Efficient and targeted COVID-19 border testing via reinforcement learning.

Throughout the coronavirus disease 2019 (COVID-19) pandemic, countries have relied on a variety of ad hoc border control protocols to allow for non-essential travel while safeguarding public health, from quarantining all travellers to restricting entry from select nations on the basis of population-level epidemiological metrics such as cases, deaths or testing positivity rates1,2. Here we report the design and performance of a reinforcement learning system, nicknamed Eva. In the summer of 2020, Eva was deployed across all Greek borders to limit the influx of asymptomatic travellers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and to inform border policies through real-time estimates of COVID-19 prevalence. In contrast to country-wide protocols, Eva allocated Greece's limited testing resources on the basis of incoming travellers' demographic information and testing results from previous travellers. By comparing Eva's performance against modelled counterfactual scenarios, we show that Eva identified 1.85 times as many asymptomatic, infected travellers as random surveillance testing, with up to 2-4 times as many during peak travel, and 1.25-1.45 times as many asymptomatic, infected travellers as testing policies that utilize only epidemiological metrics. We demonstrate that this latter benefit arises, at least partially, because population-level epidemiological metrics had limited predictive value for the actual prevalence of SARS-CoV-2 among asymptomatic travellers and exhibited strong country-specific idiosyncrasies in the summer of 2020. Our results raise serious concerns on the effectiveness of country-agnostic internationally proposed border control policies3 that are based on population-level epidemiological metrics. Instead, our work represents a successful example of the potential of reinforcement learning and real-time data for safeguarding public health.

Travel Medicine.

International travel can cause new illness or exacerbate existing conditions. Because primary care providers are frequent sources of health advice to travelers, they should be familiar with destination-specific disease risks, be knowledgeable about travel and routine vaccines, be prepared to prescribe chemoprophylaxis and self-treatment regimens, and be aware of travel medicine resources. Primary care providers should recognize travelers who would benefit from referral to a specialized travel clinic for evaluation. Those requiring yellow fever vaccination, immunocompromised hosts, pregnant persons, persons with multiple comorbid conditions, or travelers with complex itineraries may warrant specialty referral.

The provision of sexual and reproductive health information and services to travellers: an exploratory survey of Australian travel medicine clinicians.

BACKGROUND: International travel can increase the risk of exposure to infectious diseases including sexually transmissible infections (STI). Pre-travel medical consultation provides an opportunity for travel-related health risk assessments and advice. This study explored how travel medicine clinicians integrate sexual and reproductive health (SRH) services into clinical practice. METHODS: A convenience sample of travel medicine clinicians completed a cross-sectional survey online or via hard-copy disseminated at an annual national Australian travel medicine conference. RESULTS: Of the 67 respondents, most (n , 51; 76.1%) had a postgraduate qualification relevant to travel medicine and 55.2% (n , 37) had worked in travel medicine for over 10years. Only 22.4% (n , 15) reported conducting a SRH history/STI risk assessment for all travel patients. STI testing pre-departure was conducted on patient request (48, 71.6%), if symptomatic (32, 47.8%) or based on risk history (28, 41.8%). SRH information pre-departure was most frequently provided if prompted by patient questions (n , 42; 62.7%), or based on the patient's history (n , 37; 55.2%). Over half the sample (n , 40; 59.7%) expressed interest in further training in SRH. CONCLUSION: Providing and engaging with additional training may assist travel medicine clinicians to take a more proactive approach to SRH consultations and STI testing. Additional research is needed to explore models of care that will allow comprehensive SRH and STI services to be integrated into standard pre- and post-travel care.

Analysis of patients with acute hepatitis E treated at the Clinic of Infectology and Travel Medicine in Kosice. / Analýza pacientov s akútnou hepatitídou E na Klinike infektológie a cestovnej medicíny v Kosiciach.

AIM: To analyse clinical, laboratory, and epidemiological data of a cohort of patients with acute hepatitis E treated at the Clinic of Infectology and Travel Medicine (CITM) in Kosice. MATERIAL AND METHODS: Retrospective analysis of hospital information system data on patients diagnosed with acute hepatitis E who were examined or hospitalized at CITM in 2015-2023. Statistical evaluation of the available data with a focus on epidemiology, course, and complications. RESULTS: The cohort consisted of 62 patients. Fifty-eight percent were male. The mean age was 56 years. Seventy-four percent of patients were hospitalized, with a mean length of hospital stay of 10 days. The most common clinical manifestation was jaundice (in 40% of patients). Six patients had stool HEV RNA testing and all were confirmed to have genotype 3. In 5% of patients, the infection was classified as imported (they did not have HEV RNA tested), and 95% of cases were autochthonous. A history of contact with an HEV infected person was reported by 26% of patients. A history of preexisting liver disease was noted in 13% of patients who were confirmed with higher bilirubin, GMT, and ammonia levels. No statistically significant differences were found for patients with a history of immune deficiency. One patient with preexisting liver disease developed fulminant infection resulting in death. Four hepatitis E patients with neurological symptoms had lower bilirubin levels. CONCLUSIONS: The study cohort included predominantly older men. Genotype 3 was confirmed in all patients who underwent HEV RNA testing. Higher bilirubin, ammonia, and GMT levels were confirmed in patients with preexisting liver disease. Patients with neurological complications had lower bilirubin levels. One patient with preexisting liver disease died.

Psychological and Social Aspects of Vaccination Hesitancy-Implications for Travel Medicine in the Aftermath of the COVID-19 Crisis: A Narrative Review.

Vaccines are an important tool of preventive medicine. Although organized vaccination programs have saved large populations from serious infectious diseases, there is a considerable part of the population who oppose vaccinations. In particular, anti-vaccination perceptions, among travelers to countries with endemic diseases, are a major public health concern. Although hesitancy towards vaccinations is not a novel phenomenon, it came back to the forefront during the fight against the COVID-19 pandemic. This review explores the etiology of anti-vaccination beliefs among travelers and draws conclusions about their impact on public health and society in general. For this purpose, a purposeful search for data on the causative factors of vaccine hesitancy and their impact on people's health was conducted. A descriptive analysis of the findings and conclusions regarding possible implications in health policy and clinical practice are presented. A fear of side effects, lack of credence in the necessity of vaccines, and mistrust of medical authorities are important causative factors. Their interplay shapes hesitancy towards vaccines. However, anti-vaccination beliefs can also be an aspect of a more general unconventional stance of life. Health care professionals and organizations must be ready to tackle vaccine hesitancy by making the necessary interventions. Correcting misconceptions about vaccinations is a prerequisite for ensuring personal and public health, especially in the context of a pandemic or epidemic. Moreover, ensuring the efficacy and safety of vaccines, especially in cases of modern technology applications, is a fundamental factor in addressing people's concerns about vaccines. For this purpose, medical authorities and organizations must provide accurate and clear information on vaccines so as to eliminate misinformation. Furthermore, clinicians should cultivate their communication skills in order to convey the appropriate messages to prospective recipients of vaccinations.

Barriers to seeking health care among returning travellers with malaria: A systematic review.

OBJECTIVE: To identify barriers to seeking health care among returning travellers with malaria with the aim of developing targeted interventions that improve early health care-seeking behaviour, diagnosis and treatment. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic review of published medical literature, selecting studies that investigated and reported barriers to seeking health care among returning travellers and migrants with malaria. In total, 633 articles were screened, of which four studies met the inclusion criteria after a full-text review. RESULTS: The four studies reported barriers to seeking healthcare among returning travellers in China, the United States, Thailand and the Dominican Republic. Three studies had an observational design. The identified barriers were summarised based on the appraisal delay, illness delay and utilisation delay stages. During appraisal delays, low awareness of malaria was the most significant factor. Once the patient assessed that he or she was ill, belonging to a specific minority ethnicity, being infected with P. vivax and receiving a low level of social support were predictors of delayed health care-seeking. Finally, the most significant factor associated with utilisation delays was the monetary cost. CONCLUSION: The health care-seeking behaviour of returning travellers with malaria should be further investigated and improved. Addressing the identified barriers and gaps in health care-seeking behaviour among returning travellers with malaria, particularly among groups at high risk of travel-associated infections, is important to prevent severe disease and deaths as well as secondary transmission and epidemics.

Travel medicine meets conservation medicine in St. Kitts: Disinhibition, cognitive-affective inconsistency, and disease risk among vacationers around green monkeys (Chlorocebus sabaeus).

Despite concern about environmental protection, travelers often underestimate the contribution they may have to disease transmission to other species, as well as the risk of becoming infected themselves. Tourists in general tend to accept more physical risks when traveling than when at home, and much of this can be blamed on the temporary loss of situational awareness and loss of inhibition with a corresponding relaxed attitude toward safety. To better understand environmental attitudes and travel health knowledge and behaviors, a detailed survey of adult tourists was distributed on the island of St. Kitts, home to many green monkeys. Data from 1097 respondents were collected at two locations where cruise ship passengers typically visit the island. Results revealed that even though individuals with more positive environmental attitudes were more willing to take steps to mitigate tourism-related disease transmission, they were also more likely to report wanting to touch or feed a monkey/ape. Similarly, those more willing to prevent the spread of diseases (e.g., wear a mask and report any illnesses to park authorities) were actually more likely to want to touch or feed a monkey/ape. The human desire for physical contact with other species may be partly the result of biophilia, emotionally arousing events (like contact with exotic species) that can lead to further disinhibition, and social media platforms that provide opportunities for exhibitionism. The attitude-behavior incongruency identified here may also be explained through cognitive-affective inconsistency: environmentally-oriented individuals believe that it is prudent to take steps to prevent zoonotic disease transmission but also desire to touch or feed exotic species as it may be emotionally rewarding. Individuals for whom physically interacting with monkeys/apes may be emotionally rewarding may not alter their behavior in response to cognitive means of persuasion; techniques aimed at appealing to emotions may be more effective.

Impact d'une consultation de médecine des voyages sur les attitudes et les pratiques des voyageurs.

Introduction : Traveling regularly to malaria endemic areas increasingly exposes travelers to various risks which could be mitigated by a pre-travel health consultation. The objective was to study the impact of advice provided during a pre-travel consultation on travelers’ behaviors and practices to identify travelers’ profiles and adapt the prevention recommendations before trave-ling to intertropical zones.Methods : Two self-assessment questionnaires (Q1-before and Q2-after travelling) were proposed to 271 individuals over 5 months of traveler consultations to assess behaviors (Q1) and practices (Q2). Questionnaires gathered travelers’ profiles, source of information, travel diet and lifestyle, personal vector control, malaria chemoprophylaxis and other frequent risks.Results : Diet recommendations were the least followed (16 %), especially for people<55 (p<0.03) as well as Visiting Friends and Relatives (VFR) (p<0,001). A correlation between behaviors and practices for personal vector control and immunization and malaria chemoprophylaxis were found (resp. 89% and 78%). Mosquito nets and long sleeve clothes were underused. Changes of opinion resulting from concerns of potential side effects and lack of efficiency (<7%) explained the non-compliance to the pre-travel recommendations. During the stay, although 24% of travelers got sick, medical consultations (<5%) and hospital admissions (<1%) remained low. The General Practitioner remains the main point of contact (41%).Discussion : Better identifying travelers’ characteristics would allow to improve travel consultation, to refer to their knowledge and focus on preventive measures. It is crucial to highlight the importance of diet measures and insist on the low likelihood of adverse effects in Malaria Chemoprophylaxis.

[Collateral effects of the COVID-19 pandemic on the practice of tropical and travel medicine]. / Effets de la pandémie de Covid-19 sur la pratique de médecine tropicale et des voyages.

Undoubtedly, the COVID-19 pandemic has had impacts in many areas, including travel and by extension on daily practice in tropical and travel medicine. The intercontinental travelers in decline have been replaced by a new population of travelers who previously did not require specific consultations. SARS-CoV-2 has earned its place in the pre-travel consultation in view of the medical and administrative implications. Furthermore, the global health effects of the pandemic are broader than its direct medical consequences and should not be underestimated. The increase in malaria mortality worldwide is just one example. Preventive measures prior to exposure are more important than ever.

Indubitablement, la pandémie de Covid-19 a eu des impacts dans de nombreux domaines, notamment les voyages, et par extension sur la pratique quotidienne en médecine tropicale et des voyages. Les voyageurs intercontinentaux en diminution ont été remplacés par une nouvelle population de voyageurs qui ne nécessitait pas jusqu'alors de consultations particulières. Le SARS-CoV-2 a gagné sa place dans la consultation prévoyage au vu des implications médicales et administratives. Par ailleurs, les effets de la pandémie sur la santé globale sont plus larges que ses conséquences médicales directes et ne devraient pas être sous-estimés. L'augmentation de la mortalité due à la malaria dans le monde n'en est qu'un exemple. Les mesures préventives avant exposition sont plus que jamais d'actualité.

How coronavirus disease will change the face of travel medicine.

PURPOSE OF REVIEW: The current article will review how the coronavirus disease 2019 pandemic has changed travel and travel medicine. RECENT FINDINGS: Travelers spread severe acute respiratory syndrome coronavirus 2 globally and continue to spread variants. The characteristics of the virus, the place, and time created a perfect storm that allowed the virus to quickly spread globally. The virus spread by every mode of travel with risk of transmission influenced by proximity to an infected person, duration of trip, physical characteristics of the space, and ventilation. Superspreading events were common; a small percentage of infected people accounted for most of transmission. The travel and tourist industry was devastated as lockdowns and quarantines severely restricted domestic and international travel. A trip includes multiple segments and shared sequential spaces, mostly indoors. Creating safe travel requires attention to all segments of a trip. SUMMARY: The coronavirus disease 2019 pandemic has affected every part of travel and travel medicine. The rapid development of multiple safe and effective vaccines and their deployment is allowing resumption of travel, yet many populations lack access to vaccines, and high levels of transmission continue in many areas. Providing documentation of vaccination or immunity in a consistent, verifiable, interoperable system is one of many active issues.

Travel distance reduces follow-up compliance but has no effect on long-term weight loss success in bariatric patients.

BACKGROUND: Patients seeking bariatric surgery are traveling longer distances to reach Bariatric Centers. The purpose of this study was to evaluate the impact of travel distance on adherence to follow-up and outcomes after bariatric surgery. METHODS: A retrospective review of all consecutive patients who had undergone bariatric surgery from June 2013 to May 2014 was performed, and the patients were divided into two groups: those who traveled 50 miles or less and those who traveled more than 50 miles. Primary outcome assessed was the influence of distance on post-operative follow-up attrition over 4-year period. Secondary outcomes assessed were excess weight loss, length of stay (LOS), complications and readmission rates. RESULTS: A total of 228 patients underwent bariatric surgery with 4 years of follow-up available. Of these, 145 patients traveled 50 miles or less and 83 patients traveled greater than 50 miles. Patient demographics were similar between the two groups. Those who traveled more had statistically higher probability of attrition up to 3-year follow-up mark. There was no difference in percent excess weight loss at each follow-up visit between the two cohorts. Furthermore, there was no difference in readmission rates (2% vs 5%), minor complications (14% vs 10%), major complications (3% vs 2%) and LOS (2.6 days vs 2.6). CONCLUSION: The distance patients traveled for bariatric surgery did not affect their weight loss success, length of stay, postsurgical complications or readmission rate. Despite the lack of influence on postoperative outcomes, follow-up compliance was statistically affected by distance.

Travel medicine facilities: The first nationwide cross-sectional questionnaire survey in Japan.

INTRODUCTION: Travel medicine has gained importance in recent years; however, there is little data regarding travel medicine departments in Japanese hospitals. METHODS: This cross-sectional study contacted 488 hospitals designated by either the Japanese government or major Japanese associations. A questionnaire comprising 11 questions pertaining to the availability of pre-travel consultation, out-of-hours service for travel-related patients, number of medical doctors engaged in travel medicine and infectious disease specialists, and the number of negative pressure rooms available for inpatients and outpatients was distributed. It also asked about the facilities available to combat specific diseases like malaria, dengue, and post-exposure prophylaxis for rabies as these are most common diseases affecting returning travelers. RESULTS: Of the 263 hospitals (58.7%) that responded to our questionnaire, 82 hospitals (31.2%) provided pre-travel consulting, 188 hospitals (72.0%) accepted travel-related patients out-of-hours, median (interquartile range [IQR]) number of medical doctors involved in travel medicine was 1 (0-3), and median (IQR) number of patients accepted for admission was 2 (1-4). Only 106 (41%) hospitals could diagnose malaria at any time, 56 hospitals (21%) could immediately provide oral anti-malarial medicines; rapid diagnostic test for dengue was available in 99 hospitals (39%), while 67 hospitals (26%) could immediately administer post-exposure prophylaxis for rabies. CONCLUSIONS: Japan's medical care system is concerned about illnesses-especially malaria, dengue and rabies in returned travelers. We suggest construction of a medical care system centered on designated medical facilities for category I and II infectious diseases to build capacity for early diagnosis and treatment of common tropical infectious diseases.

The travel clinic.

Catherine is an advanced nurse practitioner working in a large general practice in the North of England. Today she is running a travel clinic. Because of the immense changes brought about by COVID-19 the world is struggling to regain a degree of normality and the possibility of travel to distant places is liberating to many. More than ever medical advice about safety precautions are necessary. Marc and Emma are consulting Catherine about a projected holiday abroad.

Passengers' destinations from China: low risk of Novel Coronavirus (2019-nCoV) transmission into Africa and South America.

Novel Coronavirus (2019-nCoV [SARS-COV-2]) was detected in humans during the last week of December 2019 at Wuhan city in China, and caused 24 554 cases in 27 countries and territories as of 5 February 2020. The objective of this study was to estimate the risk of transmission of 2019-nCoV through human passenger air flight from four major cities of China (Wuhan, Beijing, Shanghai and Guangzhou) to the passengers' destination countries. We extracted the weekly simulated passengers' end destination data for the period of 1-31 January 2020 from FLIRT, an online air travel dataset that uses information from 800 airlines to show the direct flight and passengers' end destination. We estimated a risk index of 2019-nCoV transmission based on the number of travellers to destination countries, weighted by the number of confirmed cases of the departed city reported by the World Health Organization (WHO). We ranked each country based on the risk index in four quantiles (4th quantile being the highest risk and 1st quantile being the lowest risk). During the period, 388 287 passengers were destined for 1297 airports in 168 countries or territories across the world. The risk index of 2019-nCoV among the countries had a very high correlation with the WHO-reported confirmed cases (0.97). According to our risk score classification, of the countries that reported at least one Coronavirus-infected pneumonia (COVID-19) case as of 5 February 2020, 24 countries were in the 4th quantile of the risk index, two in the 3rd quantile, one in the 2nd quantile and none in the 1st quantile. Outside China, countries with a higher risk of 2019-nCoV transmission are Thailand, Cambodia, Malaysia, Canada and the USA, all of which reported at least one case. In pan-Europe, UK, France, Russia, Germany and Italy; in North America, USA and Canada; in Oceania, Australia had high risk, all of them reported at least one case. In Africa and South America, the risk of transmission is very low with Ethiopia, South Africa, Egypt, Mauritius and Brazil showing a similar risk of transmission compared to the risk of any of the countries where at least one case is detected. The risk of transmission on 31 January 2020 was very high in neighbouring Asian countries, followed by Europe (UK, France, Russia and Germany), Oceania (Australia) and North America (USA and Canada). Increased public health response including early case recognition, isolation of identified case, contract tracing and targeted airport screening, public awareness and vigilance of health workers will help mitigate the force of further spread to naïve countries.

[Travel vaccinations for certain groups of persons]. / Reiseimpfungen für besondere Personengruppen.

The number of international travelers has been continuously increasing in recent decades. Among travelers, there are more and more people at an increased risk for acquiring diseases that could be prevented by vaccines or for the development of a severe course of disease. Risk groups in travel medicine are senior travelers, children, pregnant and breast-feeding women, persons with pre-existing medical conditions, and persons who visit their friends and relatives abroad (VFR). Individuals in these groups require attention during pretravel advice consultations, particularly with regards to recommended vaccinations. On the other hand, for some risk groups, particular vaccines cannot be given for safety reasons or because the response to vaccines is reduced. Not all risk groups or each vaccine have sufficient evidence available, so each patient's risks and benefits must be weighed during pretravel consultation. In this article, the particularities for each risk group with respect to pretravel immunization are highlighted.

[Women's health while travelling in tropical countries]. / Santé de la femme en voyage dans les pays tropicaux.

When considering women's health during travels, it is mainly pregnant women who are concerned. Indeed, because of the physiological changes, they are more vulnerable to infectious and non-infectious diseases related to the trip itself or to specific activities. This article lists the essential risks for pregnant women travelling in tropical countries and provides specific recommendations, so that the general practitioner is better able to advise this vulnerable population. If the trip is suitable and in the absence of any pre-existing complication, travelling during pregnancy is not contraindicated.

Les problèmes de santé de la femme en voyage concernent principalement la femme enceinte qui, en raison des changements physiologiques, présente une vulnérabilité aux risques infectieux et non infectieux en lien avec le voyage en tant que tel ou les activités entreprises. Cet article aborde les risques essentiels et détaille les recommandations actuelles spécifiques à cette population vulnérable afin que le praticien soit plus à même de la conseiller avant le départ. Si le voyage est adapté et en l'absence de complication préexistante, il n'est pas contre-indiqué durant la grossesse.

[Sea bathing dangers: marine envenoming, trauma, and infections]. / Envenimations, infections et traumatismes en mer.

Sea bathing is often a priority activity for travelers, with widely recognized health benefits. The dangers, in contrast, are underestimated, especially in tropical seas. We describe the scope of marine envenoming, trauma, and infections, representing 1-3 % of tropical and travel medicine consultations in the literature. Our review includes the eco-epidemiology, clinical approach, and prevention of envenoming by invertebrates (jellyfish, anemone, sea-urchin, starfish, octopus, sea cone) and some vertebrates (stingrays, stone fish, snakes). We include penetrating trauma (by stingray, stonefish, sea urchin, coral) and infections (mycobacteria, marine bacteria). Eating-related dangers (ciguatera, fugu, parasites) are not described here. We also present antidotes, antivenoms, and first-aid.

Les baignades en mer aux bienfaits reconnus font souvent partie des activités prioritaires des voyageurs. Mais les dangers, notamment en mer tropicale, sont sous-estimés. Nous décrivons l'éventail des envenimations, traumatismes et infections marins, soit 1 à 3 % des consultations de médecine tropicale et des voyages dans la littérature. Notre revue inclut l'éco-épidémiologie, l'approche clinique et la prévention des envenimations par des invertébrés (méduses, anémones, oursins, étoiles de mer, poulpes et cônes) et certains vertébrés (raies, poissons-pierre, serpents). Elle inclut les traumatismes pénétrants (raies, poissons-pierre) et les infections par contact (mycobactéries, bactéries marines). Les dangers alimentaires (ciguatera, fugu, parasites) ne sont pas décrits ici. Les antidotes, antivenins et premiers secours sont également présentés.

Drug-free Holidays: Compliance, Tolerability, and Acceptability of a 3-Day Atovaquone/Proguanil Schedule for Pretravel Malaria Chemoprophylaxis in Australian Travelers.

BACKGROUND: Poor compliance with chemoprophylaxis is a major contributing factor to the risk of malaria in travelers. Pre-travel chemoprophylaxis may improve compliance by enabling "drug-free holidays." The standard treatment dose of atovaquone/proguanil (250 mg/100 mg, 4 tablets/day for 3 days) provides protection against malaria for at least 4 weeks, and could therefore potentially be used for pre-travel chemoprophylaxis. In this study, we assessed the compliance, tolerability, and acceptability of the 3-day atovaquone/proguanil schedule for malarial chemoprophylaxis. METHODS: Two hundred thirty-three participants were recruited from 4 specialized travel medicine clinics in Australia. Adults traveling to malaria-endemic areas with low/medium risk for ≤4 weeks were enrolled and prescribed the 3-day schedule of atovaquone/proguanil, completed at least 1 day before departure. Questionnaires were used to collect data on demographics, travel destination, medication compliance, side effects, and reasons for choosing the 3-day schedule. RESULTS: Overall, 97.7% of participants complied with the 3-day schedule. Although side effects were reported in 43.3% of the participants, these were well tolerated, and mainly occurred during the first and second days. None of the participants developed malaria. The main reasons for choosing the 3-day schedule over standard chemoprophylaxis options were that it was easier to remember (72.1%), required taking fewer tablets (54.0%), and to help scientific research (54.0%). CONCLUSIONS: The 3-day atovaquone/proguanil schedule had an impressively high compliance rate, and was well tolerated and accepted by travelers. Further studies are required to assess the effectiveness of this schedule for chemoprophylaxis in travelers. CLINICAL TRIALS REGISTRATION: ACTRN12616000640404.