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Study Objectives: Periodic limb movements (PLMs) of sleep, which may be linked to increased vascular events via nighttime sympathetic overactivity, have shown associations with cerebral small vessel disease (CSVD) in small studies. This study examined the relationship between PLMs and CSVD in a larger cohort, accounting for comorbidities., Methods: Patients with first-ever stroke or transient ischemic attack (TIA) were retrospectively analyzed. Polysomnography assessed the PLM index (PLMI) and PLM arousal index (PLMAI). CSVD was measured using radiographic markers, including the Fazekas score, total age-related white matter changes (ARWMC) score, microbleed counts, and lacunar infarcts. Multivariable regression models analyzed the association between an elevated PLMI and PLMAI with CSVD markers., Results: This study included 86 patients (mean age 62.2±14.3 years, 66.3% male, mean BMI 28.1±5.7), 36 with a PLMI ≥5 (41.9%) and 11 with a PLMAI ≥5 (12.8%). Regression analyses showed that PLMI ≥5 and PLMAI ≥5 both predicted increased Fazekas and ARWMC total scores after adjusting for age, sex, BMI, and other comorbidities. Sensitivity analyses using age- and sex-specific PLMI cut-offs also showed that a PLMI exceeding the upper limit of normal predicted an increased Fazekas score and approached significance for the ARWMC score. PLMI was not significantly associated with cerebral microbleeds or lacunar infarcts., Conclusions: In patients with first-ever minor stroke and TIA, a significant association was observed between PLMI and PLMAI with white matter hyperintensities (WMHs) after adjusting for confounders. Future studies may help determine the directionality of this association and whether PLMs independently predict CSVD., (© The Author(s) 2025. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Parasitic helminths secrete extracellular vesicles (EVs) into their host tissues to modulate immune responses, but the underlying mechanisms are poorly understood. We demonstrate that Ascaris EVs are efficiently internalised by monocytes in human peripheral blood mononuclear cells and increase the percentage of classical monocytes. Furthermore, EV treatment of monocytes induced a novel anti-inflammatory phenotype characterised by CD14 + , CD16 - , CC chemokine receptor 2 (CCR2 - ) and programmed death-ligand 1 (PD-L1) + cells. In addition, Ascaris EVs induced T cell anergy in a monocyte-dependent mechanism. Targeting professional phagocytes to induce both direct and indirect pathways of immune modulation presents a highly novel and efficient mechanism of EV-mediated host-parasite communication. Intra-peritoneal administration of EVs induced protection against gut inflammation in the dextran sodium sulphate model of colitis in mice. Ascaris EVs were shown to affect circulating immune cells and protect against gut inflammation; this highlights their potential as a subject for further investigation in inflammatory conditions driven by dysregulated immune responses. However, their clinical translation would require further studies and careful consideration of ethical implications., (© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Background: Tuberculosis in the UK is more prevalent in people with social risk factors- e.g. previous incarceration, homelessness - and in migrants from TB endemic countries. The management of TB infection is part of TB elimination strategies, but is challenging to provide to socially excluded groups and the evidence base for effective interventions is small., Methods: We evaluated a TB infection screening and treatment programme provided by a peer-led service (Find&Treat) working in inclusion health settings (e.g. homeless hostels) in London. IGRA (interferon-gamma release assay) testing and TB infection treatment were offered to eligible adults using a community-based model. The primary outcome was successful progression through the cascade of care. We also evaluated socio-demographic characteristics associated with a positive IGRA., Results: 42/312 (13.5%) participants had a positive IGRA and no one had evidence of active TB. 35/42 completed a medical evaluation; 22 started treatment, and 17 completed treatment. Having a positive IGRA was associated with previous incarceration and being born outside of the UK., Discussion: Provision of TB infection diagnosis and management to this socially excluded population has several challenges including maintaining people in care and drug-drug interactions. Peer-support workers provided this service safely and effectively with appropriate support. Further work to generate data to inform risks and benefits of treatment for TB infection in this group is needed to facilitate joint decision making., (© 2024. The Author(s).)

Rationale: The association of obstructive sleep apnea (OSA) with idiopathic intracranial hypertension (IIH) remains unclear, and few studies have used objective in-laboratory polysomnography (PSG) data. Thus, we used PSG data to examine the: 1) association between OSA, and its severity, with IIH and 2) sex differences in OSA severity in those with and without IIH., Methods: We retrospectively analyzed diagnostic PSG data from January 2015 to August 2023 for patients who were diagnosed with IIH by a neuro-ophthalmologist using the modified Dandy criteria. We selected three age, sex, and body mass index (BMI) matched controls for each IIH patient. We examined potential associations of IIH with OSA using regression. Sex differences were analyzed using ANOVA., Results: Of 3482 patients who underwent PSG, we analyzed 78 IIH patients (16 males) and 234 matched controls (48 males). Five (6.4 %) IIH and 39 (16.7 %) control patients had OSA, defined as AHI≥15. After adjusting for age, sex, BMI, and comorbidities, IIH was negatively associated with the presence of OSA (OR 0.29, 95%CI 0.10-0.87, p = 0.03). However, models that adjusted for acetazolamide use, with or without comorbidities, showed no significant relationship with OSA (OR 0.31, p = 0.20). Males with IIH had a significantly higher age (p = 0.020), OSA severity (p = 0.032), and arousal index (p = 0.046) compared to females with IIH., Conclusions: IIH treated with acetazolamide was not an independent risk factor for OSA presence or severity. The presence of IIH treated with acetazolamide likely does not warrant routine screening for OSA, but related risk factors may identify appropriate patients., Competing Interests: Declaration of competing interest Mark Boulos received consulting fees from Jazz pharmaceuticals, Paladin labs, and Eisai as well as medical equipment from Braebon and Interaxon. No other authors report any conflicts of interest other than below stated funding., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We evaluated a hepatitis B virus (HBV) screening programme, delivered by a specialist pan-London multidisciplinary outreach team, to understand population characteristics and care cascade among people who experience extreme social exclusion (Inclusion Health (IH) groups)., Methods: Point-of-care HBV screening was performed in temporary accommodation for people experiencing homelessness (PEH) and people seeking asylum (initial accommodation centres, IACs) via a mobile unit staffed by peers with lived experience, nurses, and doctors. We analysed demographics and HBV characteristics of adults screened between May 2020 and January 2022. We ascertained linkage-to-care (LTC), retention-in-care (RIC) and loss-to-follow-up (LTFU). People LTFU were contacted by peers to re-engage in care., Results: 2473 people were screened: 809 in IACs, 1664 in other temporary accommodation. Overall hepatitis B surface antigen (HBsAg) prevalence was 1.7% (43/2473), highest in IACs (3.5%, 28/809). LTC within 3 months was 56% (24/43) and RIC, 87% (26/30). LTC was higher when referred to a local IH-specialist hepatitis service, compared to other services (77%, 17/22 vs 33%, 7/21; p = 0.006). LTFU was 30% (13/43), reduced to 21% (9/43) after intervention by peers., Conclusion: Our findings support outreach screening among IH populations and peer-supported linkage to IH-specialist hepatitis services. We recommend increased HBV testing and HBV-specific IH specialist services., Competing Interests: Declaration of Competing Interest Philippa C. Matthews receives funding from GSK to support a PhD fellow in her team, outside of the work presented here. No other authors have competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Solid organ transplant recipients are at an increased risk of developing skin cancers due to chronic immunosuppression, particularly with calcineurin inhibitors. Tacrolimus is the most prescribed calcineurin inhibitor in this patient cohort, and understanding tacrolimus concentrations in the skin will facilitate the development of anti-cancer preventive and therapeutic strategies. Here, we show that in mice, tacrolimus blood levels peaked rapidly ∼1 h post last oral dose while skin levels rose more slowly and remained high for at least 6 h. Subsequently, tacrolimus skin and blood concentrations were assessed in 15 kidney transplant recipients. The mean age was 61 years, the average time post-transplant was 7 years (range 0-21 years) and 87% were male. The average skin sampling time post tacrolimus dosing was 6 h 32 min. Skin tacrolimus concentrations ranged from 7.1 ng/g to 71.2 ng/g and correlated with blood concentrations (r = 0.6). Mouse and human mean skin concentrations were in a similar range. Our data suggests that tacrolimus measurements in the blood may be used to approximate tacrolimus concentrations in the skin of kidney transplant recipients, and further exploited for the delivery of anti-cancer therapies designed to antagonize the immunosuppressive effects of tacrolimus in the skin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sartain, Viecelli, Veitch, Franklin, Dymock, Wells and Campbell.)

Background: Despite subsidised access to direct-acting antivirals (DAAs), hepatitis C (HCV) treatment uptake in Australia is declining. Interventions are needed to link people living with HCV to care and treatment. We implemented and measured effectiveness of a state-wide, health department-led, enhanced case management through the primary care practitioner for all HCV notifications, aiming to encourage and support treatment commencement., Methods: A randomised controlled trial compared enhanced case management, delivered by the health department to diagnosing clinicians, with standard of care using notifiable disease systems in Tasmania, Australia (2020-21). The intervention involved a nurse specialist contacting and providing support by telephone to primary care practitioners making an HCV notification. The primary outcome was the proportion of cases notified with chronic hepatitis C who commenced treatment within 12 weeks of notification. We allowed a 12-week extended follow-up period at the end of the study for participants with no outcomes., Results: Eighty-five primary care practitioners randomised to the intervention and 86 to standard of care arms notified 111 and 115 HCV cases, respectively. The proportion of cases notified with chronic hepatitis (HCV RNA detected) commencing treatment within 12 weeks was similar between study arms (41% vs 33%; p=0·51) and after extended study follow-up (65% vs 48%; p=0·18). RNA test completion was higher in the intervention than in standard of care arm (89% vs. 78%; p=0·03), while completing pre-treatment workup for chronic patients (65% vs. 64%; p=0·93) was similar., Conclusion: This was the first prospective randomised study of the utility of immediate HCV notification follow-up of primary care practitioners to enhance treatment uptake using disease notification surveillance data. We demonstrated improvement in HCV RNA testing and trend toward better engagement in care, but no significant increase in treatment uptake., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JSD, MS, and MH report investigator-initiated research funding to their institution from Gilead Science, and AbbVie. JSD reports honoraria for speaking to his institution from Gilead Sciences and AbbVie, and MS reports consultant fees from Gilead Sciences. JR reports honoraria for speaking from Gilead Sciences and AbbVie. AP has received investigator-initiated grant funding from Gilead Sciences, MSD, and Abbvie and speaker fees from Gilead Sciences for unrelated work., (Copyright © 2023. Published by Elsevier B.V.)

Study Objective: To assess the incidence of postoperative delirium and its outcomes in older non-cardiac surgical patients., Design: A systematic review and meta-analysis with multiple databases searched from inception to February 22, 2022., Setting: Postoperative assessments., Patients: Non-cardiac and non-neurological surgical patients aged ≥60 years with and without postoperative delirium. Included studies must report ≥1 postoperative outcome. Studies with a small sample size (N < 100 subjects) were excluded., Measurements: Outcomes comprised the pooled incidence of postoperative delirium and its postoperative outcomes, including mortality, complications, unplanned intensive care unit admissions, length of stay, and non-home discharge. For dichotomous and continuous outcomes, OR and difference in means were computed, respectively, with a 95% CI., Main Results: Fifty-four studies (20,988 patients, 31 elective studies, 23 emergency studies) were included. The pooled incidence of postoperative delirium was 19% (95% CI: 16%, 23%) after elective surgery and 32% (95% CI: 25%, 39%) after emergency surgery. In elective surgery, postoperative delirium was associated with increased mortality at 1-month (OR: 6.60; 95% CI: 1.58, 27.66), 6-month (OR: 5.69; 95% CI: 2.33, 13.88), and 1-year (OR: 2.87; 95% CI: 1.63, 5.06). The odds of postoperative complications, unplanned intensive care unit admissions, prolonged length of hospital stay, and non-home discharge were also higher in delirium cases. In emergency surgery, patients with postoperative delirium had greater odds of mortality at 1-month (OR: 3.56; 95% CI: 1.77, 7.15), 6-month (OR: 2.60; 95% CI: 1.88, 3.61), and 1-year (OR: 2.30; 95% CI: 1.77, 3.00)., Conclusions: Postoperative delirium was associated with higher odds of mortality, postoperative complications, unplanned intensive care unit admissions, length of hospital stay, and non-home discharge. Prevention and perioperative management of delirium may optimize surgical outcomes., Competing Interests: Declaration of Competing Interest Frances Chung: reports research support from the Ontario Ministry of Health Innovation Grant, ResMed Foundation, University Health Network Foundation, Consultant to Takeda, and STOP-Bang Questionnaire proprietary to University Health Network. All other authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus., Methods: In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure., Results: Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood., Conclusions: Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients., Competing Interests: Competing interests: The use of Q-2361 as disclosed in this study has been patented (WO2021248189), with JWW, BWD, AH, T-AC, RP, and KB as coinventors. All other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and surgery, vaccination against HPV is a promising therapeutic option with fewer side effects. A peptide derived from the HPV-16 E7 protein, called 8Qm, in combination with adjuvants showed promise as a therapeutic vaccine. Here, the ability of polymerized natural amino acids to act as a self-adjuvating delivery system as a therapeutic vaccine was investigated for the first time. Thus, 8Qm was conjugated to polyleucine by standard solid-phase peptide synthesis and self-assembled into nanoparticles or incorporated in liposomes. The liposome bearing the 8Qm conjugate significantly increased mice survival and decreased tumor growth after a single immunization. Further, these liposomes eradicated seven-day-old well-established tumors in mice. Dendritic cell (DC)-targeting moieties were introduced to further enhance vaccine efficacy, and the newly designed liposomal vaccine was tested in mice bearing 11-day-old tumors. Interestingly, these DCs-targeting moieties did not significantly improve vaccine efficacy, whereas the simple liposomal formulation of 8Qm-polyleucine conjugate was still effective in tumor eradication. In summary, a peptide-based anticancer vaccine was developed that stimulated strong cellular immune responses without the help of a classical adjuvant.

Introduction: Healthcare facilities are high-risk settings for coronavirus disease 2019 (COVID-19) transmission. Early in the COVID-19 pandemic, the first large healthcare-associated outbreak within Australia occurred in Tasmania. Several operational research studies were conducted amongst workers from the implicated hospital campus, to learn more about COVID-19 transmission., Methods: Healthcare workers (HCWs) from the implicated hospital campus were invited to complete an online survey and participate in a serology study. Blood samples for serological testing were collected at approximately 12 weeks (round one) and eight months (round two) after the outbreak. A descriptive analysis was conducted of participant characteristics, serology results, and longevity of antibodies., Results: There were 261 HCWs in round one, of whom 44 (17%) were polymerase chain reaction (PCR) confirmed outbreak cases; 129 of the 261 (49%) participated in round two, of whom 34 (27%) were outbreak cases. The prevalence of positive antibodies at round one was 15% (n = 38) and at round two was 12% (n = 15). There were 15 participants (12%) who were seropositive in both rounds, with a further 9% (n = 12) of round two participants having equivocal results after previously being seropositive. Six HCWs not identified as cases during the outbreak were seropositive in round one, with three still seropositive in round two. Of those who participated in both rounds, 68% (n = 88) were seronegative at both time points., Discussion: Our findings demonstrate that serological testing after this large healthcare-associated COVID-19 outbreak complemented the findings of earlier diagnostic testing, with evidence of additional infections to those diagnosed when use of PCR testing had been restricted. The results also provide evidence of persisting SARS-CoV-2 antibody response eight months after an outbreak in an unvaccinated population. The high proportion of HCWs who remained seronegative is consistent with low community transmission in Tasmania after this outbreak., (© Commonwealth of Australia CC BY-NC-ND.)

Introduction: Pregnancy associated osteoporosis (PAO) is a rare and complex condition. Its etiology is unclear, but possible predisposing factors include osteoporosis in a first degree relative, low body mass index, celiac or other malabsorption disorders, poor nutrition, low vitamin D and calcium intake, long-term use of medications associated with bone loss, physical inactivity, and prolonged amenorrhea. There is no standard for diagnosis or treatment. Diagnosis is typically made following reports of severe pain and imaging establishing the presence of fractures in vertebrae, pelvic structures, or the femoral neck. Research has focused on diagnosis and effective treatments. The absence of descriptive statistics and qualitative data about the presentation, recovery, and psychosocial dimensions of PAO represents a striking gap in the existing literature. The objectives for this preliminary study were to identify key features and the range of experiences of individuals with PAO to aid midwives, who are uniquely situated to identify the condition early in the postpartum course, and to inform future midwifery research on supporting recovery from this complex condition., Methods: A 39-47 question survey was developed in Qualtrics; questions were primarily quantitative. Members (N = 306) of a closed, international Osteoporosis and Pregnancy Facebook group were recruited with a post announcing the study and a link to the survey, followed by 2 reminders between June and August 2020. Data were analyzed in Qualtrics. Descriptive statistics were compiled. Qualitative data were analyzed using a grounded theory approach with both open and selective coding., Findings: Sixty-nine individuals (22% response rate) representing 12 countries responded to the survey, with most respondents from the United States, the United Kingdom, and Australia. Respondents frequently reported delays in diagnosis; only 4.4% of respondents were diagnosed within one month of the onset of fracture pain. Cessation of breastfeeding to reverse physiologic hypoestrogenemia and to stop calcium loss, dietary supplementation, orthopedic braces, and osteoanabolic medications or parathyroid hormone analogues were commonly reported treatment approaches. PAO has a prolonged impact on mobility and infant care. Six months from the onset of fracture pain, only 42% of respondents were physically able to care for their infants alone., Conclusion: PAO is a rare and complex condition in need of further research. Dismissal of pain and lack of knowledge about PAO are frequently encountered by those seeking care, which midwives may be able to mitigate with timely referrals to appropriate specialists. PAO often has a prolonged impact on the ability to care for an infant alone. This should be considered in the development of comprehensive care plans. The core competencies of the International Confederation of Midwives include assessing health status and screening for risks, facilitating individualized decision-making about care, and recognizing conditions outside midwifery scope of practice and referring appropriately (ICM 2019). As members of diverse health care teams, midwives may have opportunities to facilitate diagnosis through timely referral, encourage collaborative decision-making on treatment and future perinatal care, and weigh in on the impact of individual social determinants of health., Competing Interests: Conflicts of Interest None declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The objective of the study was to characterize the baseline intra-individual and inter-individual variability of immune cell subsets within abdominoplasty skin specimens., Methods: Abdominoplasty biopsies were taken from 5 patients and analysed using the Vectra 3 automated quantitative pathology imaging system with inForm software., Results: Adjacent skin regions demonstrated intra-patient variability in immune subset counts ranging from 1- to 5-fold. Inter-variability between patients was approximately 2- to 7-fold for most subsets, except for HLA-DR + antigen presenting cells, which varied 19-fold., Conclusions: Our data highlight the importance of including multiple patients and multiple patient samples when designing dermatological studies that utilise abdominoplasty skin., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Termedia & Banach.)

Introduction: By subsidising access to direct acting antivirals (DAAs) for all people living with hepatitis C (HCV) in 2016, Australia is positioned to eliminate HCV as a public health threat. However, uptake of DAAs has declined over recent years and new initiatives are needed to engage people living with HCV in care. Active follow-up of HCV notifications by the health department to the notifying general practitioner (GP) may increase treatment uptake. In this study, we explore the impact of using hepatitis C notifications systems to engage diagnosing GPs and improve patient access to treatment., Methods and Analysis: This study is a randomised controlled trial comparing enhanced case management of HCV notifications with standard of care. The intervention includes phone calls from a department of health (DoH) specialist HCV nurse to notifying GPs and offering HCV management support. The level of support requested by the GP was graded in complexity: level 1: HCV information only; level 2: follow-up testing advice; level 3: prescription support including linkage to specialist clinicians and level 4: direct patient contact. The study population includes all GPs in Tasmania who notified HCV diagnosis to the DoH between September 2020 and December 2021. The primary outcome is proportion of HCV cases who initiate DAAs after 12 weeks of HCV notification to the health department. Secondary outcomes are proportion of HCV notifications that complete HCV RNA testing, treatment workup and treatment completion. Multiple logistic regression modelling will explore factors associated with the primary and secondary outcomes. The sample size required to detect a significant difference for the primary outcome is 85 GPs in each arm with a two-sided alpha of 0.05% and 80% power., Ethics and Dissemination: The study was approved by University of Tasmania's Human Research Ethics Committee (Protocol ID: 18418) on 17 December 2019. Results of the project will be presented in scientific meetings and published in peer-reviewed journals., Trial Registration Number: NCT04510246., Trial Progression: The study commenced recruitment in September 2020 and end of study expected December 2021., Competing Interests: Competing interests: JD, MAS and MH report investigator-initiated research funding to their institution from Gilead Science, AbbVie and Merck. JD reports honoraria for speaking to his institution from Gilead Sciences and AbbVie and MAS reports consultant fees from Gilead Sciences. AEP has received investigator-initiated grant funding from Gilead Sciences, MSD and Abbvie and speaker fees from Gilead Sciences for unrelated work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Problem: One month after the initial case of coronavirus disease 2019 (COVID-19) in Tasmania, an island state of Australia, two health-care workers (HCWs) from a single regional hospital were notified to public health authorities following positive tests for SARS-CoV-2 nucleic acid. These were the first recognized cases in an outbreak that overwhelmed the hospital's ability to function., Context: The outbreak originated from two index cases. Both had returned to Tasmania following travel on a cruise ship and required hospital admission for management of COVID-19. A total of 138 cases were subsequently linked to this outbreak: 81 HCWs (most being nurses) and 23 patients across three hospitals, one resident of an aged-care facility and 33 close contacts., Action: The outbreak was controlled through the identification and isolation of cases, identification and quarantining of close contacts and their household members, closure of the affected facilities and community-level restrictions to reduce social mixing in the affected region., Lessons Learnt: Factors that were likely to have contributed to ongoing transmission in this setting included workplace practices that prevented adequate physical distancing, attending work while symptomatic, challenges in rapidly identifying contacts, mobility of staff and patients between facilities, and challenges in the implementation of infection control practices., Discussion: Many commonly accepted hospital practices before the COVID-19 pandemic amplified the outbreak. The lessons learnt from this investigation changed work practices for HCWs and led to wider public health interventions in the management of potential primary and secondary contacts., ((c) 2021 The authors; licensee World Health Organization.)

Objective: We undertook an integrated analysis of genomic and epidemiological data to investigate a large health-care-associated outbreak of coronavirus disease 2019 (COVID-19) and to better understand the epidemiology of COVID-19 cases in Tasmania, Australia., Methods: Epidemiological data collected on COVID-19 cases notified in Tasmania between 2 March and 15 May 2020, and positive samples of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or RNA extracted from the samples were included. Sequencing was conducted by tiled amplicon polymerase chain reaction with ARTIC v1 or v3 primers and Illumina sequencing. Consensus sequences were generated, sequences were aligned to a reference sequence and phylogenetic analysis was performed. Genomic clusters were determined and integrated with epidemiological data to provide additional information., Results: All 231 COVID-19 cases notified in Tasmania during the study period and 266 SARS-CoV-2-positive samples, representing 217/231 (94%) notified cases, were included; 184/217 (84%) were clustered, 21/217 (10%) were unique and 12/217 (6%) could not be sequenced. Genomics confirmed the presence of seven clusters already identified through epidemiological links, clarified transmission networks in which the epidemiology had been unclear and identified one cluster that had not previously been recognized., Discussion: Genomic analysis provided useful additional information on COVID-19 in Tasmania, including evidence of a large health-care-associated outbreak linked to an overseas cruise, the probable source of infection in cases with no previously identified epidemiological link and confirmation that there was no identified community transmission from other imported cases. Genomic insights are an important component of the response to COVID-19, and continuing genomic surveillance is warranted., ((c) 2021 The authors; licensee World Health Organization.)

Background: Australian adolescents are routinely offered HPV and dTpa (diphtheria, tetanus, pertussis) vaccines simultaneously in the secondary school vaccination program. We identified schools where HPV initiation was lower than dTpa coverage and associated school-level factors across three states., Methods: HPV vaccination initiation rates and dTpa vaccination coverage in 2016 were calculated using vaccine databases and school enrolment data. A multivariate analysis assessed sociodemographic and school-level factors associated with HPV initiation being >5% absolute lower than dTpa coverage., Results: Of 1280 schools included, the median school-level HPV initiation rate was 85% (interquartile range (IQR):75-90%) and the median dTpa coverage was 86% (IQR:75-92%). Nearly a quarter (24%) of all schools had HPV vaccination initiation >5% lower than dTpa coverage and 11 % had >10% difference. School-level factors independently associated with >5% difference were remote schools (aOR:3.5, 95% CI = 1.7-7.2) and schools in major cities (aOR:1.8, 95% CI = 1.0-3.0), small schools (aOR:3.3, 95% CI = 2.3-5.7), higher socioeconomic advantage (aOR:1.7, 95% CI = 1.1-2.6), and lower proportions of Language-background-other-than-English (aOR:1.9, 95% CI = 1.2-3.0)., Conclusion: The results identified a quarter of schools had lower HPV than dTpa initiation coverage, which may indicate HPV vaccine hesitancy, and the difference was more likely in socioeconomically advantaged schools. As hesitancy is context specific, it is important to understand the potential drivers of hesitancy and future research needs to understand the reasons driving differential uptake.

Microarray patches (MAPs) have the potential to be a safer, more acceptable, easier to use and more cost-effective method for administration of vaccines when compared to the needle and syringe. Since MAPs deliver vaccine to the dermis and epidermis, a degree of local immune response at the site of application is expected. In a phase 1 clinical trial (ACTRN 12618000112268), the Vaxxas high-density MAP (HD-MAP) was used to deliver a monovalent, split inactivated influenza virus vaccine into the skin. HD-MAP immunisation led to significantly enhanced humoral responses on day 8, 22 and 61 compared with IM injection of a quadrivalent commercial seasonal influenza vaccine (Afluria Quadrivalent®). Here, the aim was to analyse cellular responses to HD-MAPs in the skin of trial subjects, using flow cytometry and immunohistochemistry. HD-MAPs were coated with a split inactivated influenza virus vaccine (A/Singapore/GP1908/2015 [H1N1]), to deliver 5 μg haemagglutinin (HA) per HD-MAP. Three HD-MAPs were applied to the volar forearm (FA) of five healthy volunteers (to achieve the required 15 μg HA dose), whilst five control subjects received three uncoated HD-MAPs (placebo). Local skin response was recorded for over 61 days and haemagglutination inhibition antibody titres (HAI) were assessed on days 1, 4, 8, 22, and 61. Skin biopsies were taken before (day 1), and three days after HD-MAP application (day 4) and analysed by flow-cytometry and immunohistochemistry to compare local immune subset infiltration. HD-MAP vaccination with 15 μg HA resulted in significant HAI antibody titres compared to the placebo group. Application of uncoated placebo HD-MAPs resulted in mild erythema and oedema in most subjects, that resolved by day 4 in 80% of subjects. Active, HA-coated HD-MAP application resulted in stronger erythema responses on day 4, which resolved between days 22-61. Overall, these erythema responses were accompanied by an influx of immune cells in all subjects. Increased cell infiltration of CD3+, CD4+, CD8+ T cells as well as myeloid CD11b+ CD11c+ and non-myeloid CD11b- dendritic cells were observed in all subjects, but more pronounced in active HD-MAP groups. In contrast, CD19+/CD20+ B cell counts remained unchanged. Key limitations include the use of an influenza vaccine, to which the subjects may have had previous exposure. Different results might have been obtained with HD-MAPs inducing a primary immune response. In conclusion, influenza vaccine administered to the forearm (FA) using the HD-MAP was well-tolerated and induced a mild to moderate skin response with lymphocytic infiltrate at the site of application., Competing Interests: Some of the authors were employed by commercial companies. Vaxxas Pty was the sole funder of the study, and the contributions of these authors were supported by Vaxxas, either as employees, consultants, or fee-for-service contracts. I have read the journal’s policy and the authors of this manuscript have the following competing interests: - AHF, ACID and KW are employees of Vaxxas Pty Ltd. - JWW, CDA, PT, JH and GJPF received consulting fees from Vaxxas Pty Ltd to support their contribution to this research. - JWW and MV are employees of the University of Queensland, which carried out some assay development on a contract basis paid for by Vaxxas Pty Ltd. - JDL, is an employee of Nucleus Network, which carried out the clinical trial (trial site) on a contract basis paid for by Vaxxas Pty Ltd. - This commercial affiliation does not alter Vaxxas’ adherence to PLOS ONE policies on sharing data and materials. There are no restrictions on sharing of data and/or materials.

Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8 + T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4 + Treg and FoxP3 + NKT cells. The number of these accumulated during treatment, the increase in FoxP3 + NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effector to suppressive NKT cells. Whereas tumour infiltrating CD8 + T cell PD-1 and tumour PD-L1 expression was increased with treatment, peripheral CD4 + and CD8 + T cells retained strong anti-tumour activity. Despite increased CD8 + T cell PD-1, combination with anti-PD-1 did not improve response, indicating that immunosuppression from Tregs and FoxP3 + NKT cells are major contributors to the immunosuppressive tumour microenvironment. This demonstrates that therapies targeting replication stress can be well tolerated, not adversely affect immune responses, and trigger an effective anti-tumour immune response.

Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8 + T cells, but not CD4 + T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8 + T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8 + T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8 + T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8 + T cells.

Background: Emergency services working to protect communities from harm during wildfires aim to provide regular public advisories on the hazards from fire and smoke. However, there are few studies evaluating the success of public health communications regarding the management of smoke exposure. We explored the responses to smoke-related health advisories of people living in a severely smoke-affected region during extensive wildfires in Tasmania, Australia early in 2019. We also evaluated the acceptability of portable high efficiency particle air (HEPA) cleaners used in study participant's homes during the smoky period. Methods: We conducted semi-structured interviews with 24 households in the Huon Valley region of Tasmania following a severe smoke episode. These households were initially recruited into a HEPA cleaner study. Interviews were recorded, transcribed, and analyzed for common themes using an inductive framework approach. Results: Public health messaging during the 2019 wildfire event in Tasmania was widely shared and understood, with social media playing a central role. However, some participants expressed concerns about the timeliness and effectiveness of the recommended interventions, and some would have appreciated more detailed information about the health risks from smoke. Public messages and actions to protect households from wildfire threat were, at times, contradictory or dominated in coverage over the smoke messaging, and many participants were conflicted with the multiple public messages and action relating to the more serious perceived threat from the fire. Conclusions: Public messaging about smoke and health should continue to use multiple avenues of communication, with a focus on simple messages provided through social media. Messaging about the smoke hazard should be available from a trusted central source regarding all aspects of the wildfire emergency, with links to more detailed information including local air quality data alongside interpretation of the associated health risks., (Copyright © 2020 Marfori, Campbell, Garvey, McKeown, Veitch, Wheeler, Borchers-Arriagada and Johnston.)

Background: The Vaxxas high-density microarray patch (HD-MAP) consists of a high density of microprojections coated with vaccine for delivery into the skin. Microarray patches (MAPs) offer the possibility of improved vaccine thermostability as well as the potential to be safer, more acceptable, easier to use, and more cost-effective for the administration of vaccines than injection by needle and syringe (N&S). Here, we report a phase I trial using the Vaxxas HD-MAP to deliver a monovalent influenza vaccine that was to the best of our knowledge the first clinical trial to evaluate the safety, tolerability, and immunogenicity of lower doses of influenza vaccine delivered by MAPs., Methods and Findings: HD-MAPs were coated with a monovalent, split inactivated influenza virus vaccine containing A/Singapore/GP1908/2015 H1N1 haemagglutinin (HA). Between February 2018 and March 2018, 60 healthy adults (age 18-35 years) in Melbourne, Australia were enrolled into part A of the study and vaccinated with either: HD-MAPs delivering 15 μg of A/Singapore/GP1908/2015 H1N1 HA antigen (A-Sing) to the volar forearm (FA); uncoated HD-MAPs; intramuscular (IM) injection of commercially available quadrivalent influenza vaccine (QIV) containing A/Singapore/GP1908/2015 H1N1 HA (15 μg/dose); or IM injection of H1N1 HA antigen (15 μg/dose). After 22 days' follow-up and assessment of the safety data, a further 150 healthy adults were enrolled and randomly assigned to 1 of 9 treatment groups. Participants (20 per group) were vaccinated with HD-MAPs delivering doses of 15, 10, 5, 2.5, or 0 μg of HA to the FA or 15 μg HA to the upper arm (UA), or IM injection of QIV. The primary objectives of the study were safety and tolerability. Secondary objectives were to assess the immunogenicity of the influenza vaccine delivered by HD-MAP. Primary and secondary objectives were assessed for up to 60 days post-vaccination. Clinical staff and participants were blind as to which HD-MAP treatment was administered and to administration of IM-QIV-15 or IM-A/Sing-15. All laboratory investigators were blind to treatment and participant allocation. Two further groups in part B (5 participants per group), not included in the main safety and immunological analysis, received HD-MAPs delivering 15 μg HA or uncoated HD-MAPs applied to the forearm. Biopsies were taken on days 1 and 4 for analysis of the cellular composition from the HD-MAP application sites. The vaccine coated onto HD-MAPs was antigenically stable when stored at 40°C for at least 12 months. HD-MAP vaccination was safe and well tolerated; any systemic or local adverse events (AEs) were mild or moderate. Observed systemic AEs were mostly headache or myalgia, and local AEs were application-site reactions, usually erythema. HD-MAP administration of 2.5 μg HA induced haemagglutination inhibition (HAI) and microneutralisation (MN) titres that were not significantly different to those induced by 15 μg HA injected IM (IM-QIV-15). HD-MAP delivery resulted in enhanced humoral responses compared with IM injection with higher HAI geometric mean titres (GMTs) at day 8 in the MAP-UA-15 (GMT 242.5, 95% CI 133.2-441.5), MAP-FA-15 (GMT 218.6, 95% CI 111.9-427.0), and MAP-FA-10 (GMT 437.1, 95% CI 254.3-751.3) groups compared with IM-QIV-15 (GMT 82.8, 95% CI 42.4-161.8), p = 0.02, p = 0.04, p < 0.001 for MAP-UA-15, MAP-FA-15, and MAP-FA-10, respectively. Higher titres were also observed at day 22 in the MAP-FA-10 (GMT 485.0, 95% CI 301.5-780.2, p = 0.001) and MAP-UA-15 (367.6, 95% CI 197.9-682.7, p = 0.02) groups compared with the IM-QIV-15 group (GMT 139.3, 95% CI 79.3-244.5). Results from a panel of exploratory immunoassays (antibody-dependent cellular cytotoxicity, CD4+ T-cell cytokine production, memory B cell (MBC) activation, and recognition of non-vaccine strains) indicated that, overall, Vaxxas HD-MAP delivery induced immune responses that were similar to, or higher than, those induced by IM injection of QIV. The small group sizes and use of a monovalent influenza vaccine were limitations of the study., Conclusions: Influenza vaccine coated onto the HD-MAP was stable stored at temperatures up to 40°C. Vaccination using the HD-MAP was safe and well tolerated and resulted in immune responses that were similar to or significantly enhanced compared with IM injection. Using the HD-MAP, a 2.5 μg dose (1/6 of the standard dose) induced HAI and MN titres similar to those induced by 15 μg HA injected IM., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR.org.au), trial ID 108 ACTRN12618000112268/U1111-1207-3550., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: AHF, KW, ACID are paid employees of Vaxxas Pty Ltd. JWW, PT, GJPF and JH received consulting fees from Vaxxas Pty Ltd. JWW and MV are employees of the University of Queensland which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. MP is an employee of 360Biolabs Pty Ltd which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. JDL is an employee of Nucleus Network which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. BF is an employee of Avance Clinical (formerly CPR Pharma Services) which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. AW is an employee of Melbourne University which carried out work for the study on a contract basis paid for by Vaxxas Pty Ltd. AW has received travel expenses from Vaxxas Pty Ltd to attend data-review meetings.

We used phylogenomic and risk factor data on isolates of Salmonella enterica serovars Mississippi and Typhimurium definitive type 160 (DT160) collected from human, animal, and environmental sources to elucidate their epidemiology and disease reservoirs in Australia and New Zealand. Sequence data suggested wild birds as a likely reservoir for DT160; animal and environmental sources varied more for Salmonella Mississippi than for Salmonella Typhimurium. Australia and New Zealand isolates sat in distinct clades for both serovars; the median single-nucleotide polymorphism distance for DT160 was 29 (range 8-66) and for Salmonella Mississippi, 619 (range 565-737). Phylogenomic data identified plausible sources of human infection from wildlife and environmental reservoirs and provided evidence supporting New Zealand-acquired DT160 in a group of travelers returning to Australia. Wider use of real-time whole-genome sequencing in new locations and for other serovars may identify sources and routes of transmission, thereby aiding prevention and control.

Objective: To describe the epidemiology and clinical characteristics of Tasmania-acquired rickettsial disease notified to the Department of Health in Tasmania from 2012 to 2017 inclusive., Methods: Data on rickettsiosis cases acquired and notified in Tasmania between 1 January 2012 and 31 December 2017 were analysed descriptively., Results: Eighteen cases of rickettsial infection notified in Tasmania 2012-17 and likely acquired in the state met one of three case definitions: 12 confirmed (67%), four probable (22%), and two possible (11%). The mean number of cases per year was 3.0 (population rate 0.6 per 100,000 population/year); 60% of cases occurred in November and December. Cases were more commonly older males. Fever, lethargy, and rash were commonly reported symptoms. Thirteen cases were likely acquired on Flinders Island, three around Great Oyster Bay and two in the Midlands., Conclusions: This study extends our knowledge of the epidemiology of rickettsial disease in Tasmania. This is the first account including confirmed cases acquired in the Midlands of Tasmania. Implications for public health: Increased knowledge and awareness of epidemiology of rickettsial infection in Tasmania is essential for timely diagnosis and appropriate treatment. These findings bear wider relevance outside Tasmania because visitors may also be at risk., (© 2019 The Authors.)

Squamous cell carcinoma (SCC) accounts for the majority of non-melanoma skin cancer related deaths, particularly in immunosuppressed persons. Identification of biomarkers that could be used to identify or treat SCC would be of significant benefit. The anthrax toxin receptors, Tumor Endothelial Marker 8 (TEM8) and Capillary Morphogenesis Gene 2 (CMG2), are endothelial receptors involved in extracellular matrix homeostasis and angiogenesis that are selectively upregulated on numerous tumors. One method of targeting these receptors is Protective Antigen (PA), a protein produced by B. anthracis that mediates binding and translocation of anthrax toxins into cells. PA targeted toxins have been demonstrated to selectively inhibit tumor growth and angiogenesis, but tumor selectivity of PA is currently unknown. In this work fluorescently labeled PA was shown to maintain receptor dependent binding and internalization in vitro . Utilizing a human papillomavirus transgenic mouse model that develops cutaneous SCC in response to ultraviolet irradiation we identified tumor uptake of PA i n vivo . The intravenously administered PA resulted in tumor specific localization, with exclusive tumor detection 24 h post injection. Ex vivo analysis identified significantly higher fluorescence in the tumor compared to adjacent healthy tissue and major clearance organs, demonstrating low non-specific uptake and rapid clearance. While both TEM8 and CMG2 were observed to be overexpressed in SCC tumor sections compared to control skin, the intravenously administered PA was primarily co-localized with TEM8. These results suggest that PA could be systemically administered for rapid identification of cutaneous SCC, with potential for further therapeutic development.

Patients receiving immunosuppressive drugs to prevent organ transplant rejection exhibit a greatly increased risk of developing cutaneous squamous cell carcinoma (SCC). However, not all immunosuppressive drugs confer the same risk. Randomised, controlled trials demonstrate that switching renal transplant recipients receiving calcineurin inhibitor-based therapies to mammalian target of rapamycin (mTOR) inhibitors results in a reduced incidence of de novo SSC formation, and can even result in the regression of pre-existing premalignant lesions. However, the contribution played by residual immune function in this setting is unclear. We examined the hypotheses that mTOR inhibitors promote the enhanced differentiation and function of CD8 + memory T cells in the skin. Here, we demonstrate that the long-term oral administration of rapamycin to achieve clinically-relevant whole blood drug target thresholds, creates a "low rapamycin dose" environment in the skin. While both rapamycin and the calcineurin inhibitor tacrolimus elongated the survival of OVA-expressing skin grafts, and inhibited short-term antigen-specific CD8 + T cell responses, rapamycin but not tacrolimus permitted the statistically significant infiltration of CD8 + effector memory T cells into UV-induced SCC lesions. Furthermore, rapamycin uniquely enhanced the number and function of CD8 + effector and central memory T cells in a model of long-term contact hypersensitivity provided that rapamycin was present during the antigen sensitization phase. Thus, our findings suggest that patients switched to mTOR inhibitor regimens likely experience enhanced CD8 + memory T cell function to new antigen-challenges in their skin, which could contribute to their lower risk of de novo SSC formation and regression of pre-existing premalignant lesions.

Objective: We identified two water tanks in Tasmania with water lead concentrations exceeding the Australian Drinking Water Guidelines (ADWG) limit; they had been constructed with stainless steel and high-lead solder from a single manufacturer. An investigation was initiated to identify all tanks constructed by this manufacturer and prevent further exposure to contaminated water., Methods: To identify water tanks we used sales accounts, blood and water lead results from laboratories, and media. We analysed blood and water lead concentration results from laboratories and conducted a nested cohort study of blood lead concentrations in children aged <18 years., Results: We identifed 144 tanks constructed from stainless steel and high lead solder. Median water lead concentrations were significantly higher in the stainless steel tanks (121µg/L) than in the galvanised tanks (1µg/L). Blood lead concentrations ranged from 1 to 26µg/dL (median 5µg/dL); of these, 77% (n=50) were below the then-recommended health-related concentration of 10µg/dL. Concentrations in the 15 people (23%) above this limit ranged from 10-26µg/dL, with a median of 14µg/dL. The median blood lead concentration in the nested cohort of children was initially 8.5µg/dL, dropping to 4.5µg/dL after follow-up., Conclusions: Lead concentrations in the water tanks constructed from stainless steel and high-lead solder were up to 200 times above the recommended ADWG limits. Implications for public health: This investigation highlights the public health risk posed by use of non-compliant materials in constructing water tanks., (© 2017 Department of Health and Human Services Tasmania.)

The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be "mouse cetuximab" and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Salmonella is a key cause of foodborne gastroenteritis in Australia and case numbers are increasing. We used negative binomial regression to analyze national surveillance data for 2000-2013, for Salmonella Typhimurium and non-Typhimurium Salmonella serovars. We estimated incidence rate ratios adjusted for sex and age to show trends over time. Almost all states and territories had significantly increasing trends of reported infection for S. Typhimurium, with states and territories reporting annual increases as high as 12% (95% confidence interval 10-14%) for S. Typhimurium in the Australian Capital Territory and 6% (95% CI 5-7%) for non-Typhimurium Salmonella in Victoria. S. Typhimurium notification rates were higher than non-Typhimurium Salmonella rates in most age groups in the south eastern states of Australia, while non-Typhimurium rates were higher in most age groups elsewhere. The S. Typhimurium notification rate peaked at 12-23 months of age and the non-Typhimurium Salmonella notification rate peaked at 0-11 months of age. The age-specific pattern of S. Typhimurium cases suggests a foodborne origin, while the age and geographic pattern for non-Typhimurium may indicate that other transmission routes play a key role for these serovars., Competing Interests: The authors have declared that no competing interests exist.