registered on 11 September 2015., (© 2021. The Author(s).)

Background: The intense interactions between people, animals and environmental systems in urban informal settlements compromise human and environmental health. Inadequate water and sanitation services, compounded by exposure to flooding and climate change risks, expose inhabitants to environmental contamination causing poor health and wellbeing and degrading ecosystems. However, the exact nature and full scope of risks and exposure pathways between human health and the environment in informal settlements are uncertain. Existing models are limited to microbiological linkages related to faecal-oral exposures at the individual level, and do not account for a broader range of human-environmental variables and interactions that affect population health and wellbeing., Methods: We undertook a 12-month health and environmental assessment in 12 flood-prone informal settlements in Makassar, Indonesia. We obtained caregiver-reported health data, anthropometric measurements, stool and blood samples from children < 5 years, and health and wellbeing data for children 5-14 years and adult respondents. We collected environmental data including temperature, mosquito and rat species abundance, and water and sediment samples. Demographic, built environment and household asset data were also collected. We combined our data with existing literature to generate a novel planetary health model of health and environment in informal settlements., Results: Across the 12 settlements, 593 households and 2764 participants were enrolled. Two-thirds (64·1%) of all houses (26·3-82·7% per settlement) had formal land tenure documentation. Cough, fever and diarrhoea in the week prior to the survey were reported among an average of 34.3%, 26.9% and 9.7% of children aged < 5 years, respectively; although proportions varied over time, prevalence among these youngest children was consistently higher than among children 5-14 years or adult respondents. Among children < 5 years, 44·3% experienced stunting, 41·1% underweight, 12.4% wasting, and 26.5% were anaemic. There was self- or carer-reported poor mental health among 16.6% of children aged 5-14 years and 13.9% of adult respondents. Rates of potential risky exposures from swimming in waterways, eating uncooked produce, and eating soil or dirt were high, as were exposures to flooding and livestock. Just over one third of households (35.3%) had access to municipal water, and contamination of well water with E. coli and nitrogen species was common. Most (79·5%) houses had an in-house toilet, but no houses were connected to a piped sewer network or safe, properly constructed septic tank. Median monthly settlement outdoor temperatures ranged from 26·2 °C to 29.3 °C, and were on average, 1·1 °C warmer inside houses than outside. Mosquito density varied over time, with Culex quinquefasciatus accounting for 94·7% of species. Framed by a planetary health lens, our model includes four thematic domains: (1) the physical/built environment; (2) the ecological environment; (3) human health; and (4) socio-economic wellbeing, and is structured at individual, household, settlement, and city/beyond spatial scales., Conclusions: Our planetary health model includes key risk factors and faecal-oral exposure pathways but extends beyond conventional microbiological faecal-oral enteropathogen exposure pathways to comprehensively account for a wider range of variables affecting health in urban informal settlements. It includes broader ecological interconnections and planetary health-related variables at the household, settlement and city levels. It proposes a composite framework of markers to assess water and sanitation challenges and flood risks in urban informal settlements for optimal design and monitoring of interventions., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Infant influenza and pertussis disease causes considerable morbidity and mortality worldwide. We examined the effectiveness of maternal influenza and pertussis vaccines in preventing these diseases in infants., Methods: This inception cohort study comprised women whose pregnancies ended between September 1, 2015, and December 31, 2017, in Victoria, Australia. Maternal vaccination status was sourced from the Victorian Perinatal Data Collection and linked to 5 data sets to ascertain infant outcomes and vaccination. The primary outcome of interest was laboratory-confirmed influenza or pertussis disease in infants aged <2 months, 2 to <6 months, and <6 months combined. Secondary outcomes included infant hospitalization (emergency presentation or admission) and death. Risk ratios and 95% confidence intervals (CIs) were estimated by Poisson regression. Vaccine effectiveness (VE) was estimated as (1 minus the risk ratio) x 100%., Results: Among 186 962 pregnant women, 85 830 (45.9%) and 128 060 (68.5%) were vaccinated against influenza and pertussis, respectively. There were 175 and 51 infants with laboratory-confirmed influenza and pertussis disease, respectively. Influenza VE was 56.1% (95% CI, 23.3% to 74.9%) for infants aged <2 months and 35.7% (2.2% to 57.7%) for infants aged 2 to <6 months. Pertussis VE was 80.1% (95% CI, 37.1% to 93.7%) for infants aged <2 months and 31.8% (95% CI, -39.1% to 66.6%) for infants aged 2 to <6 months., Conclusions: Our study provides evidence of the direct effectiveness of maternal influenza and pertussis vaccination in preventing these diseases in infants aged <2 months. The findings strengthen the importance of maternal vaccination to prevent these diseases in infants., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: Multiple bacteria, viruses, protists, and helminths cause enteric infections that greatly impact human health and wellbeing. These enteropathogens are transmited via several pathways through human, animal, and environmental reservoirs. Individual qPCR assays have been extensively used to detect enteropathogens within these types of samples, whereas the TaqMan array card (TAC), which allows simultaneous detection of multiple enteropathogens, has only previously been validated in human clinical samples., Methods: In this methodological comparison study, we compared the performance of a custom 48-singleplex TAC relative to standard qPCR. We established the sensitivity and specificity of each method for the detection of eight enteric targets, by using spiked samples with varying levels of PCR inhibition. We then tested the prevalence and abundance of pathogens in wastewater from Melbourne (Australia), and human, animal, and environmental samples from informal settlements in Suva, Fiji using both TAC and qPCR., Findings: Both methods exhibited similarly h specificity (TAC 100%, qPCR 94%), sensitivity (TAC 92%, qPCR 100%), and quantitation accuracy (TAC 91%, qPCR 99%) in non-inhibited sample matrices with spiked gene fragments. PCR inhibitors substantially affected detection via TAC, though this issue was alleviated by ten-fold sample dilution. Among samples from informal settlements, the two techniques performed similarly for detection (89% agreement) and quantitation (R 2 0·82) for the eight enteropathogen targets. The TAC additionally included 38 other enteric targets, enabling detection of diverse faecal pathogens and extensive environmental contamination that would be prohibitively labour intensive to assay by standard qPCR., Interpretation: The two techniques produced similar results across diverse sample types, with qPCR prioritising greater sensitivity and quantitation accuracy, and TAC trading small reductions in these for a cost-effective larger enteropathogen panel enabling a greater number of enteric pathogens to be analysed concurrently, which is beneficial given the abundance and variety of enteric pathogens in environments such as urban informal settlements. The ability to monitor multiple enteric pathogens across diverse reservoirs could allow better resolution of pathogen exposure pathways, and the design and monitoring of interventions to reduce pathogen load., Funding: Wellcome Trust Our Planet, Our Health programme., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: The Australian National COVID-19 Clinical Evidence Taskforce is a consortium of 31 Australian health professional organisations developing living, evidence-based guidelines for care of people with COVID-19, which are updated weekly. This article describes the methods used to develop and maintain the guidelines., Methods: The guidelines use the GRADE methods and are designed to meet Australian NHMRC standards. Each week, new evidence is reviewed, current recommendations are revised, and new recommendations made. These are published in MAGIC and disseminated through traditional and social media. Relevant new questions to be addressed are continually sought from stakeholders and practitioners. For prioritized questions, the evidence is actively monitored and updated. Evidence surveillance combines horizon scans and targeted searches. An evidence team appraises and synthesizes evidence and prepares evidence-to-decision frameworks to inform development of recommendations. A guidelines leadership group oversees the development of recommendations by multidisciplinary guidelines panels and is advised by a consumer panel., Results: The Taskforce formed in March 2020, and the first recommendations were published 2 weeks later. The guidelines have been revised and republished on a weekly basis for 24 weeks, and as of October 2020, contain over 90 treatment recommendations, suggesting that living methods are feasible in this context., Conclusions: The Australian guidelines for care of people with COVID-19 provide an example of the feasibility of living guidelines and an opportunity to test and improve living evidence methods., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sepsis is a serious global health issue and a major cause of death and disability. The availability of a simple, community-based preventive strategy could substantially reduce the burden of sepsis. We aimed to establish whether low-dose aspirin reduced deaths or hospital admissions associated with sepsis in older people., Methods: ANTISEPSIS was a substudy of ASPREE (a randomised controlled primary prevention trial of low-dose aspirin [100 mg per day] compared with placebo in community dwelling older adults conducted in Australia and the USA), with the Australian cohort included in the ANTISEPSIS substudy. Inclusion criteria were participants aged at least 70 years who did not have major illnesses. Participants were block randomised (1:1) via a centralised web portal and stratified by general practice and age. Participants, investigators, and staff were masked to the intervention. Teams of clinical specialist investigators assessed potential sepsis events to establish if they satisfied the primary endpoint of death associated with sepsis. The analyses were by intention-to-treat with univariate survival analysis methods, the log-rank test, and Cox proportional hazards regression. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000349741., Results: Between March 10, 2010, and Dec 24, 2014, of 20 288 individuals assessed for eligibility, 16 703 participants aged 70 years and older at trial entry were enrolled and followed up for a median of 4·6 years (IQR 3·6-5·6). 8322 (49·8%) participants were assigned to receive aspirin and 8381 (50·2%) to placebo. 203 deaths were considered to be associated with sepsis. Univariate analysis showed similar rates of death associated with sepsis in the two study groups (hazard ratio for aspirin vs placebo 1·08, 95% CI 0·82-1·43; p=0·57). Adverse events were previously reported in the ASPREE trial., Interpretation: Daily low-dose aspirin treatment did not reduce deaths associated with sepsis in community dwelling older adults. Our findings do not support the use of aspirin as a primary prevention strategy to reduce the burden of sepsis in this population., Funding: National Health and Medical Research Council of Australia, National Institutes of Health, Monash University., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The use of artemisinin derivatives has been recommended by the WHO guidelines in malaria treatment largely due to its rapid parasite clearance and safety profile. This case report details the development of delayed haemolysis and subsequent severe acute kidney injury (AKI) 13 days after commencing intravenous artesunate treatment for malaria in an Australian returned traveller. Delayed haemolysis may be an under-recognised complication following artesunate use and if severe, can be complicated by AKI. Therefore, close patient follow-up following treatment is required to ensure prompt recognition of this phenomenon., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Increasing urban populations have led to the growth of informal settlements, with contaminated environments linked to poor human health through a range of interlinked pathways. Here, we describe the design and methods for the Revitalising Informal Settlements and their Environments (RISE) study, a transdisciplinary randomised trial evaluating impacts of an intervention to upgrade urban informal settlements in two Asia-Pacific countries., Methods and Analysis: RISE is a cluster randomised controlled trial among 12 settlements in Makassar, Indonesia, and 12 in Suva, Fiji. Six settlements in each country have been randomised to receive the intervention at the outset; the remainder will serve as controls and be offered intervention delivery after trial completion. The intervention involves a water-sensitive approach, delivering site-specific, modular, decentralised infrastructure primarily aimed at improving health by decreasing exposure to environmental faecal contamination. Consenting households within each informal settlement site have been enrolled, with longitudinal assessment to involve health and well-being surveys, and human and environmental sampling. Primary outcomes will be evaluated in children under 5 years of age and include prevalence and diversity of gastrointestinal pathogens, abundance and diversity of antimicrobial resistance (AMR) genes in gastrointestinal microorganisms and markers of gastrointestinal inflammation. Diverse secondary outcomes include changes in microbial contamination; abundance and diversity of pathogens and AMR genes in environmental samples; impacts on ecological biodiversity and microclimates; mosquito vector abundance; anthropometric assessments, nutrition markers and systemic inflammation in children; caregiver-reported and self-reported health symptoms and healthcare utilisation; and measures of individual and community psychological, emotional and economic well-being. The study aims to provide proof-of-concept evidence to inform policies on upgrading of informal settlements to improve environments and human health and well-being., Ethics: Study protocols have been approved by ethics boards at Monash University, Fiji National University and Hasanuddin University., Trial Registration Number: ACTRN12618000633280; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Hepatitis E virus (HEV) is widely distributed worldwide and is endemic in developing countries. Travel-related HEV infection has been reported at national levels, but global data are missing. Moreover, the global availability of HEV diagnostic testing has not been explored so far. The aim of this study is to describe the epidemiology of HEV infections in returning travellers and availability of HEV diagnostic testing in the GeoSentinel surveillance network., Methods: This was a multicentre retrospective cross-sectional study. All confirmed and probable HEV travel-related infections reported in the GeoSentinel Network between 1999 and 2018 were evaluated. GeoSentinel sites were asked to complete a survey in 2018 to assess the availability and accessibility of HEV diagnostic procedures (i.e. serology and molecular tests) throughout the study period., Results: Overall, 165 travel-related HEV infections were reported, mainly since 2010 (60%) and in tourists (50%). Travellers were exposed to hepatitis E in 27 countries; most travellers (62%) were exposed to HEV in South Asia. One patient was pregnant at the time of HEV infection and 14 had a concomitant gastrointestinal infection. No deaths were reported. In the 51% of patients with information available, there was no pre-travel consultation. Among 44 GeoSentinel sites that responded to the survey, 73% have access to HEV serology at a local level, while 55% could perform (at a local or central level) molecular diagnostics., Conclusion: Reported access to HEV diagnostic testing is suboptimal among sites that responded to the survey; this could negatively affect diagnosing HEV. Pre-travel consultations before travel to South Asia and other low-income and high-prevalence areas with a focus on food and water precautions could be helpful in preventing hepatitis E infection. Improved HEV diagnostic capacity should be implemented to prevent and correctly diagnose travel-related HEV infection., (© International Society of Travel Medicine 2020. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Enteric fever, caused by Salmonella enterica serovar Typhi ( S Typhi) and S. enterica serovar Paratyphi ( S Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site's national guidelines. A total of 889 travelers ( S Typhi infections, n  = 474; S Paratyphi infections, n  = 414; coinfection, n  = 1) were included; 114 (13%) were children of <18 years old. Most individuals (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S Typhi and 75 S Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children., (Copyright © 2020 American Society for Microbiology.)

Introduction: International travellers contribute to the rapid spread of Zika virus (ZIKV) and its sentinel identification globally. We describe ZIKV infections among international travellers seen at GeoSentinel sites with a focus on ZIKV acquired in the Americas and the Caribbean, describe countries of exposure and traveller characteristics, and assess ZIKV diagnostic testing by site., Methods: Records with an international travel-related diagnosis of confirmed or probable ZIKV from January 2012 through December 2019 reported to GeoSentinel with a recorded illness onset date were included to show reported cases over time. Records from March 2016 through December 2019 with an exposure region of the Americas or the Caribbean were included in the descriptive analysis. A survey was conducted to assess the availability, accessibility and utilization of ZIKV diagnostic tests at GeoSentinel sites., Results: GeoSentinel sites reported 525 ZIKV cases from 2012 through 2019. Between 2012 and 2014, eight cases were reported, and all were acquired in Asia or Oceania. After 2014, most cases were acquired in the Americas or the Caribbean, a large decline in ZIKV cases occurred in 2018-19.Between March 2016 and December 2019, 423 patients acquired ZIKV in the Americas or the Caribbean, peak reporting to these regions occurred in 2016 [330 cases (78%)]. The median age was 36 years (range: 3-92); 63% were female. The most frequent region of exposure was the Caribbean (60%). Thirteen travellers were pregnant during or after travel; one had a sexually acquired ZIKV infection. There was one case of fetal anomaly and two travellers with Guillain-Barré syndrome. GeoSentinel sites reported various challenges to diagnose ZIKV effectively., Conclusion: ZIKV should remain a consideration for travellers returning from areas with risk of ZIKV transmission. Travellers should discuss their travel plans with their healthcare providers to ensure ZIKV prevention measures are taken., (Published by Oxford University Press 2020.)

Competing Interests: None declared.