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The emergence of acquired drug resistance in cancer represents a major barrier to treatment success. While research has traditionally focused on genetic sources of resistance, recent findings suggest that cancer cells can acquire transient resistant phenotypes via epigenetic modifications and other non-genetic mechanisms. Although these resistant phenotypes are eventually relinquished by individual cells, they can temporarily 'save' the tumor from extinction and enable the emergence of more permanent resistance mechanisms. These observations have generated interest in the potential of epigenetic therapies for long-term tumor control or eradication. In this work, we develop a mathematical model to study how phenotypic switching at the single-cell level affects resistance evolution in cancer. We highlight unique features of non-genetic resistance, probe the evolutionary consequences of epigenetic drugs and explore potential therapeutic strategies. We find that even short-term epigenetic modifications and stochastic fluctuations in gene expression can drive long-term drug resistance in the absence of any bona fide resistance mechanisms. We also find that an epigenetic drug that slightly perturbs the average retention of the resistant phenotype can turn guaranteed treatment failure into guaranteed success. Lastly, we find that combining an epigenetic drug with an anti-cancer agent can significantly outperform monotherapy, and that treatment outcome is heavily affected by drug sequencing., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020. Published by Elsevier Ltd.)

Consumption of unsafe drinking water contributes to the global disease burden, necessitating identification and implementation of effective, acceptable, and sustainable water interventions in resource-limited settings. In a quantitative stepped-wedge cluster randomized trial of a community-based water intervention in rural India, we identified low rates of intervention uptake and reported diarrhea. To better understand and explain these findings, we performed a qualitative study examining barriers and enablers to intervention uptake and health reporting using the COM-B model, where capabilities, opportunities, and motivators interact to generate behavior. We conducted 20 focus groups and one semi-structured interview with participants and four focus groups with data collectors. Multifactorial barriers to intervention uptake included distorted perceptions of water-related health effects, implementation issues that reduced treated water availability; convenience of, and preference for, alternative drinking water sources; delivery of water to plastic storage tanks (perceived as affecting water quality and taste); and resistance to change. Enablers included knowledge of water-related health risks, proximity to tanks, and social opportunity. Barriers to health reporting included variability in interpretation of illness, suspicion regarding the consequences of reporting disease, weariness with repeated questions, and perceived inaction on health data already provided; low survey implementation fidelity was also important. Enablers included surveyor initiatives to encourage reporting and a sense of social responsibility. This qualitative explanatory study allowed better understanding of our quantitative results. It also identified obstacles and facilitators to implementing and evaluating community water interventions, providing insight on how to achieve better intervention uptake and health reporting in future studies.

Sustainable and low-cost methods for delivery of safe drinking water in resource-limited settings remain suboptimal, which contributes to global diarrhea morbidity. We aimed to assess whether delivery of riverbank filtration-treated water to newly installed water storage tanks (improved quality and access, intervention condition) reduced reported diarrhea in comparison to delivery of unfiltered river water (improved access alone, control condition) in rural Indian villages. We used a stepped wedge cluster-randomized trial (SW-CRT) design involving four clusters (villages). Selection criteria included village size, proximity to a river, and lack of existing or planned community-level safe water sources. All adults and children were eligible for enrollment. All villages started in the control condition and were sequentially randomized to receive the intervention at 3-month intervals. Our primary outcome was 7-day-period prevalence of self- or caregiver-reported diarrhea, measured at 3-month intervals (five time points). Analysis was by intention to treat. Because blinding was not possible, we incorporated questions about symptoms unrelated to water consumption to check response validity (negative control symptoms). We measured outcomes in 2,222 households (9,836 participants). We did not find a measurable reduction in diarrhea post-intervention (RR: 0.98 [95% CI: 0.24-4.09]); possible explanations include low intervention uptake, availability of other safe water sources, low baseline diarrheal prevalence, and reporting fatigue. Our study highlights both the difficulties in evaluating the impact of real-world interventions and the potential for an optimized SW-CRT design to address budgetary, funding, and logistical constraints inherent in such evaluations.

To explore the consistency in impact evaluation based on reported diarrhea, we compared diarrhea data collected through two different surveys and with observed diarrhea-associated hospitalization for children aged ≤ 5 years from a non-blinded cluster-randomized trial conducted over 2 years in urban Dhaka. We have previously reported that the interventions did not reduce diarrhea-associated hospitalization for children aged ≤ 5 years in this trial. We randomly allocated 90 geographic clusters comprising > 60,000 low-income households into three groups: cholera vaccine only, vaccine plus behavior change (cholera vaccine and handwashing plus drinking water chlorination promotion), and control. We calculated reported diarrhea prevalence within the last 2 days using data collected from two different survey methods. The "census" data were collected from each household every 6 months for updating household demographic information. The "monthly survey" data were collected every month from a subset of randomly selected study households for monitoring the uptake of behavior change interventions. We used binomial regression with a logarithmic link accounting for clustering to compare diarrhea prevalence across intervention and control groups separately for both census and monthly survey data. No intervention impact was detected in the census (vaccine only versus control: 2.32% versus 2.53%; P = 0.49; vaccine plus behavior change versus control: 2.44% versus 2.53%; P = 0.78) or in the vaccine only versus control in the monthly survey (3.39% versus 3.80%; P = 0.69). However, diarrhea prevalence was lower in the vaccine-plus-behavior-change group than control in the monthly survey (2.08% versus 3.80%; P = 0.02). Although the reasons for different observed treatment effects in the census and monthly survey data in this study are unclear, these findings emphasize the importance of assessing objective outcomes along with reported outcomes from non-blinded trials.

Although the costs of dengue illness to patients and households have been extensively studied in endemic populations, international travelers have not been the focus of costing studies. As globalization and human travel activities intensify, travelers are increasingly at risk for emerging and reemerging infectious diseases, such as dengue. This exploratory study aims to investigate the impact and out-of-pocket costs of dengue illness among travelers. We conducted a prospective study in adult travelers with laboratory-confirmed dengue and recruited patients at travel medicine clinics in eight different countries from December 2013 to December 2015. Using a structured questionnaire, we collected information on patients and their health-care utilization and out-of-pocket expenditures, as well as income and other financial losses they incurred because of dengue illness. A total of 90 patients participated in the study, most of whom traveled for tourism (74%) and visited countries in Asia (82%). Although 22% reported hospitalization and 32% receiving ambulatory care while traveling, these percentages were higher at 39% and 71%, respectively, after returning home. The out-of-pocket direct and indirect costs of dengue illness were US$421 (SD 744) and US$571 (SD 1,913) per episode, respectively, averaging to a total out-of-pocket cost of US$992 (SD 2,052) per episode. The study findings suggest that international travelers incur important direct and indirect costs because of dengue-related illness. This study is the first to date to investigate the impact and out-of-pocket costs of travel-related dengue illness from the patient's perspective and paves the way for future economic burden studies in this population.

We assessed the impact of handwashing promotion on reported respiratory illness as a secondary outcome from among > 60,000 low-income households enrolled in a cluster-randomized trial conducted in Bangladesh. Ninety geographic clusters were randomly allocated into three groups: cholera-vaccine-only; vaccine-plus-behavior-change (handwashing promotion and drinking water chlorination); and control. Data on respiratory illness (fever plus either cough or nasal congestion or breathing difficulty within previous 2 days) and intervention uptake (presence of soap and water at handwashing station) were collected through monthly surveys conducted among a different subset of randomly selected households during the intervention period. We determined respiratory illness prevalence across groups and used log-binomial regression to examine the association between respiratory illness and presence of soap and water in the handwashing station. Results were adjusted for age, gender, wealth, and cluster-randomized design. The vaccine-plus-behavior-change group had more handwashing stations with soap and water present than controls (45% versus 25%; P < 0.001). Reported respiratory illness prevalence was similar across groups (vaccine-plus-behavior-change versus control: 2.8% versus 2.9%; 95% confidence interval [CI]: -0.008, 0.006; P = 0.6; cholera-vaccine-only versus control: 3.0% versus 2.9%; 95% CI: -0.006, 0.009; P = 0.4). Irrespective of intervention assignment, respiratory illness was lower among people who had soap and water present in the handwashing station than among those who did not (risk ratio adjusted : 0.82; 95% CI: 0.69-0.98). With modest uptake of the handwashing intervention, we found no impact of this large-scale intervention on respiratory illness. However, those who actually had a handwashing station with soap and water had less illness. This suggests improving the effectiveness of handwashing promotion in achieving sustained behavior change could result in health benefits.

Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O 6 -methylguanine-DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM-surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis.

Objectives: To review the use of data linkage by Australian state and territory communicable disease control units, and to identify barriers to and enablers of data linkage to inform communicable disease surveillance and control activities., Methods: Semi-structured telephone interviews were carried out with one key informant from communicable disease control units in all eight Australian states and territories between October 2017 and January 2018., Results: Key informants from all Australian states and territories participated in the interview. A variety of existing practices were identified, with few jurisdictions making systematic use of available data linkage infrastructure. Key barriers identified from the review included: a lack of perceived need; system factors; and resources. Existing regulatory tools enable data linkage to enhance communicable disease surveillance and control., Conclusions: We identified considerable variation in the use of data linkage to inform communicable disease surveillance and control activities between jurisdictions. We suggest that routinely collected, disparate data are systematically integrated into existing surveillance and response policy cycle to improve communicable disease prevention and control efforts. Implications for public health: Existing gaps in communicable disease surveillance data may affect prevention and control efforts. Data linkage is recognised as a valuable method to close surveillance gaps and should be used to enhance the value of publicly held health data., (© 2018 State Government of Victoria, Department of Health & Human Sciences.)

The epidemiology of H5N1 and H7N9 avian viruses of humans infected in China differs despite both viruses being avian reassortants that have inherited six internal genes from a common ancestor, H9N2. The median age of infected populations is substantially younger for H5N1 virus (26 years) compared with H7N9 virus (63 years). Population susceptibility to infection with seasonal influenza is understood to be influenced by cross-reactive CD8+ T cells directed towards immunogenic peptides derived from internal viral proteins which may provide some level of protection against further influenza infection. Prior exposure to seasonal influenza peptides may influence the age-related infection patterns observed for H5N1 and H7N9 viruses. A comparison of relatedness of immunogenic peptides between historical human strains and the two avian emerged viruses was undertaken for a possible explanation in the differences in age incidence observed. There appeared to be some relationship between past exposure to related peptides and the lower number of H5N1 virus cases in older populations, however the relationship between prior exposure and older populations among H7N9 virus patients was less clear.

Background: Bali, Indonesia, presents significant infectious and non-infectious health risks for Australian travellers. Understanding this spectrum of illnesses has the potential to assist clinicians in evaluating unwell returning travellers and guide provision of pre-travel advice., Aim: To describe the spectrum of illnesses seen in returned travellers from Bali., Methods: Using a novel text mining approach, we performed a retrospective, observational study of all adult emergency department presentations to a metropolitan health service in Melbourne, from 2011 to 2015. Outcome measures included demographic, clinical and laboratory features of travel-related illnesses., Results: A total of 464 patients met inclusion criteria. Gastroenteritis (119/464, 26%), systemic febrile illness (88/464, 19%) and respiratory tract infection (51/464, 11%) were the most common diagnoses. Dengue was the most common laboratory-confirmed diagnosis (25/464, 5%). No cases of malaria were identified. Common non-infectious presentations included traumatic injury (47/464, 10%) and animal bites requiring rabies post-exposure prophylaxis (29/464, 6%). A total of 110 patients (24%) was admitted to the hospital; those presenting with systemic febrile illness were more likely to be admitted compared to those presenting with other illnesses (odds ratio 3.42, 95% confidence interval 2.02-5.75, P < 0.001)., Conclusion: This is the first study to use a text mining approach to identify and describe emergency department presentations related to diseases acquired in Bali by Australian travellers. Although infections are important causes of illness, trauma and animal bites account for a significant number of hospital presentations. Our findings contribute to the knowledge on the health risks for travellers to Bali, and will assist clinicians in relevant pre- and post-travel evaluations., (© 2018 Royal Australasian College of Physicians.)

Background: Recent studies demonstrate that rabies post-exposure prophylaxis (RPEP) in international travelers is suboptimal, with only 5-20% of travelers receiving rabies immune globulin (RIG) in the country of exposure when indicated. We hypothesized that travelers may not be receiving RIG appropriately, and practices may vary between countries. We aim to describe the characteristics of travelers who received RIG and/or RPEP during travel., Methodology/principal Findings: We conducted a multi-center review of international travelers exposed to potentially rabid animals, collecting information on RPEP administration. Travelers who started RPEP before (Group A) and at (Group B) presentation to a GeoSentinel clinic during September 2014-July 2017 were included. We included 920 travelers who started RPEP. About two-thirds of Group A travelers with an indication for rabies immunoglobulin (RIG) did not receive it. Travelers exposed in Indonesia were less likely to receive RIG in the country of exposure (relative risk: 0.30; 95% confidence interval: 0.12-0.73; P = 0.01). Travelers exposed in Thailand [Relative risk (RR) 1.38, 95% Confidence Interval (95% CI): 1.0-1.8; P = 0.02], Sri Lanka (RR 3.99, 95% CI: 3.99-11.9; P = 0.013), and the Philippines (RR 19.95, 95% CI: 2.5-157.2; P = 0.01), were more likely to receive RIG in the country of exposure., Conclusions/significance: This analysis highlights gaps in early delivery of RIG to travelers and identifies specific countries where travelers may be more or less likely to receive RIG. More detailed country-level information helps inform risk education of international travelers regarding appropriate rabies prevention., Competing Interests: The authors have declared that no competing interests exist.

Background: Estimates of travel-related illness have focused predominantly on populations from highly developed countries visiting low- or middle-income countries, yet travel to and within high-income countries is very frequent. Despite being a top international tourist destination, few sources describe the spectrum of infectious diseases acquired among travellers to the USA., Methods: We performed a descriptive analysis summarizing demographic and travel characteristics, and clinical diagnoses among non-US-resident international travellers seen during or after travel to the USA at a GeoSentinel clinic from 1 January 1997 through 31 December 2016., Results: There were 1222 ill non-US-resident travellers with 1393 diagnoses recorded during the 20-year analysis period. Median age was 40 (range 0-86 years); 52% were female. Patients visited from 63 countries and territories, most commonly Canada (31%), Germany (14%), France (9%) and Japan (7%). Travellers presented with a range of illnesses; skin and soft tissue infections of unspecified aetiology were the most frequently reported during travel (29 diagnoses, 14% of during-travel diagnoses); arthropod bite/sting was the most frequently reported after travel (173 diagnoses, 15% after-travel diagnoses). Lyme disease was the most frequently reported arthropod-borne disease after travel (42, 4%). Nonspecific respiratory, gastrointestinal and systemic infections were also among the most frequently reported diagnoses overall. Low-frequency illnesses (<2% of cases) made up over half of diagnoses during travel and 41% of diagnoses after travel, including 13 cases of coccidioidomycosis and mosquito-borne infections like West Nile, dengue and Zika virus diseases., Conclusions: International travellers to the USA acquired a diverse array of mostly cosmopolitan infectious diseases, including nonspecific respiratory, gastrointestinal, dermatologic and systemic infections comparable to what has been reported among travellers to low- and middle-income countries. Clinicians should consider the specific health risks when preparing visitors to the USA and when evaluating and treating those who become ill.

Objectives: Acute respiratory infections (ARIs) disproportionately affect those living in low- and middle-income countries (LMICs). We aimed to determine whether hygiene interventions delivered in childcare, school or domestic settings in LMICs effectively prevent or reduce ARIs., Methods: We registered our systematic review with PROSPERO (CRD42017058239) and searched MEDLINE, EMBASE, CENTRAL, and Scopus from inception to 17 October 2017 for randomised controlled trials (RCTs) examining the impact of hygiene interventions on ARI morbidity in adults and children in community-based settings in LMICs. We stratified data into childcare, school and domestic settings and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess evidence quality., Results: We identified 14 cluster RCTs evaluating hand-hygiene interventions in LMICs with considerable heterogeneity in setting, size, intervention delivery and duration. We found reduced ARI-related absenteeism and illness in childcare settings (low- to moderate-quality evidence). In school settings, we found reduced ARI-related absenteeism and laboratory-confirmed influenza (moderate- to high-quality evidence), but no reduction in ARI illness (low-quality evidence). In domestic settings, we found reduced ARI illness and pneumonia amongst children in urban settlements (high-quality evidence) but not in rural settlements (low-quality evidence), and no effect on secondary transmission of influenza in households (moderate-quality evidence)., Conclusions: Evidence suggests that hand-hygiene interventions delivered in childcare, school and domestic settings can reduce ARI morbidity, but effectiveness varies according to setting, intervention target and intervention compliance. Further studies are needed to develop, deliver and evaluate targeted and sustainable hygiene interventions in LMICs., (© 2018 John Wiley & Sons Ltd.)

Background: Overwhelming post-splenectomy infection (OPSI) is a serious complication of asplenia. Clinical guidelines recommend numerous measures to reduce the risk of OPSI, but awareness and adherence to preventative measures are generally poor. We aimed to determine whether a registry for asplenic/hyposplenic patients was associated with a reduction in the incidence of infection with encapsulated bacteria., Methods: We performed a retrospective cohort study of asplenic/hyposplenic patients in the state of Victoria, Australia, who registered with Spleen Australia from 2003 through 2014. Spleen Australia provides education, clinical guidance, and annual vaccination reminders to registrants and their healthcare providers. We compared the incidence of infection with Streptococcus pneumoniae, Haemophilus influenzae type B (Hib), and Neisseria meningitidis before and after registration. Registry data were linked with Victorian notifiable disease data on invasive pneumococcal disease (IPD), invasive meningococcal disease (IMD), and Hib between 2000 and 2014., Results: Twenty-seven cases of IPD and 1 of IMD occurred among 3221 registrants. No cases of Hib were reported. The rate of IPD/IMD was 150 per 100000 patient-years prior to registration and 36 per 100000 patient-years after registration; registration was associated with a 69% reduction in the risk of infection (incidence rate ratio, 0.31; 95% confidence interval, 0.12 to 0.83; P = .019). Based on the absolute reduction in incidence, we estimate that Spleen Australia prevents 5-6 invasive infections with encapsulated organisms annually among registrants., Conclusions: Systematic, long-term approaches to post-splenectomy care can significantly reduce the risk of infection with encapsulated organisms among individuals with asplenia/hyposplenism.

Leptospirosis is a potentially fatal emerging zoonosis with worldwide distribution and a broad range of clinical presentations and exposure risks. It typically affects vulnerable populations in (sub)tropical countries but is increasingly reported in travelers as well. Diagnostic methods are cumbersome and require further improvement. Here, we describe leptospirosis among travelers presenting to the GeoSentinel Global Surveillance Network. We performed a descriptive analysis of leptospirosis cases reported in GeoSentinel from January 1997 through December 2016. We included 180 travelers with leptospirosis (mostly male; 74%; mostly tourists; 81%). The most frequent region of infection was Southeast Asia (52%); the most common source countries were Thailand ( N = 52), Costa Rica ( N = 13), Indonesia, and Laos ( N = 11 each). Fifty-nine percent were hospitalized; one fatality was reported. We also distributed a supplemental survey to GeoSentinel sites to assess clinical and diagnostic practices. Of 56 GeoSentinel sites, three-quarters responded to the survey. Leptospirosis was reported to have been most frequently considered in febrile travelers with hepatic and renal abnormalities and a history of freshwater exposure. Serology was the most commonly used diagnostic method, although convalescent samples were reported to have been collected infrequently. Within GeoSentinel, leptospirosis was diagnosed mostly among international tourists and caused serious illness. Clinical suspicion and diagnostic workup among surveyed GeoSentinel clinicians were mainly triggered by a classical presentation and exposure history, possibly resulting in underdiagnosis. Suboptimal usage of available diagnostic methods may have resulted in additional missed, or misdiagnosed, cases.

Background: Acute gastroenteritis illness is a common illness that causes considerable morbidity, but current estimates of the cost to the Australian healthcare system are unknown., Objective: To estimate the current healthcare utilisation and direct public healthcare system costs attributable to acute gastroenteritis illness in Australia., Methods: This is an incidence-based cost-of-illness study focused on quantifying direct health care costs using a bottom-up approach. Data on general practitioner consultations, prescribed medications, diagnostic tests, specialist consultations, emergency department visits and hospital admissions were collected from national reports., Results: Using 2016 prices, the estimated annual direct per capita cost of acute gastroenteritis illness was AUD$14.87 (USD$10.71), equating to AUD$20.27 (USD$14.59) per case. The estimated overall economic burden in Australia was AUD$359 million (USD$258 million; AUD$1.5 million per 100,000 people). The major contributors to this cost were hospital admissions (57.1%), emergency department visits (17.7%), and general practitioner consultations (14.0%). Children under five years of age have the highest per capita rates of acute gastroenteritis illness; however, service utilisation rates vary by age group and both young children and older adults accounted for a substantial proportion of the overall economic burden attributable to acute gastroenteritis illness., Conclusions: Although chronic diseases comprise a large cost burden on the healthcare system, acute illnesses, including acute gastroenteritis illness, also impose substantial direct healthcare system costs. Providing data on current cost estimates is useful for prioritizing public health interventions, with our findings suggesting that it would be ideal if targeted interventions to reduce hospitalisation rates among young children and older adults were available.

The design of optimal protocols plays an important role in cancer treatment. However, in clinical applications, the outcomes under the optimal protocols are sensitive to variations of parameter settings such as drug effects and the attributes of age, weight, and health conditions in human subjects. One approach to overcoming this challenge is to formulate the problem of finding an optimal treatment protocol as a robust optimization problem (ROP) that takes parameter uncertainty into account. In this chapter, we describe a method to model toxicity uncertainty. We then apply a mixed integer ROP to derive the optimal protocols that minimize the cumulative tumor size. While our method may be applied to other cancers, in this work we focus on the treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI). For simplicity, we focus on one particular mode of toxicity arising from TKI therapy, low blood cell counts, in particular low absolute neutrophil count (ANC). We develop optimization methods for locating optimal treatment protocols assuming that the rate of decrease of ANC varies within a given interval. We further investigated the relationship between parameter uncertainty and optimal protocols. Our results suggest that the dosing schedule can significantly reduce tumor size without recurrence in 360 weeks while insuring that toxicity constraints are satisfied for all realizations of uncertain parameters.

Background: Analysis of a large cohort of business travelers will help clinicians focus on frequent and serious illnesses. We aimed to describe travel-related health problems in business travelers., Methods: GeoSentinel Surveillance Network consists of 64 travel and tropical medicine clinics in 29 countries; descriptive analysis was performed on ill business travelers, defined as persons traveling for work, evaluated after international travel 1 January 1997 through 31 December 2014., Results: Among 12 203 business travelers seen 1997-2014 (14 045 eligible diagnoses), the majority (97%) were adults aged 20-64 years; most (74%) reported from Western Europe or North America; two-thirds were male. Most (86%) were outpatients. Fewer than half (45%) reported a pre-travel healthcare encounter. Frequent regions of exposure were sub-Saharan Africa (37%), Southeast Asia (15%) and South Central Asia (14%). The most frequent diagnoses were malaria (9%), acute unspecified diarrhea (8%), viral syndrome (6%), acute bacterial diarrhea (5%) and chronic diarrhea (4%). Species was reported for 973 (90%) of 1079 patients with malaria, predominantly Plasmodium falciparum acquired in sub-Saharan Africa. Of 584 (54%) with malaria chemoprophylaxis information, 92% took none or incomplete courses. Thirteen deaths were reported, over half of which were due to malaria; others succumbed to pneumonia, typhoid fever, rabies, melioidosis and pyogenic abscess., Conclusions: Diarrheal illness was a major cause of morbidity. Malaria contributed substantial morbidity and mortality, particularly among business travelers to sub-Saharan Africa. Underuse or non-use of chemoprophylaxis contributed to malaria cases. Deaths in business travelers could be reduced by improving adherence to malaria chemoprophylaxis and targeted vaccination for vaccine-preventable diseases. Pre-travel advice is indicated for business travelers and is currently under-utilized and needs improvement.

Background: Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of isoniazid (9H). A 3-month course of weekly isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain., Aim: Cost-analysis of standard and short-course therapy for LTBI in an Australian context., Methods: Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily isoniazid or a 12-week course of weekly isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine., Results: Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01)., Conclusions: This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia., (© 2017 Royal Australasian College of Physicians.)

Background: Information on the impact of hygiene interventions on severe outcomes is limited. As a pre-specified secondary outcome of a cluster-randomized controlled trial among >400 000 low-income residents in Dhaka, Bangladesh, we examined the impact of cholera vaccination plus a behaviour change intervention on diarrhoea-associated hospitalization., Methods: Ninety neighbourhood clusters were randomly allocated into three areas: cholera-vaccine-only; vaccine-plus-behaviour-change (promotion of hand-washing with soap plus drinking water chlorination); and control. Study follow-up continued for 2 years after intervention began. We calculated cluster-adjusted diarrhoea-associated hospitalization rates using data we collected from nearby hospitals, and 6-monthly census data of all trial households., Results: A total of 429 995 people contributed 500 700 person-years of data (average follow-up 1.13 years). Vaccine coverage was 58% at the start of analysis but continued to drop due to population migration. In the vaccine-plus-behaviour-change area, water plus soap was present at 45% of hand-washing stations; 4% of households had detectable chlorine in stored drinking water. Hospitalization rates were similar across the study areas [events/1000 person-years, 95% confidence interval (CI), cholera-vaccine-only: 9.4 (95% CI: 8.3-10.6); vaccine-plus-behaviour-change: 9.6 (95% CI: 8.3-11.1); control: 9.7 (95% CI: 8.3-11.6)]. Cholera cases accounted for 7% of total number of diarrhoea-associated hospitalizations., Conclusions: Neither cholera vaccination alone nor cholera vaccination combined with behaviour-change intervention efforts measurably reduced diarrhoea-associated hospitalization in this highly mobile population, during a time when cholera accounted for a small fraction of diarrhoea episodes. Affordable community-level interventions that prevent infection from multiple pathogens by reliably separating faeces from the environment, food and water, with minimal behavioural demands on impoverished communities, remain an important area for research., (© The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association)

Background: Zika virus (ZIKV) was first isolated in Africa; decades later, caused large outbreaks in the Pacific, and is considered endemic in Asia. We aim to describe ZIKV disease epidemiology outside the Americas, the importance of travelers as sentinels of disease transmission, and discrepancies in travel advisories from major international health organizations., Methods and Findings: This descriptive analysis using GeoSentinel Surveillance Network records involves sixty-four travel and tropical medicine clinics in 29 countries. Ill returned travelers with a confirmed or probable diagnosis of ZIKV disease acquired in Africa, Asia and the Pacific seen between 1 January 2012 and 31 December 2016 are included, and the frequencies of demographic, trip, and diagnostic characteristics described. ZIKV was acquired in Asia (18), the Pacific (10) and Africa (1). For five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon), GeoSentinel patients were sentinel markers of recent Zika activity. Additionally, the first confirmed ZIKV infection acquired in Kiribati was reported to GeoSentinel (2015), and a probable case was reported from Timor Leste (April 2016), representing the only case known to date. Review of Zika situation updates from major international health authorities for country risk classifications shows heterogeneity in ZIKV country travel advisories., Conclusions: Travelers are integral to the global spread of ZIKV, serving as sentinel markers of disease activity. Although GeoSentinel data are collected by specialized clinics and do not capture all imported cases, we show that surveillance of imported infections by returned travelers augments local surveillance system data regarding ZIKV epidemiology and can assist with risk categorization by international authorities. However, travel advisories are variable due to risk uncertainties.

Travellers visiting friends and relatives (VFRs) often have complex pre-travel needs. We identified the characteristics, destinations, vaccinations and pre-travel advice provided to VFRs and compared these with non-VFR travellers. The significant differences we found suggest that future research should focus on improving the uptake of recommended interventions in VFR travellers., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: More than 30,000 malaria cases are reported annually among international travellers. Despite improvements in malaria control, malaria continues to threaten travellers due to inaccurate perception of risk and sub-optimal pre-travel preparation., Methods: Records with a confirmed malaria diagnosis after travel from January 2003 to July 2016 were obtained from GeoSentinel, a global surveillance network of travel and tropical medicine providers that monitors travel-related morbidity. Records were excluded if exposure country was missing or unascertainable or if there was a concomitant acute diagnosis unrelated to malaria. Records were analyzed to describe the demographic and clinical characteristics of international travellers with malaria., Results: There were 5689 travellers included; 325 were children <18 years. More than half (53%) were visiting friends and relatives (VFRs). Most (83%) were exposed in sub-Saharan Africa. The median trip duration was 32 days (interquartile range 20-75); 53% did not have a pre-travel visit. More than half (62%) were hospitalized; children were hospitalized more frequently than adults (73 and 62%, respectively). Ninety-two per cent had a single Plasmodium species diagnosis, most frequently Plasmodium falciparum (4011; 76%). Travellers with P. falciparum were most frequently VFRs (60%). More than 40% of travellers with a trip duration ≤7 days had Plasmodium vivax. There were 444 (8%) travellers with severe malaria; 31 children had severe malaria. Twelve travellers died., Conclusion: Malaria remains a serious threat to international travellers. Efforts must focus on preventive strategies aimed on children and VFRs, and chemoprophylaxis access and preventive measure adherence should be emphasized.

Background: Travel medicine needs are changing. New patterns of travel, including greater travel by individuals from emerging economies with different values in costs, risks and benefits, must be considered. This review aims to (1) highlight selected studies that have been published that address previously identified gaps in knowledge; (2) propose possible ways to consider questions regarding travel medicine practice for travelers from emerging economies, underscoring priorities for research focusing on these important populations; (3) highlight potential deficiencies in relevance of current international guidelines as they pertain to travelers from emerging economies; (4) frame research questions for travelers from emerging economies and (5) consider roles for ISTM in closing the gap., Methods: We reviewed past travel medicine research priorities published in 2010 to identify publications that responded to some research questions posed. We also reviewed CDC and WHO recommendations and assessed their applicability to travelers from emerging economies., Results: Recent publications have responded to some research questions, but gaps remain and new questions have emerged. Re-framing of several key research questions is needed for travelers from emerging economies., Discussion: A new challenge looms for traditional travel medicine fields to identify and attend to knowledge and guideline gaps, particularly to rethink questions regarding travel medicine to make them relevant for travelers from emerging economies. The International Society of Travel Medicine is well positioned to assist emerging economies assess their resources and needs, formulate research priorities and tailor the development of travel medicine into a framework aligned to their requirements., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

AbstractUniversal access to safe drinking water is a global priority. To estimate the annual disease burden of campylobacteriosis, nontyphoidal salmonellosis, cryptosporidiosis, giardiasis, and norovirus attributable to waterborne transmission in Australia, we multiplied regional World Health Organization (WHO) estimates of the proportion of cases attributable to waterborne transmission by estimates of all-source disease burden for each study pathogen. Norovirus was attributed as causing the most waterborne disease cases (479,632; 95% uncertainty interval [UI]: 0-1,111,874) followed by giardiasis and campylobacteriosis. The estimated waterborne disability-adjusted life year (DALY) burden for campylobacteriosis (2,004; 95% UI: 0-5,831) was 7-fold greater than other study pathogens and exceeded the WHO guidelines for drinking water quality (1 × 10 -6 DALY per person per year) by 90-fold. However, these estimates include disease transmitted via either drinking or recreational water exposure. More precise country-specific and drinking water-specific attribution estimates would better define the health burden from drinking water and inform changes to treatment requirements.

Autoimmune inflammatory rheumatic diseases (AIIRD), such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities and the use of immunosuppressive conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and more recently, targeted synthetic DMARDs and biologic DMARDs that block specific pro-inflammatory enzymes, cytokines or cell types. The use of these various DMARDs has revolutionised the treatment of AIIRD. This has led to a marked improvement in quality of life for AIIRD patients, who often now travel for prolonged periods. Many infections are preventable with vaccination. However, as protective immune responses induced by vaccination may be impaired by immunosuppression, where possible, vaccination may need to be performed prior to initiation of immunosuppression. Vaccination status should also be reviewed when planning overseas travel. Limited data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult. However, a vaccination history should be part of the initial work-up in all AIIRD patients. Those caring for AIIRD patients should regularly consider vaccination to prevent infection within the practicalities of routine clinical practice., (© 2017 Royal Australasian College of Physicians.)

Background: Vaccination is a safe and effective public health intervention that not only protects individual travellers from vaccine-preventable diseases (VPDs), but prevents them from becoming a source of disease in their destination and on their return. Obtaining an accurate vaccination history from travellers during a pre-travel review can be difficult; serology may be used to identify patients who are non-immune to specific diseases in order to guide vaccination requirements. Clinically relevant data about the usefulness of serology in this setting are lacking. We performed a retrospective audit of pre-travel VPD serology requested by practitioners of a busy community-based travel clinic., Methods: All serological results for measles, mumps, rubella, varicella zoster virus, hepatitis A and B requested over a 5-year period were extracted and analysed. Results were stratified by gender and year of birth and compared using Stata., Results: Four thousand four hundred and fifty-one serological assays from 1445 individual were assessed. Overall, 47% of patients tested had at least one negative serological result. High rates of seropositivity for measles, mumps and rubella were seen in those born prior to 1966 but >10% of travellers born after 1966 lacked serological evidence of protection against these diseases. Hepatitis A and B serological results revealed broadly lower rates of immunity in our community likely reflecting the absence of these vaccines from historical vaccine protocols., Conclusions: Serology can be a useful tool in the identification of non-immune travellers to enable targeted vaccination prior to travel. We recommend that travel health clinicians assess patients' vaccination and infection histories, and strongly consider serology or vaccination where there is doubt about immunity. This will help protect the traveller and prevent importation of disease into destination or home communities., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Objectives: To describe the epidemiology, clinical and laboratory features and outcomes of dengue in returned Australian travellers, applying the revised WHO dengue classification (2009) to this population., Design, Setting and Participants: Retrospective case series analysis of confirmed dengue cases hospitalised at one of four Australian tertiary hospitals, January 2012 - May 2015., Main Outcome Measures: Clinical features, laboratory findings and outcomes of patients with dengue; dengue classification according to 2009 WHO guidelines., Results: 208 hospitalised patients (median age, 32 years; range, 4-76 years) were included in the study. Dengue was most frequently acquired in Indonesia (94 patients, 45%) and Thailand (40, 19%). The most common clinical features were fever (98% of patients) and headache (76%). 84 patients (40%) met the WHO criteria for dengue with warning signs, and one the criteria for severe dengue; the most common warning signs were mucosal bleeding (44 patients, 21%) and abdominal pain (43, 21%). Leukopenia (176 patients, 85%), thrombocytopenia (133, 64%), and elevated liver enzyme levels (154, 76%) were the most common laboratory findings. 46 patients (22%) had serological evidence of previous exposure to dengue virus. WHO guidelines were documented as a management benchmark in ten cases (5%); 46 patients (22%) received non-steroidal anti-inflammatory drugs (NSAIDs)., Conclusions: A significant proportion of returning Australian travellers hospitalised for dengue have unrecognised warning signs of severe disease. Many received NSAIDs, which can increase the risk of haemorrhage in dengue. As travel to Asia from Australia continues to increase, it is vital for averting serious outcomes that clinicians can recognise and manage dengue.

We reviewed key attributes (flexibility, data quality and timeliness) of Australia's National Notifiable Diseases Surveillance System (NNDSS) over its first 21 years. Cases notified to NNDSS from 1991 to 2011 were examined by jurisdiction (six states and two territories) and sub-period to describe changes in the number of notifiable diseases, proportion of cases diagnosed using PCR tests, data quality (focusing on data completeness), and notification delays. The number of notifiable diseases increased from 37 to 65. The proportion of cases diagnosed by PCR increased from 1% (1991-1997) to 49% (2005-2011). Indigenous status was complete for only 44% notifications (jurisdictional range 19-87%). Vaccination status was complete for 62% (jurisdictional range 32-100%) and country of acquisition for 24% of relevant cases. Data completeness improved over the study period with the exception of onset date. Median time to notification was 8 days (interquartile range 4-17 days, jurisdictional range 5-15 days); this decreased from 11 days (1991-1997) to 5 days (2005-2011). NNDSS expanded during the study period. Data completeness and timeliness improved, likely related to mandatory laboratory reporting and electronic data transfer. A nationally integrated electronic surveillance system, including electronic laboratory reporting, would further improve infectious disease surveillance in Australia.

Introduction: Diarrhoea is a leading cause of death globally, mostly occurring as a result of insufficient or unsafe water supplies, inadequate sanitation and poor hygiene. Our study aims to investigate the impact of a community-level hygiene education program and a water quality intervention using riverbank filtration (RBF) technology on diarrhoeal prevalence., Methods and Analysis: We have designed a stepped wedge cluster randomised trial to estimate the health impacts of our intervention in 4 rural villages in Karnataka, India. At baseline, surveys will be conducted in all villages, and householders will receive hygiene education. New pipelines, water storage tanks and taps will then be installed at accessible locations in each village and untreated piped river water will be supplied. A subsequent survey will evaluate the impact of hygiene education combined with improved access to greater water volumes for hygiene and drinking purposes (improved water quantity). Villages will then be randomly ordered and RBF-treated water (improved water quality) will be sequentially introduced into the 4 villages in a stepwise manner, with administration of surveys at each time point. The primary outcome is a 7-day period prevalence of self-reported diarrhoea. Secondary outcomes include self-reported respiratory and skin infections, and reported changes in hygiene practices, household water usage and water supply preference. River, tank and tap water from each village, and stored water from a subset of households, will be sampled to assess microbial and chemical quality., Ethics and Dissemination: Ethics approval was obtained from the Monash University Human Research Ethics Committee in Australia and The Energy and Resources Institute Institutional Ethics Committee in India. The results of the trial will be presented at conferences, published in peer-reviewed journals and disseminated to relevant stakeholders. This study is funded by an Australian National Health and Medical Research Council (NHMRC) project grant., Trial Registration Number: ACTRN12616001286437; pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background.: Travellers' diarrhoea (TD) is a common problem, affecting millions of tourists each year and creating a large economic burden. Risk factors for TD are known and guidelines exist to assist practitioners in advising travellers on how to prevent and treat TD. However, data are lacking regarding actual prescribing practices or approaches used in TD management. This study aims to establish a baseline which identifies uniformities and diversities in practice., Methods.: An online survey created using the SurveyMonkey tool was developed to test respondent approaches to TD pre-travel management. An invitation to participate in the survey was distributed early 2016 through selected Australian and New Zealand speciality travel medicine centres and through the electronic mailing list of the International Society of Travel Medicine (ISTM). Descriptive statistics and analyses using Chi Square analysis and two-sided Fishers exact tests for significance were used., Results.: Three hundred and sixty-four completed or partially completed surveys were collected from respondents in 23 countries. Approach to TD, antibiotic choice and management of four different clinical scenarios were assessed, with analyses focused on identifying significant differences in approach according to region of practice, professional background and level of experience. The responses to the clinical scenarios suggest most uniformity in recommended treatment strategies in clearly mild or severe disease, and greater variability in moderate disease., Conclusions.: There is practice diversity in the discussion of preventative techniques and prescribing of self-treatment medications for TD, especially for moderate TD disease. Evidence-based guidelines that address the competing issues of patient health and morbidity vs the risk of colonization with resistant organisms may lead to more consistent antibiotic prescribing practices., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

In this work we explore the temporal dynamics of spatial heterogeneity during the process of tumorigenesis from healthy tissue. We utilize a spatial stochastic model of mutation accumulation and clonal expansion in a structured tissue to describe this process. Under a two-step tumorigenesis model, we first derive estimates of a non-spatial measure of diversity: Simpson's Index, which is the probability that two individuals sampled at random from the population are identical, in the premalignant population. We next analyze two new measures of spatial population heterogeneity. In particular we study the typical length scale of genetic heterogeneity during the carcinogenesis process and estimate the extent of a surrounding premalignant clone given a clinical observation of a premalignant point biopsy. This evolutionary framework contributes to a growing literature focused on developing a better understanding of the spatial population dynamics of cancer initiation and progression.

Introduction: Sepsis is a leading global cause of morbidity and mortality, and is more common at the extremes of age. Moreover, the cost of in-hospital care for elderly patients with sepsis is significant. There are indications from experimental and observational studies that aspirin may reduce inflammation associated with infection. This paper describes the rationale and design of the AspiriN To Inhibit SEPSIS (ANTISEPSIS) trial, a substudy of ASPirin in Reducing Events in the Elderly (ASPREE). ANTISEPSIS primarily aims to determine whether low-dose aspirin reduces sepsis-related deaths in older people. Additionally, it will assess whether low-dose aspirin reduces sepsis-related hospitalisations and sepsis-related Intensive Care Unit (ICU) admissions., Methods and Analysis: ASPREE is a double-blinded, randomised, placebo-controlled primary prevention trial that will determine whether daily low-dose aspirin extends disability-free longevity in 19 000 healthy older people recruited in Australia and the USA. The ANTISEPSIS substudy involves additional ASPREE trial data collection to assess the impact of daily low-dose aspirin on sepsis-related events in the 16 703 ASPREE participants aged 70 years and over, recruited in Australia. The intervention is a daily 100 mg dose of enteric-coated aspirin versus matching placebo, with 1:1 randomisation. The primary outcome for the ANTISEPSIS substudy is the incidence of sepsis-related death in eligible patients. The incidence of sepsis-related hospital and ICU admissions are secondary outcomes. ANTISEPSIS is to be conducted between 2012 and 2018., Discussion: This substudy will determine whether aspirin, an inexpensive and accessible therapy, safely reduces sepsis-related deaths and hospitalisations in older Australians. If shown to be the case, this would have profound effects on the health of older Australians., Trial Registration Number: Pre-results, ACTRN12613000349741., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Zika virus has spread rapidly in the Americas and has been imported into many nonendemic countries by travelers., Objective: To describe clinical manifestations and epidemiology of Zika virus disease in travelers exposed in the Americas., Design: Descriptive, using GeoSentinel records., Setting: 63 travel and tropical medicine clinics in 30 countries., Patients: Ill returned travelers with a confirmed, probable, or clinically suspected diagnosis of Zika virus disease seen between January 2013 and 29 February 2016., Measurements: Frequencies of demographic, trip, and clinical characteristics and complications., Results: Starting in May 2015, 93 cases of Zika virus disease were reported. Common symptoms included exanthema (88%), fever (76%), and arthralgia (72%). Fifty-nine percent of patients were exposed in South America; 71% were diagnosed in Europe. Case status was established most commonly by polymerase chain reaction (PCR) testing of blood and less often by PCR testing of other body fluids or serology and plaque-reduction neutralization testing. Two patients developed Guillain-Barré syndrome, and 3 of 4 pregnancies had adverse outcomes (microcephaly, major fetal neurologic abnormalities, and intrauterine fetal death)., Limitation: Surveillance data collected by specialized clinics may not be representative of all ill returned travelers, and denominator data are unavailable., Conclusion: These surveillance data help characterize the clinical manifestations and adverse outcomes of Zika virus disease among travelers infected in the Americas and show a need for global standardization of diagnostic testing. The serious fetal complications observed in this study highlight the importance of travel advisories and prevention measures for pregnant women and their partners. Travelers are sentinels for global Zika virus circulation and may facilitate further transmission., Primary Funding Source: Centers for Disease Control and Prevention, International Society of Travel Medicine, and Public Health Agency of Canada.

Overwhelming post-splenectomy infection (OPSI) is a serious complication of asplenia and is associated with encapsulated organisms, most commonly Streptococcus pneumoniae, but also Haemophilus influenzae and Neisseria meningitidis. We aimed to estimate the risk of infection in this patient group. We reviewed data collected by the Victorian Spleen Registry in Australia. On registration, all patients are asked about significant infections requiring admission to hospital for intravenous antibiotics; those requiring admission to ICU were defined as OPSI. In the 3274 asplenic patients registered 492 patients reported at least one episode of infection. There were 47 episodes of OPSI requiring intensive care (incidence rate 1·11/1000 patient-years). The risk of OPSI was highest in older patients, and there were no statistically significant differences in incidence by reason for splenectomy except for a higher rate in patients with medical hyposplenia. This study reinforces that post-splenectomy infection is a clinically significant but uncommon complication, and that fulminant infection requiring intensive care is a minority of all infections.

Background: Australia is a high-income country with a well established and largely publicly funded health-care system. However, some populations within Australia have shorter life expectancy and worse health outcomes than others. We explored geographical variations and sociodemographic inequities in infectious disease notifications in Australia., Methods: In this retrospective study, we analysed National Notifiable Diseases Surveillance System (NNDSS) notifications from 1991-2011 (n=2·4 million). We assessed the effect of socioeconomic disadvantage and remoteness of residence on national notification incidence. We calculated Gini coefficients, adjusted relative risks (aRRs), population attributable fractions (PAFs), and attributable notifications. We reported aRRs for Indigenous status in three jurisdictions with more than 75% completeness of Indigenous status reporting from the Northern Territory, South Australia, and Western Australia., Findings: Of the eight most commonly notified diseases from Jan 1, 1991, to Dec 31, 2011, gonococcal infection was the most geographically unequal and campylobacteriosis was the most evenly distributed across the country. Overall, notification incidence was higher in remote and very remote areas than in major cities (aRR 3·37), and higher in the most socioeconomically disadvantaged quintiles compared with less disadvantaged quintiles (aRR 1·15). The PAF for socioeconomic disadvantage was high for blood-borne viral hepatitis but decreased in other disease groups. In 2011, sexually transmitted infections had 11 093 notifications attributed to remoteness and 5597 notifications attributable to socioeconomic disadvantage. Notification incidence was higher in Indigenous than in non-Indigenous Australians (aRR 5·3)., Interpretation: All diseases had differing geographical concentration and sociodemographic risk. Overall, sociodemographic inequities in infectious disease notifications have decreased, but remain unacceptably high. National communicable disease control is complex, requiring both targeted and population-wide interventions., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We reviewed the first 21 years (1991-2011) of Australia's National Notifiable Diseases Surveillance System (NNDSS). All nationally notified diseases (except HIV/AIDS and Creutzfeldt-Jakob disease) were analysed by disease group (n = 8), jurisdiction (six states and two territories), Indigenous status, age group and notification year. In total, 2 421 134 cases were analysed. The 10 diseases with highest notification incidence (chlamydial infection, campylobacteriosis, varicella zoster, hepatitis C, influenza, pertussis, salmonellosis, hepatitis B, gonococcal infection, and Ross River virus infection) comprised 88% of all notifications. Annual notification incidence was 591 cases/100 000, highest in the Northern Territory (2598/100 000) and in children aged <5 years (698/100 000). A total of 8·4% of cases were Indigenous Australians. Notification incidence increased by 6·4% per year (12% for sexually transmissible infections and 15% for vaccine-preventable diseases). The number of notifiable diseases also increased from 37 to 65. The number and incidence of notifications increased throughout the study period, partly due to addition of diseases to the NNDSS and increasing availability of sensitive diagnostic tests. The most commonly notified diseases require a range of public health responses addressing high-risk sexual and drug-use behaviours, food safety and immunization. Our results highlight populations with higher notification incidence that might require tailored public health interventions.

Current seasonal influenza vaccines require regular updates due to antigenic drift causing loss of effectiveness and therefore providing little or no protection against novel influenza A subtypes. Next generation vaccines capable of eliciting CD8(+) T cell (CTL) mediated cross-protective immunity may offer a long-term alternative strategy. However, measuring pre- and existing levels of CTL cross-protection in humans is confounded by differences in infection histories across individuals. During 2000-2003, H1N2 viruses circulated persistently in the human population for the first time and we hypothesized that the viral nucleoprotein (NP) contained novel CTL epitopes that may have contributed to the survival of the viruses. This study describes the immunogenic NP peptides of H1N1, H2N2, and H3N2 influenza viruses isolated from humans over the past century, 1918-2003, by comparing this historical dataset to reference NP peptides from H1N2 that circulated in humans during 2000-2003. Observed peptides sequences ranged from highly conserved (15%) to highly variable (12%), with variation unrelated to reported immunodominance. No unique NP peptides which were exclusive to the H1N2 viruses were noted. However, the virus had inherited the NP from a recently emerged H3N2 variant containing novel peptides, which may have assisted its persistence. Any advantage due to this novelty was subsequently lost with emergence of a newer H3N2 variant in 2003. Our approach has potential to provide insight into the population context in which influenza viruses emerge, and may help to inform immunogenic peptide selection for CTL-inducing influenza vaccines. J. Med. Virol. 88:1725-1732, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Unlabelled: In this work we review past articles that have mathematically studied cancer heterogeneity and the impact of this heterogeneity on the structure of optimal therapy. We look at past works on modeling how heterogeneous tumors respond to radiotherapy, and take a particularly close look at how the optimal radiotherapy schedule is modified by the presence of heterogeneity. In addition, we review past works on the study of optimal chemotherapy when dealing with heterogeneous tumors., Reviewers: This article was reviewed by Thomas McDonald, David Axelrod, and Leonid Hanin.

Much of the travel medicine literature focuses on travel to 'developing' regions by travellers from 'developed' regions; however literature about travel to developed regions is scarce. This article examines presentations to a travel medicine clinic over a 17-year period with illnesses resulting from travel to developed regions. From a cohort of general presentations to the clinic of 1077 patients, 85 patients acquired infections due to travel to developed regions, with a total of 99 infectious diagnoses made. This serves to highlight the risk of infectious disease even among travel to only developed regions, and the importance of travel advice in these situations., (© International Society of Travel Medicine, 2016.. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)