Surveillance of adverse events following immunisation in Australia annual report, 2021.

Abstract: Annual seasonal influenza epidemics cause substantial disease and economic burden worldwide. During the coronavirus disease 2019 (COVID-19) pandemic in 2020 and 2021, influenza activity significantly declined. However, influenza resurged in Australia following the relaxation of non-pharmaceutical interventions, with increased influenza virus circulation in early 2022 coinciding with the SARS-CoV-2 Omicron BA.2 variant wave. Together with other respiratory virus diseases, these disease impacts on the Australian population and healthcare system have re-emphasised the importance of influenza vaccination and control. We aim to provide an overview of the current seasonal influenza vaccination program in Australia and summarise evidence and considerations underpinning potential future immunisation strategies. Influenza causes disproportionately higher morbidity and mortality in young children and older adults. Other populations at elevated risk from influenza include Aboriginal and Torres Strait Islander peoples, pregnant women, and people with certain underlying medical conditions. All Australians aged ≥ 6 months are recommended to receive influenza vaccine every year. The National Immunisation Program (NIP) provides free vaccine for eligible at-risk populations. While approximately 70% of older adults had received influenza vaccine in 2022, coverage in other age groups remains suboptimal. There are several key unmet needs and challenges, but also potential strategies for enhancing the influenza vaccination program in Australia. Improved monitoring and evaluation, including the use of relevant linked datasets for such purposes, is imperative to better understand variations in coverage and vaccination impact in specific populations. Adoption of evidence-based strategies, such as culturally appropriate resources that consider the characteristics of diverse Australian populations, may also help to achieve higher vaccine coverage rates. Additionally, greater vaccine uptake across the population could be facilitated by expanding the NIP-eligible population where cost-effective, and adopting the use of more effective and different types of vaccines when available.

COVID-19 vaccines in 2023.

Most Australian adults now have hybrid immunity to the SARS-CoV-2 virus, referring to a combination of protection from previous vaccine doses and past infection. Protection from both vaccination and past infection wanes over time. Booster doses are recommended to ensure that those who are at increased risk of severe COVID-19 remain protected. The optimal timing of future booster doses to maintain adequate protection against severe illness is not yet known. Older age remains the most important risk factor for severe COVID-19, including in the current Omicron variant era. The original COVID-19 vaccines are monovalent vaccines based on the ancestral strain of the SARS-CoV-2 virus. Bivalent vaccines have been developed based on earlier Omicron subvariants (BA.1 or BA.4-5) and the ancestral strain. These provide enhanced protection against severe illness from Omicron compared with the original monovalent vaccines. Updated monovalent vaccines based on a more recent Omicron subvariant (XBB.1.5) have been developed. COVID-19 vaccines have an excellent safety record, and serious adverse events are extremely rare.

ATAGI Targeted Review 2022: Vaccination for prevention of herpes zoster in Australia.

Abstract: In November 2016, herpes zoster (HZ) vaccination for older adults, using the live-attenuated zoster vaccine (Zostavax; ZVL) was added to the Australian National Immunisation Program (NIP) with the aim of reducing morbidity from HZ and its complications, particularly for people at increased risk. Prior to the program, there were on average 5.6 cases of HZ per 1,000 persons annually in Australia, with highest risk of disease in older and in immunocompromised people. The burden of complications of HZ, such as post-herpetic neuralgia (PHN), was also highest in older and immunocompromised groups. No formal comprehensive program evaluation has been undertaken since program commencement. This review examined published literature and available vaccine administration data to summarise the evidence and considerations underpinning current use of HZ vaccines and potential future program directions in Australia. There have been modest reductions in the incidence of HZ and its complications since program introduction. However, five years into the program, challenges remain, including suboptimal vaccine coverage and significant safety concerns arising from inadvertent use of ZVL in immunocompromised people, who are contraindicated to receive this vaccine. This reduces opportunities to offset the burden of HZ-related disease. The recombinant subunit zoster vaccine (Shingrix; RZV), first registered in Australia in 2018, became available on the Australian market in June 2021. This vaccine has higher efficacy than ZVL and, as a non-live vaccine, can be used in both immunocompetent and immunocompromised people. RZV has potential to address the unmet needs of at-risk population groups. However, it has not yet demonstrated cost-effectiveness for inclusion as a funded vaccine under the NIP. The Australian HZ vaccination program has had limited effectiveness in meeting its aim in highest risk groups. Future options and challenges anticipated in using vaccination to reduce the burden of HZ and its complications are discussed in this review.

Disseminated varicella zoster virus infection following live attenuated herpes zoster vaccine: descriptive analysis of reports to Australia's spontaneous vaccine pharmacovigilance system, 2016-2020.

OBJECTIVES: To examine the reported incidence and features of disseminated varicella zoster virus (VZV) infection following live attenuated herpes zoster vaccine live (ZVL: Zostavax, Merck) in immunocompromised people in Australia. DESIGN AND SETTING: ZVL was funded in 2016 in Australia for people aged 70 years, with a catch-up programme for those 71-79 years. From 2016 to 2020, three deaths due to disseminated vaccine-strain VZV infection occurred following inadvertent ZVL administration in individuals with varying levels of immunocompromise. This descriptive study examined 4 years of national surveillance data reported to the Therapeutic Goods Administration's Adverse Event Monitoring System (AEMS). Denominator data for rates were from doses recorded in the Australian Immunisation Register. PARTICIPANTS: Individuals vaccinated between 1 November 2016 and 31 December 2020 who experienced adverse event(s) following immunisation (AEFI) after ZVL recorded in the AEMS. PRIMARY AND SECONDARY OUTCOME MEASURES: Rates and outcomes of confirmed (Oka strain positive) or probable disseminated VZV infection, and inadvertent administration of ZVL in immunocompromised individuals. RESULTS: 854 AEFI were reported from 1 089 966 doses of ZVL administered (78.4 per 100 000 doses). Of those, 14 were classified as confirmed (n=6, 0.55 per 100 000) or probable (n=8) disseminated VZV infection. The confirmed cases were all hospitalised, and most (5/6) were immunocompromised; three cases died. Thirty-seven individuals were reported as vaccinated despite a contraindication due to immunocompromise (3.4 per 100 000), with 12/37 (32%) hospitalised. CONCLUSIONS: Disseminated VZV is potentially life-threatening and occurs mostly in those with severe immunocompromise. Inadvertent administration of ZVL to immunocompromised individuals has occurred despite initial provider guidance and education. Multiple additional strategies to assist providers to identify contraindications have been implemented to prevent adverse outcomes.

General practitioner knowledge gaps regarding live attenuated zoster vaccination of immunocompromised individuals: An ongoing concern?

BACKGROUND AND OBJECTIVES: Live attenuated herpes zoster vaccine (Zostavax [CSL/Merck]) was included on the Australian National Immunisation Program from 1 November 2016 for adults aged 70 years, with a catch-up program for adults aged 71-79 years. The aim of this study was to assess the knowledge of Australian general practitioners (GPs) regarding Zostavax. METHOD: A national cross-sectional online survey was distributed to GPs by Healthed, a private health education provider. RESULTS: Of 605 GPs, 502 responded to the survey (response rate 83%). Eighty-nine per cent were aware that Zostavax is funded and recommended for adults aged 70-79 years. Approximately 10% incorrectly responded that immunocompromise is not a contraindication to Zostavax, and 8% were unsure. For five clinical scenarios assessing knowledge of Zostavax contraindications, the proportion of correct responses ranged 25-82%. DISCUSSION: While most GPs surveyed had good knowledge, notable gaps were identified. Further efforts are needed to promote awareness of recommendations, particularly for immunocompromised individuals. The availability of Shingrix, a non-live recombinant subunit zoster vaccine, in the private market provides an alternative, especially for immuncompromised patients.

Recommendation of Single Time Point Leachables Testing for Lyophilized Biotechnology Products Stored in Rubber Stoppered Glass Vial Systems.

As a popular format of primary container closure systems, rubber stoppered glass vials are often used in storing and delivering lyophilized and liquid formulated therapeutic protein products. Assessing extractables and leachables from rubber stoppered glass vial systems is required to ensure drug product quality and patient safety. Lyophilized biopharmaceutical drug products are generally considered as less impacted by leachables during storage and transportation than the liquid formulated drug products. Single time point leachables testing for lyophilized biopharmaceutic drug products is recommended. The recommendation is based on our published comprehensive leachable data collected at multiple time points for five lyophilized drug products stored in different rubber stoppered glass vial systems with additional supporting comprehensive leachable data collected for nineteen liquid formulated drug products stored in different syringe and vial systems, which is statistically and scientifically sound. The leachable data evaluated herein were generated based on a holistic approach which ensured successful qualification of different vial systems as primary containers and delivery systems for various biotherapeutic products. The organic and elemental impurities of the leachable profiles of all the twenty-four drug product samples were below the limit of detection at all the time points. For lyophilized drug products, product surface interaction during storage time and shipping is unlikely. Timing of single time point leachables testing can be flexible. Performing leachables testing at one-year time point is recommended as it allows for enough time for chemicals to leach out from product contact surfaces into drug products and thus provides the earliest opportunity for mitigation of unpredicted leachables of concern, if any. However, testing at other stability time points can also be considered depending on the development strategy of the sponsor. Therefore, recommendation of single time point leachables testing for lyophilized drug products stored in rubber stopped glass vials at an appropriate time point is a scientifically sound approach.

Structural Equation Modeling Based on PRECEDE Model for the Quality of Life in the Elderly with Dementia in Rural Area / 農村醫學 地域保健

Purpose@#This study was designed to test structural equation modeling of the quality of life of elderly diagnosed dementia living in the community in order to provide guidelines for development of intervention and strategies to improve their quality of life. @*Methods@#The participants in the study were elderly who visited the public health center in C rural between May 30 and september 15, 2017. Data collection was carried out through one-on-one interviews. Demographic factors, knowledge, Attitude, Self-Efficacy, social support, accessibility, request for Information, health practice, depression, subjective memory complaints, dependence scale and quality of life were investigated. @*Results@#The final analysis included 192 elderly. Fitness of the hypothesis model was appropriate(χ2 =192.89, p=.000, GFI=0.90, SRMR=0.08, NNFI=0.94, CFI=0.95, PNFI=0.72, RMSEA=0.07). Depression, subjective memory complaints and dependence were found to be significant explaining varience in quality of life. Social support, dementia preventive behavior and health practice had an indirect effect on the quality of life. @*Conclusions@#To improve the quality of life of elderly diagnosed dementia living in the community, comprehensive interventions are necessary to manage knowledge, attitude, self-efficacy, social support, health practice, depression, subjective memory complaints and dependence that can contribute to enchance the quality of life of elderly diagnosed dementia living in the community.

The Distinctive Immunologic Pathogenesis Differentiates Atopic Comorbidity Status in Prurigo Nodularis / 대한피부과학회지

Background@#Prurigo nodularis (PN) is a chronic pruritic skin disorder with a large number of hyperkeratotic nodules. The precise mechanisms of its pathogenesis remain unknown. PN has been linked to atopic dermatitis (AD), but its association remains unclear. @*Objective@#We aimed to investigate the clinical, histological, and immunohistochemical characteristics of patients with PN and PN underlying AD (PN-AD). @*Methods@#Eight patients were recruited for PN, PN-AD, and eight normal subjects, respectively. Skin tissues were obtained from patients and healthy subjects for histological and immunohistochemical analyses. @*Results@#Histological examination showed increased epidermal thickness and dermal inflammatory cell counts in the PN-AD and PN groups compared to normal subjects. Immunohistochemical analyses revealed that the expression of interleukin (IL)-4, IL-13, IL-18, IL-31, IL-33, interferon (IFN)-γ, stromal-derived factor (SDF) 1-α and thymic stromal lymphopoietin (TSLP) was increased in the tissues of PN-AD and PN groups, in which the staining intensities of IL-4, IL-13, SDF1-α and TSLP in the PN-AD group were higher than those in the PN group, but the differences were not statistically significant. Conversely, the staining intensities of IL-18, IL-33 and IFN-γ were significantly higher in the PN group than those in the PN-AD group. @*Conclusion@#The pathogenesis of PN may differ from that of PN-AD, in which IL-18, IL-33 and IFN-γ may be associated, implying that epidermal injury is the initial cause of IL-18 and IL-33 induction, which then increases IFN-γ, resulting in the inflammatory process of PN.

Observation and Mitigation of Leachables from Non-Product Contact Materials in Electromechanical Delivery Devices for Biotechnology Products.

Battery-powered drug delivery devices are widely used as primary containers for storing and delivering therapeutic protein products to improve patient compliance and quality of life. Compared to conventional delivery approaches such as pre-filled syringes, battery-powered devices are more complex in design requiring new materials/components for proper functionality, which could cause potential product safety and quality concerns from the extractable and leachables (E&L) of the new materials/components. In this study, E&L assessments were performed on a battery-powered delivery device during the development and qualification of the device, where novel compound 2­hydroxy-2-methylpropiophenone (HMPP) and related compounds were observed in both E&L. The source of the HMPP and related compounds was identified to be the nonproduct contact device batteries, in which HMPP photo-initiator was used as a curing agent in the battery sealant to prevent leakage of the battery electrolytes. Toxicology assessment was performed, which showed the levels of HMPP observed in the device lots were acceptable relative to the permitted daily exposure. A drug product HMPP spike study was also performed, where no product impact was observed. Based on these assessments, an action threshold and specification limits could be established as a control strategy, if needed, to mitigate the potential risks associate with the observed leachables. As a full resolution, seven battery candidates from different suppliers were screened and one new battery was successfully qualified for the delivery devices. Overall, the holistic E&L approach was fully successful in the development and qualification of the battery-powered devices for biotherapeutic products delivery ensuring product quality and patient safety. Non-product contact materials are commonly rated as low or no risk and typically considered as out of scope of E&L activities for delivery systems following industry benchmark and regulatory agency guidance. This case study is novel as it brings into attention the materials that might not normally be in consideration during the development process. It is highly recommended to understand materials in the context of intended use on a case-by-case basis and not to generalize to ensure successful development and qualification.

A Holistic Approach of Extractables and Leachables Assessment of Rubber Stoppered Glass Vial Systems for Biotechnology Products.

Rubber stoppered glass vial systems are widely used as primary containers for storing and delivering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from rubber stoppered glass vial systems requires implementation of an extractable and leachable evaluation program based on material understanding, risk assessment, literature review, and a comprehensive scientifically sound analytical testing methodology. The extractable and leachable study design consisted of twelve drug products filled in twelve different size glass vials capped with laminated and nonlaminated rubber stoppers made from three different rubber formulations. Design of the model solvents was successful as they had little to no analytical interference and mimicked the formulation conditions and generated representative extractables capable of predicting leachables. The extraction conditions of time and temperature were appropriate as not to degrade the test materials or the extractable compounds, and yet generated significant quantities for identification of the extractable compounds with confidence. The extractables testing results were capable of predicting the leachable profiles of the twelve drug products. In each case, the leachable profile was a subset of the extractable profile. The organic and elemental impurities of the leachable profiles of drug products were the end-to-end verification of the quality of the glass vials, rubber stoppers and drug product lifecycles. Overall, the holistic approach was fully successful in the qualification of different vial systems as primary containers and delivery systems for different biotherapeutic products to ensure product quality and patient safety.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

Holistic Extractables and Leachables Program: Evaluations of Prefilled Syringe Systems for Biotechnology Products.

Prefilled syringes (PFS) are a container and delivery device of choice for storing and administering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from PFS requires implementation of an extractable and leachable program based on understanding of materials, risk assessment, review of existing literature, and testing supported by a sound scientific foundation. Extractables and leachables data generated as part of a thorough and holistic program are presented for five PFS systems, including glass and plastic syringes filled with 12 biologic drug products encompassing the implementation of traditional and single-use biotechnology manufacturing processes. The comprehensive extractables and leachables data presented demonstrate and substantiate a holistic extractable and leachable program designed to ensure product quality and patient safety.

Assessment of the impact of PS3-induced resistance to downy mildew on grapevine physiology.

Elicitor-induced resistance against diseases is an attractive strategy that could contribute to reduce the use of fungicides for plant protection. However, activation of defenses has an energetic cost that plants have to fuel by a mobilization of their primary metabolism with possible adverse effect on their physiology. In this context, this study was performed to determine whether elicitor-induced resistance of grapevine leaves against downy mildew impacted its development and metabolism. The elicitor PS3 (sulfated ß-glucan laminarin) was sprayed on grapevine herbaceous cuttings grown in greenhouses once or three times, and its impact was studied on young and older grapevine leaves, prior to, and after Plasmopara viticola inoculation. PS3 did not affect grapevine development during the time course of the experiment. A metabolomic analysis, mainly focused on primary metabolites, highlighted a leaf age dependent effect of PS3 treatment. Nitrogen compounds, and sugars to a lesser extent, were impacted. The results obtained complete the current knowledge of the impact of elicitor-induced resistance on plant physiology. They will be helpful to guide further experiments required to better determine the costs and benefits of elicitor-induced resistance in plants.

F-CphI represents a new homing endonuclease family using the Endo VII catalytic motif.

BACKGROUND: There are six known families of homing endonucleases, LAGLIDADG, GIY-YIG, HNH, His-Cys box, PD-(D/E)-XK, and EDxHD, which are characterized by their conserved residues. Previously, we discovered a novel homing endonuclease F-CphI encoded by ORF177 of cyanophage S-PM2. F-CphI does not resemble any characterized homing endonucleases. Instead, the C-terminus of F-CphI aligns well with the N-terminal catalytic domain of a Holliday junction DNA resolvase, phage T4 endonuclease VII (Endo VII). RESULTS: A PSI-BLAST search resulted in a total of 313 Endo VII motif-containing sequences in sequenced genomes. Multiple sequence alignment showed that the catalytically important residues of T4 Endo VII were all well conserved in these proteins. Our site-directed mutagenesis studies further confirmed that the catalytically important residues of T4 Endo VII were also essential for F-CphI activity, and thus F-CphI might use a similar protein fold as Endo VII for DNA cleavage. A phylogenetic tree of the Endo VII motif-containing sequences showed that putative resolvases grouped into one clade while putative homing endonucleases and restriction endonucleases grouped into another clade. CONCLUSIONS: Based on the unique conserved residues, we proposed that F-CphI represents a new homing endonuclease family, which was named the DHHRN family. Our phylogenetic analysis could be used to predict the functions of many previously unknown proteins.

Impact of Fever and Antipyretic Use on Influenza Vaccine Immune Reponses in Children.

BACKGROUND: Comparing postvaccination fever rates in pediatric influenza vaccine clinical trials is difficult due to variability in how fever is reported. The impact of vaccine-related fever and antipyretic use on trivalent influenza vaccine immunogenicity in children is also unclear. METHODS: In this pilot study, we used individual-level data provided by GlaxoSmithKline from 3 pediatric clinical trials of GlaxoSmithKline versus comparator trivalent influenza vaccine. We explored a primary study (NCT00764790), the largest trial involving young children (6-35 months, n = 3317), and further explored key findings in the 2 other trials (3-17 years, NCT00980005; 6 months to 17 years, NCT00383123). We analyzed postvaccination fever and antipyretic use, and their association with immunogenicity through use of multivariable regression. RESULTS: Postvaccination fever data were reanalyzed from the primary study using the Brighton Collaboration standardized definition (vaccine-related fever ≥38°C, measured by any route, reported after each dose). Rates were substantially lower after first (2.7%-3.4%) and second doses (3.3%-4.1%), than those published (6.2%-6.6%; combined dose data, any causality). A pooled immunogenicity analysis combining the 3 studies (n = 5902) revealed children with postvaccination fever had significantly higher adjusted geometric mean titers than those without fever (ratio, 1.21-1.39; P ≤ 0.01). Conversely those with antipyretic use had significantly lower adjusted geometric mean titers (ratio, 0.80-0.87; P < 0.0006), dependent on virus strain. CONCLUSIONS: Varying analyses and reporting methods can result in substantially different reported fever rates in studies. Standardized reporting of fever is needed to facilitate comparison between studies. Fever and antipyretic use may have important associations with influenza vaccine immunogenicity in children and need further prospective investigation.

Differential interaction of PRMT1 with RGG-boxes of the FET family proteins EWS and TAF15.

The FET sub-family (FUS/TLS, EWS, TAF15) of RNA-binding proteins have remarkably similar overall structure but diverse biological and pathological roles. The molecular basis for FET protein specialization is largely unknown. Gly-Arg-Rich regions (RGG-boxes) within FET proteins are targets for methylation by Protein-Arginine-Methyl-Transferase-1 (PRMT1) and substrate capture is thought to involve electrostatic attraction between positively charged polyRGG substrates and negatively charged surface channels of PRMT1. Unlike FUS and EWS, a high proportion of TAF15 RGG-boxes are embedded within neutrally charged YGGDR(S/G)G repeats, suggesting that they might not bind well to PRMT1. This notion runs contrary however to a report that YGGDR(S/G)G repeats are methylated by PRMT1. Using peptide-based polyRGG substrates and a novel 2-hybrid binding assay, we find that the Asp residue in YGGDR(S/G)G repeats confers poor binding to PRMT1. Our results therefore indicate that YGGDR(S/G)G repeats may contribute to TAF15 specialization by enabling differential interactions with PRMT1 and reduced overall levels of TAF15 methylation compared with other FET proteins. By analogy with molecular recognition of other disordered polyvalent ligands by globular protein partners, we also propose a dynamic polyelectrostatic model for substrate capture by PRMT1.

Three-Dimensional Superresolution Imaging of the FtsZ Ring during Cell Division of the Cyanobacterium Prochlorococcus.

Superresolution imaging has revealed subcellular structures and protein interactions in many organisms. However, superresolution microscopy with lateral resolution better than 100 nm has not been achieved in photosynthetic cells due to the interference of a high-autofluorescence background. Here, we developed a photobleaching method to effectively reduce the autofluorescence of cyanobacterial and plant cells. We achieved lateral resolution of ~10 nm with stochastic optical reconstruction microscopy (STORM) in the sphere-shaped cyanobacterium Prochlorococcus and the flowering plant Arabidopsis thaliana During the cell cycle of Prochlorococcus, we characterized the three-dimensional (3D) organization of the cell division protein FtsZ, which forms a ring structure at the division site and is important for cytokinesis of bacteria and chloroplasts. Although the FtsZ ring assembly process in rod-shaped bacteria has been studied extensively, it has rarely been studied in sphere-shaped bacteria. Similarly to rod-shaped bacteria, our results with Prochlorococcus also showed the assembly of FtsZ clusters into incomplete rings and then complete rings during cell division. Differently from rod-shaped bacteria, the FtsZ ring diameter was not found to decrease during Prochlorococcus cell division. We also discovered a novel double-Z-ring structure, which may be the Z rings of two daughter cells in a predivisional mother cell. Our results showed a quantitative picture of the in vivo Z ring organization of sphere-shaped bacteria.IMPORTANCE Superresolution microscopy has not been widely used to study photosynthetic cells due to their high-autofluorescence background. Here, we developed a photobleaching method to reduce the autofluorescence of cyanobacteria and plant cells. After photobleaching, we performed superresolution imaging in the cyanobacterium Prochlorococcus and the flowering plant Arabidopsis thaliana with ~10-nm resolution, which is the highest resolution in a photosynthetic cell. With this method, we characterized the 3D organization of the cell division protein FtsZ in Prochlorococcus We found that the morphological variation of the FtsZ ring during cell division of the sphere-shaped cyanobacterium Prochlorococcus is similar but not identical to that of rod-shaped bacteria. Our method might also be applicable to other photosynthetic organisms.

The Spectrum and Burden of Influenza-Associated Neurological Disease in Children: Combined Encephalitis and Influenza Sentinel Site Surveillance From Australia, 2013-2015.

Background: There are few longitudinal studies of seasonal influenza-associated neurological disease (IAND) and none from the Southern Hemisphere. Methods: We extracted prospectively acquired Australian surveillance data from 2 studies nested within the Paediatric Active Enhanced Disease Surveillance (PAEDS) network: the Influenza Complications Alert Network (FluCAN) study and the Australian Childhood Encephalitis (ACE) study between 2013 and 2015. We described the clinical features and severity of IAND in children, including influenza-associated encephalitis/encephalopathy (IAE). We calculated the proportion of hospitalized influenza that is associated with IAND and IAE, and incidence of IAE. Results: Over 3 influenza seasons, we identified 54 cases of IAND at 2 tertiary children's hospitals from Australia that accounted for 7.6% of hospitalized influenza. These included 10 cases of IAE (1.4% hospitalized influenza). The mean annual incidence of IAE among Australian children (aged ≤14 years) was 2.8 per 1000000. The spectrum of IAND was broad and included IAE (n = 10) including distinct acute encephalopathy syndromes, simple febrile seizures (n = 14), other seizures (n = 16), acute ataxia (n = 4), and other subacute syndromes (transverse myelitis [n = 1], opsoclonus myoclonus [n = 1]). Two-thirds of children with IAND were aged ≤4 years; less than half had preexisting neurological disease or other risk factors for severe influenza. IAE caused death or neurological morbidity in half of cases. Conclusions: Seasonal influenza is an important cause of acute neurological disease in Australian children. The spectrum of seasonal IAND appears similar to that described during the 2009 H1N1 pandemic. IAE is associated with high morbidity and mortality.

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.