Search

Abstract Background Forecasting models predicting trends in hospitalization rates have the potential to inform hospital management during seasonal epidemics of respiratory diseases and the associated surges caused by acute hospital admissions. Hospital bed requirements for elective surgery could be better planned if it were possible to foresee upcoming peaks in severe respiratory illness admissions. Forecasting models can also guide the use of intervention strategies to decrease the spread of respiratory pathogens and thus prevent local health system overload. In this study, we explore the capability of forecasting models to predict the number of hospital admissions in Auckland, New Zealand, within a three-week time horizon. Furthermore, we evaluate probabilistic forecasts and the impact on model performance when integrating laboratory data describing the circulation of respiratory viruses. Methods The dataset used for this exploration results from active hospital surveillance, in which the World Health Organization Severe Acute Respiratory Infection (SARI) case definition was consistently used. This research nurse-led surveillance has been implemented in two public hospitals in Auckland and provides a systematic laboratory testing of SARI patients for nine respiratory viruses, including influenza, respiratory syncytial virus, and rhinovirus. The forecasting strategies used comprise automatic machine learning, one of the most recent generative pre-trained transformers, and established artificial neural network algorithms capable of univariate and multivariate forecasting. Results We found that machine learning models compute more accurate forecasts in comparison to naïve seasonal models. Furthermore, we analyzed the impact of reducing the temporal resolution of forecasts, which decreased the model error of point forecasts and made probabilistic forecasting more reliable. An additional analysis that used the laboratory data revealed strong season-to-season variations in the incidence of respiratory viruses and how this correlates with total hospitalization cases. These variations could explain why it was not possible to improve forecasts by integrating this data. Conclusions Active SARI surveillance and consistent data collection over time enable these data to be used to predict hospital bed utilization. These findings show the potential of machine learning as support for informing systems for proactive hospital management.

Objectives and importance of the study: Pharmacist-administered vaccination has expanded in Australia but has not been comprehensively assessed. We aimed to assess the pharmacists’ role in vaccination in Australia before and during the first year of the COVID-19 pandemic, as well as the completeness of data on pharmacist-administered immunisations. Study type: Cross-sectional study. Methods: We analysed data on pharmacist-administered vaccinations that were reported to the Australian Immunisation Register (AIR) between 2016 and 2019, categorised by gender, jurisdiction, age group and vaccine type. We conducted a national survey of community pharmacists providing vaccination services during June and July 2020 to understand how pharmacists record and report vaccinations to the AIR. We assessed data completeness by comparing the number of vaccinations reported by surveyed pharmacists to the number recorded on the AIR. Results: 576 780 pharmacist-administered vaccinations were recorded on the AIR between 2016 and 2019, of which 94.7% were influenza vaccines. The proportion of vaccinations given by pharmacists increased each year, from

BackgroundIn Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations.Methods and findingsIn 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size.ConclusionsIn this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation.Trial registrationClinicalTrials.gov NCT01735084 and NCT01174849.

Vaccination against invasive pneumococcal disease is recommended for older adults but the optimal age group to target has not been determined and may vary by epidemiological setting. Here, the authors use statistical modelling to estimate the optimal ages for vaccination in Brazil, England, Malawi, and South Africa.

Measurement(s) temperature of water • temperature profile Technology Type(s) digital curation Factor Type(s) lake location • temporal interval Sample Characteristic - Environment lake • reservoir Sample Characteristic - Location global Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14619009

Objective: Pregnant women are recognised as being at risk of serious illness from influenza. Despite this, and longstanding national recommendations for vaccination in pregnancy, vaccine uptake remains suboptimal. This study aims to determine factors associated with women declining influenza vaccination in pregnancy. Method: We surveyed pregnant women from antenatal clinics at two Sydney hospitals as part of an evaluation of the New South Wales (NSW) Health 2017 influenza vaccination in pregnancy campaign. Factors associated with a woman’s decision to decline influenza vaccination were assessed using Pearson’s chi-square test and multivariable logistic regression. Results: Among 642 women surveyed, 58% self-reported influenza vaccination during pregnancy and 19% reported they had declined vaccination. Factors associated with a decision to decline vaccination included lack of a recommendation from a maternity care provider (adjusted odds ratio [aOR] 6.06; 95% confidence interval [CI] 3.50, 10.50), recommendation against vaccination (aOR 4.17; 95% CI 2.07, 8.38), having never previously been vaccinated for influenza (aOR 2.75; 95% CI 1.64, 4.59) and, among third-trimester women, not having been vaccinated for pertussis (aOR 2.55; 95% CI 1.32, 4.89). On univariate analyses, women who declined vaccination were more likely to disagree or feel uncertain about vaccine safety or effectiveness compared with women who chose to be vaccinated. Conclusion: Recommendations from maternity care providers remain key to a woman’s decision to be vaccinated for influenza during pregnancy. Time should be allocated for vaccine discussions early in pregnancy as part of routine care. Continued efforts are needed to improve messaging to pregnant women on the benefits, safety and efficacy of influenza vaccination.

Abstract Background Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months. Methods In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2–4-6 months (_PPP), Synflorix™ (S) at 2–4-6 months (_SSS), or Synflorix™ at 1–2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM). Results Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM. Conclusions Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life. Trial registration ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.gov NCT01174849 registered 04/08/2010.

Altered mental status is a major criterion for a diagnosis of encephalitis to be made with alteration in behavior, a key manifestation of altered mental status. We reviewed all evaluated cases identified by the Australian Childhood Encephalitis study between May 2013 and June 2018, to review the frequency and features of altered behavior (ALB). ALB was reported in >72% of cases of childhood encephalitis in all three major etiologic groups (infectious, immune-mediated, and unknown). The duration of ALB was >7 days in a minority, but significantly more frequent in immune-mediated compared with infectious encephalitis (27 and 10%, respectively, p < 0.01). ALB was most frequently characterized as irritability/agitation (47%), which predominated in children aged 1 year and most frequent in immune-mediated encephalitis. Hallucinations, paranoia, and aggression were all infrequent; suicidality/self-harm was not observed. ALB was reported in 20 of 21 cases of anti-N-methyl-d-aspartate receptor (anti-NMDAr), 19% for >7 days, and disorientation/confusion was the most frequent feature. Only one case was reported as presenting with “psychosis” and was diagnosed with anti-NMDAr encephalitis. Clinician-reported ALB is frequent but most often non-specific in childhood encephalitis. A longer duration of ALB is associated with an immune-mediated cause. More specific psychiatric symptoms (hallucinations, paranoia) are very infrequent. ALB is a hallmark of anti-NMDAr encephalitis, but psychosis is uncommon in contrast to the disorder in adults.

Cantu syndrome, or hypertrichotic osteochondrodysplasia, is a rare, autosomal dominant genetically heterogeneous disorder. It is characterized by hypertrichosis, cardiac and skeletal anomalies and distinctive coarse facial features. We report a case where slowed growth velocity at 13 years led to identification of multiple pituitary hormone deficiencies. This adds to other reports of pituitary abnormalities in this condition and supports inclusion of endocrine monitoring in the clinical surveillance of patients with Cantu syndrome.

Background: Aboriginal children living in remote communities are at high risk of early and persistent otitis media. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are primary pathogens. Vaccines with potential to prevent early OM have not been evaluated in this population. We compared immunogenicity (ELISA and opsonophagocytic activity) of a combination of Synflorix™ (PHiD-CV10, 10 serotypes and protein D of NTHi) and Prevenar13™ (PCV13, 10 serotypes plus 3, 6A, and 19A), with recommended schedules. Methods: This open-label superiority trial randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to PCV13 (P) at 2–4-6 months (_PPP), PHiD-CV10 (S) at 2–4-6 months (_SSS), or PHiD-CV10 at 1–2–4 plus PCV13 at −6 months (SSSP). Primary outcomes (blinded) were immunogenicity against PCV13-only serotypes 3, 6A, 19A, and PHiD-CV10-only protein D at 7 months. Secondary outcomes include immunogenicity against all serotypes at 2, 4 and 7 months. Findings: Between 2011 and 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). An intention to treat approach including all available data was used. The SSSP group had superior immunogenicity against serotypes 3, 6A, and 19A compared to _SSS (OPA GMT ratios 8.1 to 59.5, p

Introduction Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A.Methods and analyses Our randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported.Ethics and dissemination Ethics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals.Trial registration number NCT01735084.

TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane translocation has been shown to control the response of several members of the transient receptor potential (TRP) family of ion channels to different stimuli. Here, we show that TRPV4 stimulation with GSK1016790A caused an increase in [Ca2+]i that is stable for a few minutes. Single molecule analysis of TRPV4 channels showed that the density of TRPV4 at the plasma membrane is controlled through two modes of membrane trafficking, complete, and partial vesicular fusion. Further, we show that the density of TRPV4 at the plasma membrane decreased within 20 min, as they translocate to the recycling endosomes and that the surface density is dependent on the release of calcium from the intracellular stores and is controlled via a PI3K, PKC, and RhoA signaling pathway.

Introduction: In countries where measles is rare, health-care-setting transmissions remain problematic. Australia experienced its largest measles outbreak in 15 years in 2012 with 199 cases reported nationally; 170 cases occurred in the state of New South Wales (NSW) with symptom onset between 7 April and 29 November 2012. Methods: A descriptive study was conducted using measles case data obtained from metropolitan Sydney local health districts in NSW in 2012. Characteristics of measles source and secondary cases were described. Details of health-care presentations resulting and not resulting in measles transmission were also analysed. Results: There were 168 confirmed and two probable cases resulting in 405 documented health-care presentations. Thirty-four secondary cases acquired in health-care settings were identified, including 29 cases resulting from 14 source cases and 5 cases whose source could not be identified. Health-care-acquired cases accounted for 20% of all cases in this outbreak. Source cases were more likely to be of Pacific Islander descent (p = 0.009) and to have had more presentations before diagnosis (p = 0.012) compared to other cases. The percentage of presentations to emergency departments was higher for presentations that resulted in transmission compared to those that did not (71.4% and 37.6%, respectively, p = 0.028). There were no significant differences between transmission and non-transmission presentations with respect to presence of rash and infection control measures (p = 0.762 and p = 0.221, respectively), although the power to detect these differences was limited. Rash was reported at 66% of the presentations. Conclusion: Development of and adherence to protocols for the management of patients presenting to hospitals with fever and rash will minimize secondary transmission of measles.

Infections take their greatest toll in early life necessitating robust approaches to protect the very young. Here, we review the rationale, current state, and future research directions for one such approach: neonatal immunization. Challenges to neonatal immunization include natural concern about safety as well as a distinct neonatal immune system that is generally polarized against Th1 responses to many stimuli such that some vaccines that are effective in adults are not in newborns. Nevertheless, neonatal immunization could result in high-population penetration as birth is a reliable point of healthcare contact, and offers an opportunity for early protection of the young, including preterm newborns who are deficient in maternal antibodies. Despite distinct immunity and reduced responses to some vaccines, several vaccines have proven safe and effective at birth. While some vaccines such as polysaccharide vaccines have little effectiveness at birth, hepatitis B vaccine can prime at birth and requires multiple doses to achieve protection, whereas the live-attenuated Bacille Calmette–Guérin (BCG), may offer single shot protection, potentially in part via heterologous (“non-specific”) beneficial effects. Additional vaccines have been studied at birth including those directed against pertussis, pneumococcus, Haemophilus influenza type B and rotavirus providing important lessons. Current areas of research in neonatal vaccinology include characterization of early life immune ontogeny, heterogeneity in and heterologous effects of BCG vaccine formulations, applying systems biology and systems serology, in vitro platforms that model age-specific human immunity and discovery and development of novel age-specific adjuvantation systems. These approaches may inform, de-risk, and accelerate development of novel vaccines for use in early life. Key stakeholders, including the general public, should be engaged in assessing the opportunities and challenges inherent to neonatal immunization.

ABSTRACT Objective Immunisation remains one of the most important public health interventions. However, linkage of population-based immunisation registers to perinatal and health outcome datasets to evaluate immunisation programs is limited. We have conducted the first-ever linkages of immunisation records from Australia’s Childhood Immunisation Register (ACIR) for the purposes of evaluating Australia’s unique national immunisation program. As an initial outcome of our linkage study we present estimates of pneumococcal conjugate vaccine (PCV) coverage for the 3rd dose assessed at 12 months of age in extremely preterm children (gestational age 99% were used to identify immunisation records from ACIR to link to the birth cohort. A unique scrambled pin on ACIR was used to link immunisation records to birth cohort datasets. The final cohort consisted of 1,954,019 children with 95.5% linking to at least 1 ACIR record from a total of >26.6 million ACIR records. In 2001, coverage of the 3rd dose of PCV in extremely preterm children was 0.9% and increased to 69.1% in 2004 (overall coverage 2001-2004: 25.3%). From 2005 to 2012, coverage increased to an average of 89.7%. Conclusion These are the first results of cross-jurisdictional linkages of immunisation records to state-based administrative datasets in Australia. This process has identified some improvements that are needed to streamline future linkage projects of this scale. Linkage of perinatal datasets to ACIR has enabled us to assess the first-ever coverage estimates in specific medically at-risk population subgroups. Future analyses will focus on the predictors and timeliness of vaccination coverage and population based estimates of vaccine effectiveness.

ABSTRACT Objectives Australia’s Childhood Immunisation Register (ACIR) is one of only a handful of national immunisation registers world-wide. We have, for the first time, linked the ACIR to other health datasets to measure the real-world impact of Australia’s immunisation program. In this study, we aimed to assess the population-based effectiveness of the 3-dose infant pneumococcal vaccination program (due at 2, 4, and 6 months) against invasive pneumococcal disease caused by the 7 vaccine specific serotypes. The 7-valent pneumococcal conjugate vaccine (PCV7) has been available since 2001 and a funded universal program started in 2005 (with a switch to 13-valent PCV in 2011). Approach Vaccination records from ACIR, death records, and invasive pneumococcal disease notifications for 2001-2013 were individually linked for 1.37 million children born in 2001-2012 in two Australian states (Western Australia and New South Wales). A Cox proportional hazards model (adjusting for sex, Indigenous status and year of birth) was used to estimate the hazard ratio for invasive pneumococcal disease in vaccinated compared to unvaccinated children less than 2 years old. The per cent of disease prevented by vaccination, or vaccine effectiveness, was calculated as (1-adjusted hazard ratio) x 100%. Results From 2005, vaccination coverage with dose 3 of the pneumococcal vaccine was steady at ~91% in eligible cohorts. Between 2001 and 2013, there were 468 notifications of invasive pneumococcal disease caused by the 7 vaccine specific serotypes during 2.66 million person years of observation; only 39 (8.3%) of these cases occurred after the universal program was implemented. Vaccine effectiveness against invasive pneumococcal disease caused by the 7 vaccine specific serotypes for 1, 2 and 3 doses of the pneumococcal vaccine was 68% (95%CI: 44-89%), 93% (81-97%), and 92% (95%CI: 86-93%), respectively. Conclusion This is the first study to link Australia’s national immunisation register and measure population-based vaccine effectiveness. The study provides robust evidence of the effectiveness of at least 2 doses of pneumococcal vaccine against vaccine serotype specific infection using a 3 dose infant schedule.

Acellular vaccines against Bordetella pertussis were introduced in Australia in 1997. By 2000, these vaccines had replaced whole-cell vaccines. During 2008–2012, a large outbreak of pertussis occurred. During this period, 30% (96/320) of B. pertussis isolates did not express the vaccine antigen pertactin (prn). Multiple mechanisms of prn inactivation were documented, including IS481 and IS1002 disruptions, a variation within a homopolymeric tract, and deletion of the prn gene. The mechanism of lack of expression of prn in 16 (17%) isolates could not be determined at the sequence level. These findings suggest that B. pertussis not expressing prn arose independently multiple times since 2008, rather than by expansion of a single prn-negative clone. All but 1 isolate had ptxA1, prn2, and ptxP3, the alleles representative of currently circulating strains in Australia. This pattern is consistent with continuing evolution of B. pertussis in response to vaccine selection pressure.

Objective To estimate the measles effective reproduction number (R) in Australia by modelling routinely collected notification data. Methods R was estimated for 2009–2011 by means of three methods, using data from Australia's National Notifiable Disease Surveillance System. Method 1 estimated R as 1 − P, where P equals the proportion of cases that were imported, as determined from data on place of acquisition. The other methods estimated R by fitting a subcritical branching process that modelled the spread of an infection with a given R to the observed distributions of outbreak sizes (method 2) and generations of spread (method 3). Stata version 12 was used for method 2 and Matlab version R2012 was used for method 3. For all methods, calculation of 95% confidence intervals (CIs) was performed using a normal approximation based on estimated standard errors. Findings During 2009–2011, 367 notifiable measles cases occurred in Australia (mean annual rate: 5.5 cases per million population). Data were 100% complete for importation status but 77% complete for outbreak reference number. R was estimated as

Herpes zoster (HZ) is a common condition that increases in incidence with older age but vaccines are available to prevent the disease. However, there are limited data estimating the health system burden attributable to herpes zoster by age.In this study, we quantified excess healthcare resource usage associated with HZ during the acute/sub-acute period of disease (21days before to 90 days after onset) in 5952 cases and an equal number of controls matched on age, sex, and prior healthcare resource usage. Estimates were adjusted for potential confounders in multivariable regression models. Using population-based estimates of HZ incidence, we calculated the age-specific excess number of health service usage events attributable to HZ in the population.Per HZ case, there was an average of 0.06 (95% CI 0.04-0.08) excess hospitalisations, 1.61 (95% CI 1.51-1.69) excess general practitioner visits, 1.96 (95% CI 1.86-2.15) excess prescriptions filled and 0.11 (95% CI 0.09-0.13) excess emergency department visits. The average number of healthcare resource use events, and the estimated excess per 100,000 population increased with increasing age but were similar for men and women, except for higher rates of hospitalisation in men. The excess annual HZ associated burden of hospitalisations was highest in adults ≥80 years (N = 2244, 95%CI 1719-2767); GP visits was highest in those 60-69 years (N = 50567, 95%CI 39958-61105), prescriptions and ED visits were highest in 70-79 years (N = 50524, 95%CI 40634-60471 and N = 2891, 95%CI 2319-3449 respectively).This study provides important data to establish the healthcare utilisation associated with HZ against which detailed cost-effectiveness analyses of HZ immunisation in older adults can be conducted.

Background and purpose. Arachidonic acid (AA) and its derivatives are important modulators of cellular signalling. The transient receptor potential cation channel subfamily A, member 1 (TRPA1) is a cation channel with important functions in mediating cellular responses to noxious stimuli and inflammation. There is limited information about the interactions between AA itself and TRPA1, so we investigated the effects of AA and key ethanolamide and amino acid/neurotransmitter derivatives of AA on hTRPA1.Experimental approach. HEK 293 cells expressing hTRPA1 were studied by measuring changes in intracellular calcium ([Ca]i) with a fluorescent dye and by standard whole cell patch clamp recordings.Key results. AA (30 μM) increased fluorescence in hTRPA1 expressing cells by 370% (notional EC50 13 μM). The covalent TRPA1 agonist cinnamaldehyde (300 μM) increased fluorescence by 430% (EC50, 11 μM). Anandamide (230%) and N-arachidonoyl tyrosine (170%) substantially activated hTRPA1 at 30 μM, however, N-arachidonoyl conjugates of glycine and taurine were less effective while N-acyl conjugates of 5-HT did not affect hTRPA1. Changing the acyl chain length or the number and position of double bonds reduced fatty acid efficacy at hTRPA1. Mutant hTRPA1 (Cys621, Cys641 and Cys665 changed to Ser) could be activated by AA (100 μM, 40% of wild type) but not by cinnamaldehyde (300 μM).Conclusions and implications. AA is a more potent activator of TRPA1 than its ethanolamide or amino acid/neurotransmitter derivatives and acts via a mechanism distinct from that of cinnamaldehyde, further underscoring the likelyhood of multiple pharmacologically exploitable sites on hTRPA1.

Australia, like most countries, faces high and rapidly-rising drug costs. There are longstanding concerns about pharmaceutical companies inappropriately extending their monopoly position by "evergreening" blockbuster drugs, through misuse of the patent system. There is, however, very little empirical information about this behaviour. We fill the gap by analysing all of the patents associated with 15 of the costliest drugs in Australia over the last 20 years. Specifically, we search the patent register to identify all the granted patents that cover the active pharmaceutical ingredient of the high-cost drugs. Then, we classify the patents by type, and identify their owners. We find a mean of 49 patents associated with each drug. Three-quarters of these patents are owned by companies other than the drug's originator. Surprisingly, the majority of all patents are owned by companies that do not have a record of developing top-selling drugs. Our findings show that a multitude of players seek monopoly control over innovations to blockbuster drugs. Consequently, attempts to control drug costs by mitigating misuse of the patent system are likely to miss the mark if they focus only on the patenting activities of originators.

BackgroundCross-sectional serosurveys using IgG antibody to pertussis toxin (IgG-PT) are increasingly being used to estimate trends in recent infection independent of reporting biases.Methods/principal findingsWe compared the age-specific seroprevalence of various levels of IgG-PT in cross-sectional surveys using systematic collections of residual sera from Australian diagnostic laboratories in 1997/8, 2002 and 2007 with reference to both changes in the pertussis vaccine schedule and the epidemic cycle, as measured by disease notifications. A progressive decline in high-level (≥62.5 EU/ml) IgG-PT prevalence from 19% (95% CI 16-22%) in 1997/98 to 12% (95% CI 11-14%) in 2002 and 5% (95% CI 4-6%) in 2007 was consistent with patterns of pertussis notifications in the year prior to each collection. Concomitantly, the overall prevalence of undetectable (Conclusions/significancePopulation seroprevalence of high levels of IgG-PT is accepted as a reliable indicator of pertussis disease activity over time within and between countries with varying diagnostic practices, especially in unimmunised age groups. Our novel findings suggest that increased prevalence of undetectable IgG-PT is an indicator of waning immunity useful for population level monitoring following introduction of acellular vaccines and/or schedule changes.

Objective To examine trends in varicella and herpes zoster (HZ) hospitalization following the availability and subsequent National Immunization Programme funding of one-dose varicella vaccination in Australia. Methods Varicella vaccination coverage for children born between 2001 and 2009 was obtained from the Australian Childhood Immunization Register. Principal or any coded varicella or HZ hospitalizations were retrieved from the national hospital morbidity database from 1998 to 2010. Trends in hospitalization rates in different age groups and indigenous status were assessed. Incidence rate ratios (IRR) were calculated between periods before and after implementation of immunization programme funding. Findings In the first year of the funded immunization programme, varicella vaccine coverage reached 75% in children aged 24 months and more than 80% in children aged 60 months. Compared with the pre-vaccine period, varicella hospitalization rates during the funded programme were significantly lower for age groups younger than 40 years; with the greatest reduction in children aged 18–59 months (IRR: 0.25; 95% confidence interval, CI: 0.22–0.29). Indigenous children had a higher varicella hospitalization rate compared with non-indigenous children before vaccine implementation (IRR: 1.9; 95% CI: 1.4–2.7), but afterwards reached equivalence (IRR: 1.1; 95% CI: 0.7–1.6). The age-standardized HZ hospitalization rate declined between the periods (IRR: 0.95; 95% CI: 0.92–0.97). Conclusion Rapid attainment of high coverage reduced varicella hospitalizations in the targeted age group, particularly for indigenous children, but also in non-targeted age groups, with no increase in HZ hospitalizations. This suggests high one-dose varicella vaccine coverage can have a substantial impact on severe disease.

BACKGROUND: Live attenuated varicella vaccines for the prevention of varicella (chickenpox) has been demonstrated both in randomised controlled trials (RCTs) and in population-based immunisation programmes in countries such as the United States. However, many countries do not routinely immunise children against varicella, and exposures continue to occur. Although the disease is often mild, complications such as secondary bacterial infection, pneumonitis and encephalitis occur in about 1% of cases, usually leading to hospitalisation. The use of varicella vaccine in persons who have recently been exposed to the varicella zoster virus has been studied as a form of post-exposure prophylaxis (PEP). OBJECTIVE: To assess the efficacy and safety of vaccines for use as PEP for the prevention of varicella in children and adults. CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2008, Issue 1); MEDLINE (1966 to February 2008); and EMBASE (January 1990 to February 2008). SELECTION CRITERIA: RCTs and quasi-RCTs of varicella vaccine for PEP compared with placebo or no intervention. The outcome measures were efficacy in prevention of clinical cases and/or laboratory-confirmed clinical cases and adverse effects following vaccination. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and analysed data using Review Manager software. MAIN RESULTS: Three studies involving 110 healthy children who were siblings of household contacts were identified as suitable for inclusion. The studies varied in quality, study design, vaccine used, and outcomes measured and, as such, were not suitable for meta-analysis. Overall, 13 out of 56 vaccine recipients (18%) developed varicella compared with 42 out of 54 placebo (or no vaccine) recipients (78%). Of the vaccine recipients who developed varicella, the majority only had mild disease (with less than 50 skin lesions). In the three studies, most subjects received PEP within three days following exposure; too few subjects were vaccinated four to five days post exposure to ascertain the efficacy of vaccine given more than three days after exposure. No included studies reported on adverse events following immunisation. AUTHORS CONCLUSIONS: These small trials suggest varicella vaccine administered within three days to children following household contact with a varicella case reduces infection rates and severity of cases. No RCTs for adolescents or adults were identified. However safety was not adequately addressed.