Core protocol for the adaptive Platform Trial In COVID-19 Vaccine priming and BOOsting (PICOBOO).

BACKGROUND: The need for coronavirus 2019 (COVID-19) vaccination in different age groups and populations is a subject of great uncertainty and an ongoing global debate. Critical knowledge gaps regarding COVID-19 vaccination include the duration of protection offered by different priming and booster vaccination regimens in different populations, including homologous or heterologous schedules; how vaccination impacts key elements of the immune system; how this is modified by prior or subsequent exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and future variants; and how immune responses correlate with protection against infection and disease, including antibodies and effector and T cell central memory. METHODS: The Platform Trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, multi-arm, Bayesian, adaptive, randomised controlled platform trial. PICOBOO will expeditiously generate and translate high-quality evidence of the immunogenicity, reactogenicity and cross-protection of different COVID-19 priming and booster vaccination strategies against SARS-CoV-2 and its variants/subvariants, specific to the Australian context. While the platform is designed to be vaccine agnostic, participants will be randomised to one of three vaccines at trial commencement, including Pfizer's Comirnaty, Moderna's Spikevax or Novavax's Nuvaxovid COVID-19 vaccine. The protocol structure specifying PICOBOO is modular and hierarchical. Here, we describe the Core Protocol, which outlines the trial processes applicable to all study participants included in the platform trial. DISCUSSION: PICOBOO is the first adaptive platform trial evaluating different COVID-19 priming and booster vaccination strategies in Australia, and one of the few established internationally, that is designed to generate high-quality evidence to inform immunisation practice and policy. The modular, hierarchical protocol structure is intended to standardise outcomes, endpoints, data collection and other study processes for nested substudies included in the trial platform and to minimise duplication. It is anticipated that this flexible trial structure will enable investigators to respond with agility to new research questions as they arise, such as the utility of new vaccines (such as bivalent, or SARS-CoV-2 variant-specific vaccines) as they become available for use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12622000238774. Registered on 10 February 2022.

A quality improvement study: Optimizing pneumococcal vaccination rates in children with cochlear implants.

Children with cochlear implants are at increased risk of invasive pneumococcal disease, with national and international guidelines recommending additional pneumococcal vaccines for these children. This study aimed to examine the pneumococcal immunization status and rate of invasive pneumococcal disease in children with cochlear implants at a tertiary paediatric hospital over a 12-year period. Additionally, the impacts of vaccination reminders and a dedicated immunization clinic on pneumococcal vaccination rates were assessed. This quality improvement study included 200 children who had received a cochlear implant through the Children's Hearing Implant Program at a tertiary paediatric hospital servicing the state of Western Australia. The majority of children (88%) were not up to date with additionally recommended pneumococcal vaccinations. Over the 12-year study period, 2% of children developed invasive pneumococcal disease associated with cochlear implant infections. Generic and personalized electronic immunization reminders improved pneumococcal vaccine up-take in this paediatric cochlear implant setting from 12% (19/153) at baseline to 49% (75/153, p < 0.0001) post implementation. The value of a nurse-led dedicated immunization clinic was also demonstrated with all children (42/42, 100%) up to date with Prevenar13 and the majority (34/42, 81%) up to date with Pneumovax23 post initiation of this referral pathway. These data support the expansion of this model to other medically-at-risk paediatric groups that have been highlighted consistently to be under-vaccinated.

Erratum: Azimuthal Anisotropy of K_{S}

This corrects the article DOI: 10.1103/PhysRevLett.89.132301.

Olfactory dysfunction at six months after coronavirus disease 2019 infection.

OBJECTIVE: This study aimed to assess olfactory dysfunction in patients at six months after confirmed coronavirus disease 2019 infection. METHODS: Coronavirus disease 2019 positive patients were assessed six months following diagnosis. Patient data were recoded as part of the adapted International Severe Acute Respiratory and Emerging Infection Consortium Protocol. Olfactory dysfunction was assessed using the University of Pennsylvania Smell Identification Test. RESULTS: Fifty-six patients were included. At six months after coronavirus disease 2019 diagnosis, 64.3 per cent of patients (n = 36) were normosmic, 28.6 per cent (n = 16) had mild to moderate microsmia and 7 per cent (n = 4) had severe microsmia or anosmia. There was a statistically significant association between older age and olfactory dysfunction. Hospital or intensive care unit admission did not lead to worse olfactory outcomes compared to those managed in the out-patient setting. CONCLUSION: At six months after coronavirus disease 2019 diagnosis, approximately two-thirds of patients will be normosmic. This study is the first to describe six-month outcomes for post-coronavirus disease 2019 patients in terms of olfactory dysfunction.

Erratum: Azimuthal Anisotropy at the Relativistic Heavy Ion Collider: The First and Fourth Harmonics [Phys. Rev. Lett. 92, 062301 (2004)].

This corrects the article DOI: 10.1103/PhysRevLett.92.062301.

Geospatial epidemiology of Staphylococcus aureus in a tropical setting: an enabling digital surveillance platform.

Delivery of information to clinicians on evolving antimicrobial susceptibility needs to be accurate for the local needs, up-to-date and readily available at point of care. In northern Australia, bacterial infection rates are high but resistance to first- and second-line antibiotics is poorly described and currently-available datasets exclude primary healthcare data. We aimed to develop an online geospatial and interactive platform for aggregating, analysing and disseminating data on regional bacterial pathogen susceptibility. We report the epidemiology of Staphylococcus aureus as an example of the power of digital platforms to tackle the growing spread of antimicrobial resistance in a high-burden, geographically-sparse region and beyond. We developed an online geospatial platform called HOTspots that visualises antimicrobial susceptibility patterns and temporal trends. Data on clinically-important bacteria and their antibiotic susceptibility profiles were sought from retrospectively identified clinical specimens submitted to three participating pathology providers (96 unique tertiary and primary healthcare centres, n = 1,006,238 tests) between January 2008 and December 2017. Here we present data on S. aureus only. Data were available on specimen type, date and location of collection. Regions from the Australian Bureau of Statistics were used to provide spatial localisation. The online platform provides an engaging visual representation of spatial heterogeneity, demonstrating striking geographical variation in S. aureus susceptibility across northern Australia. Methicillin resistance rates vary from 46% in the west to 26% in the east. Plots generated by the platform show temporal trends in proportions of S. aureus resistant to methicillin and other antimicrobials across the three jurisdictions of northern Australia. A quarter of all, and up to 35% of methicillin-resistant S. aureus (MRSA) blood isolates in parts of the northern Australia were resistant to inducible-clindamycin. Clindamycin resistance rates in MRSA are worryingly high in regions of northern Australia and are a local impediment to empirical use of this agent for community MRSA. Visualising routinely collected laboratory data with digital platforms, allows clinicians, public health physicians and guideline developers to monitor and respond to antimicrobial resistance in a timely manner. Deployment of this platform into clinical practice supports national and global efforts to innovate traditional disease surveillance systems with the use of digital technology and to provide practical solutions to reducing the threat of antimicrobial resistance.

Adjunctive protein synthesis inhibitor antibiotics for toxin suppression in Staphylococcus aureus infections: a systematic appraisal.

Protein synthesis inhibitor antibiotics inhibit synthesis of new proteins, including exotoxins and other important virulence determinants in Staphylococcus aureus. A summary of the literature regarding the use of adjunctive protein synthesis inhibitors for toxin suppression in the setting of S. aureus infections is presented.

Effectiveness of a 3 + 0 pneumococcal conjugate vaccine schedule against invasive pneumococcal disease among a birth cohort of 1.4 million children in Australia.

BACKGROUND: Most studies use indirect cohort or case-control methods to estimate vaccine effectiveness (VE) of 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) against invasive pneumococcal disease (IPD). Neither method can measure the benefit vaccination programs afford the unvaccinated and many studies were unable to estimate dose-specific VE. We linked Australia's national immunisation register with health data from two states to calculate IPD incidence by vaccination status and VE for a 3 + 0 PCV schedule (doses at 2, 4, 6 months, no booster) among a cohort of 1.4 million births. METHODS: Births records for 2001-2012 were probabilistically linked to IPD notifications, hospitalisations, deaths, and vaccination history (available until December 2013). IPD rates in vaccinated and unvaccinated children <2 years old were compared using Cox proportional hazards models (adjusting for potential confounders), with VE = (1 - adjusted hazard ratio) × 100. Separate models were performed for all-cause, PCV7, PCV13 and PCV13-non-PCV7 serotype-specific IPD, and for Aboriginal and non-Aboriginal children. RESULTS: Following introduction of universal PCV7 in 2005, rates of PCV7 serotype and all-cause IPD in unvaccinated children declined 89.5% and 61.4%, respectively, to be similar to rates in vaccinated children. Among non-Aboriginal children, VEs for 3 doses were 94.2% (95%CI: 81.9-98.1) for PCV7 serotype-specific IPD, 85.6% (95%CI: 60.5-94.8) for PCV13-non-PCV7 serotype-specific IPD and 80.1% (95%CI: 59.4-90.3) for all-cause IPD. There were no statistically significant differences between the VEs for 3 doses and for 1 or 2 doses against PCV13 and PCV13-non-PCV7 serotype-specific IPD, or between Aboriginal and non-Aboriginal children. CONCLUSION: Our population-based cohort study demonstrates that >90% coverage in the first year of a universal 3 + 0 PCV program provided high population-level protection, predominantly attributable to strong herd effects. The size of the cohort enabled calculation of robust dose-specific VE estimates for important population sub-groups relevant to vaccination policies internationally.

Multidrug-resistant tuberculosis in Australia, 1998-2012.

OBJECTIVE: To describe the epidemiology and outcomes of multidrug-resistant tuberculosis (MDR-TB) diagnosed in Australia between 1998 and 2012. DESIGN: A retrospective review was undertaken involving all patients with laboratory-confirmed MDR-TB notified in Australia between 1998 and 2012 inclusive. Demographic, clinical and laboratory features are described. Clinical outcomes were defined according to World Health Organization definitions of treatment success (cure and treatment completion), treatment failure, death, loss to follow-up (including transfer out), or not evaluated at treatment completion. RESULTS: A total of 244 cases of MDR-TB were diagnosed in Australia during the study period, representing 1.4% of all TB cases notified. The majority were born outside Australia, including one third in Papua New Guinea. Of those with treatment outcome data available, treatment success was demonstrated in 81%. Treatment success was positively associated with use of a second-line injectable agent. Those born in Papua New Guinea were less likely to achieve treatment success. CONCLUSION: MDR-TB is uncommon in Australia. The large number of cases born in Papua New Guinea, and the poorer outcomes in this cohort, represent challenges with cross-border management of MDR-TB in the Torres Strait. Australia has an ongoing role in the prevention and management of MDR-TB locally and in the region.

Using record linkage to examine testing patterns for respiratory viruses among children born in Western Australia.

Changes in respiratory pathogen testing can affect disease burden estimates. Using linked data, we describe changes in respiratory virus testing among children born in Western Australia in 1996-2012. We extracted data on respiratory specimens from these children from birth to age 9 years. We estimated testing rates by age, year, Aboriginal status and geographical location. Predictors of testing among children hospitalised at least once before their 10th birthday were identified using logistic regression. We compared detection methods for respiratory viruses from nasal/nasopharyngeal (NP) specimens by age and year. Of 83 199 virology testing records in 2000-2012, 80% were nasal/NP specimens. Infants aged <1 month had the highest testing rates. Testing rates in all children increased over the study period with considerable yearly fluctuations. Among hospitalised children, premature children <32 weeks gestation had over three times the odds of being tested (95% CI 3·47-4·13) than those born at term. Testing using molecular methods increased from 5% to 87% over the study period. Proportion of positive samples increased from 36·3% to 44·4% (P < 0·01); this change was greatest in children aged 2-9 years. These findings will assist in interpreting results from future epidemiology studies assessing the pathogen-specific burden of disease.

Influenza hospitalizations in Australian children.

Australia's National Immunisation Program (NIP) provides free influenza vaccination for children at high risk of severe influenza; a pilot-funded programme for vaccine in all children aged 6 months to <5 years in one of eight states, has seen poor vaccine impact, related to recent vaccine safety concerns. This retrospective review examined influenza hospitalizations in children aged <16 years from three seasons (2011-2013) at two paediatric hospitals on opposite sides of the country. Comparisons of this cohort were made with state-based data on influenza-coded hospitalizations and national immunization register data on population-level immunization coverage. Of 740 hospitalizations, the majority were aged <5 years (476/740, 64%), and a substantial proportion (57%) involved healthy children, not currently funded for influenza vaccine. Intensive care unit admission occurred in 8·5%, and 1·5% of all children developed encephalitis. Use of antiviral therapy was uncommon (20·5%) and decreasing. Of those hospitalized, only 5·0% of at-risk children, who are currently eligible for free vaccine, and 0·7% of healthy children were vaccinated prior to hospitalization. This was consistent with low population-wide estimates of influenza vaccine uptake. It highlights the need to examine alternative strategies, such as universally funded paediatric influenza vaccination, to address disease burden in Australian children.

Probabilistic linkage of national immunisation and state-based health records for a cohort of 1.9 million births to evaluate Australia's childhood immunisation program.

INTRODUCTION: Several countries have developed national immunisation registers, but only the Nordic countries have linked their registers to other health data in order to comprehensively evaluate the `real world' effectiveness of vaccines. Nordic countries can link datasets deterministically using the national person identifier, but most countries, including Australia, don't have such an identifier to enable this type of linkage. OBJECTIVES: To describe the process for assembling a linked study cohort that will enable the conduct of population-based studies related to immunisation and immunisation policy. METHODS: National death and immunisation databases along with state health data (notifications of vaccine preventable diseases, perinatal data, hospital admissions and emergency department presentations) up until December 2013 were probabilistically linked (using demographic details) for children born between 1996 and 2012 in two states: Western Australia and New South Wales (42% of Australia's population, combined). RESULTS: After exclusions there were 1.95 million children in the study cohort (live born children with both a birth and perinatal record which represents 97.5% of all live births in the state perinatal data collections - our source population) and 18.0 million person years of follow up (mean: 9.2 years per child). The characteristics of children in the cohort were generally similar to those only included in state perinatal databases and outcome measures were in keeping with expected figures from unlinked data sources. However, the lack of a dynamic national population register meant immigrants could not be included. CONCLUSIONS: We have been able to develop a similarly comprehensive system to the Nordic countries based on probabilistic linkage methods. Our experience should provide encouragement to other countries with national immunisation registers looking to establish similar systems.

Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand.

The incidence of Clostridium difficile infection (CDI) continues to rise, whilst treatment remains problematic due to recurrent, refractory and potentially severe nature of disease. The treatment of C. difficile is a challenge for community and hospital-based clinicians. With the advent of an expanding therapeutic arsenal against C. difficile since the last published Australasian guidelines, an update on CDI treatment recommendations for Australasian clinicians was required. On behalf of the Australasian Society of Infectious Diseases, we present the updated guidelines for the management of CDI in adults and children.

Mucormycosis in Australia: contemporary epidemiology and outcomes.

Mucormycosis is the second most common cause of invasive mould infection and causes disease in diverse hosts, including those who are immuno-competent. We conducted a multicentre retrospective study of proven and probable cases of mucormycosis diagnosed between 2004-2012 to determine the epidemiology and outcome determinants in Australia. Seventy-four cases were identified (63 proven, 11 probable). The majority (54.1%) were caused by Rhizopus spp. Patients who sustained trauma were more likely to have non-Rhizopus infections relative to patients without trauma (OR 9.0, p 0.001, 95% CI 2.1-42.8). Haematological malignancy (48.6%), chemotherapy (42.9%), corticosteroids (52.7%), diabetes mellitus (27%) and trauma (22.9%) were the most common co-morbidities or risk factors. Rheumatological/autoimmune disorders occurred in nine (12.1%) instances. Eight (10.8%) cases had no underlying co-morbidity and were more likely to have associated trauma (7/8; 87.5% versus 10/66; 15.2%; p <0.001). Disseminated infection was common (39.2%). Apophysomyces spp. and Saksenaea spp. caused infection in immuno-competent hosts, most frequently associated with trauma and affected sites other than lung and sinuses. The 180-day mortality was 56.7%. The strongest predictors of mortality were rheumatological/autoimmune disorder (OR = 24.0, p 0.038 95% CI 1.2-481.4), haematological malignancy (OR = 7.7, p 0.001, 95% CI 2.3-25.2) and admission to intensive care unit (OR = 4.2, p 0.02, 95% CI 1.3-13.8). Most deaths occurred within one month. Thereafter we observed divergence in survival between the haematological and non-haematological populations (p 0.006). The mortality of mucormycosis remains particularly high in the immuno-compromised host. Underlying rheumatological/autoimmune disorders are a previously under-appreciated risk for infection and poor outcome.

Comparison of text-messaging to voice telephone interviews for active surveillance of adverse events following immunisation.

OBJECTIVES: In 2013, the Follow-up and Active Surveillance of Trivalent Influenza Vaccine in Mums (FASTMum) program began using short message service (SMS) to collect adverse event information in pregnant women who recently received trivalent influenza vaccine (TIV). This study was designed to compare data collected via SMS and telephone for the purposes of monitoring vaccine safety. METHODS: A number of 344 women who received TIV were randomly assigned to a telephone interview group. They were telephoned seven days post-vaccination and administered a standard survey soliciting any adverse events following immunisation (AEFI) they experienced. They were matched by brand of vaccine, age group, and residence to 344 women who were sent a SMS seven days post-vaccination. The SMS solicited similar information. AEFI reported by SMS and telephone interview were compared by calculating risk ratios. RESULTS: Response rate was higher to SMS compared to telephone interview (90.1% vs. 63.9%). Women who were surveyed by SMS were significantly less likely to report an AEFI compared to women who were surveyed by telephone (RR: 0.41; 95% CI: 0.29-0.59). The greatest discrepancies between SMS and telephone interview were for self-reported injection site reactions (3.1% vs. 16.8%) and unsolicited (or "other") events (11.4% vs. 4.1%). Data collected by SMS was significantly timelier. CONCLUSIONS: Data collection by SMS results in significantly improved response rates and timeliness of vaccine safety data. Systems which incorporate SMS could be used to more rapidly detect safety signals and promote more rapid public health response to vaccine quality issues.

A comparison of paediatric and adult infectious diseases consultations in Australia and New Zealand.

The objective of this paper is to describe paediatric infectious diseases consultations across Australia and New Zealand. We surveyed infectious diseases physicians at 51 hospitals over a period of 2 weeks in 2012. Compared with adult consults, paediatric consults were more frequently received from general paediatricians/physicians and intensive care, yet less frequently from surgeons and emergency. Respiratory, skin/soft tissue and bone/joint infections were the most frequent consultations in children. These data demonstrate the breadth of formal infectious diseases consults in children. Differences between paediatric and infectious diseases consultations need to be considered when planning both paediatric and adult physician training and future curriculum development.

Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.

The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.

Introduction to the updated Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting, 2014.

This article introduces the second revision of the Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting. The current update occurs within the context of a growing population at risk of invasive fungal disease, improved understanding of risk factors, availability of new diagnostic tests, a much-expanded evidence base and changing clinical paradigms. Here, we provide an overview of the history and purpose of the guidelines, including changes in scope since the last clinical update was published in 2008. The process for development, and for enabling review of draft recommendations by end-users and other relevant stakeholders, is described. The approach to assigning levels of evidence and grades of recommendation is also provided, along with a comparison to international grading systems.