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Chan M, Owens L, Gray ML, Selvadurai H, Jaffe A, Homaira N. J Asthma Allergy. 2023;16:1139–1155. The authors have advised that on page 1139, “Results” section in the abstract, first sentence should read from “Of the 18,932 children with polymerase chain reaction (PCR) confirmed COVID-19 who attended SCHN, 60% received their care during delta wave, and 5.41% (n = 913) had prior diagnosis of asthma” to “Of the 18,932 children with polymerase chain reaction (PCR) confirmed COVID-19 who attended SCHN, 60% received their care during delta wave, and 5.41% (n = 1025) had prior diagnosis of asthma” and on page 1141, “Results” section, second paragraph, first sentence should read from “Of the 18,932 children with COVID-19, 913 (5.41%) were asthmatic (Table 1).” to “Of the 18,932 children with COVID-19, 1025 (5.41%) were asthmatic (Table 1).” The authors apologize for these errors.

Mei Chan,1 Louisa Owens,1,2 Melinda Louise Gray,2 Hiran Selvadurai,3,4 Adam Jaffe,1,2 Nusrat Homaira1,2,5 1Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; 2Respiratory Department, Sydney Children’s Hospital, Randwick, NSW, Australia; 3Respiratory Medicine, Children’s Hospital at Westmead, Westmead, NSW, Australia; 4Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; 5James P Grant School of Public Health, BRAC University, Dhaka, 1213, BangladeshCorrespondence: Nusrat Homaira, Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2031, Australia, Tel +612 93825526, Email n.homaira@unsw.edu.auPurpose: Earlier coronavirus-19 (COVID-19) pandemic reports did not implicate increased disease burden in asthmatics while subsequent findings have been inconsistent. To date, the impact of COVID-19 on childhood asthma remains undetermined and is further complicated with ongoing emergence of new variants. This study aimed to investigate association between asthma and COVID-19 for children in New South Wales (NSW), Australia and compare its differences across four major outbreaks from alpha, delta and omicron variants/subvariants.Methods: This is a retrospective cross-sectional study of all children aged ≤ 17 years old who sought care for COVID-19 at Sydney Children’s Hospitals Network (SCHN) between 1 January 2020 and 31 May 2022.Results: Of the 18,932 children with polymerase chain reaction (PCR) confirmed COVID-19 who attended SCHN, 60% received their care during delta wave, and 5.41% (n = 913) had prior diagnosis of asthma. Among children with COVID-19, the odds of having asthma were lower during alpha (aOR = 0.43; 95% CI, 0.19– 0.83) and delta wave (aOR = 0.84; 95% CI, 0.73– 0.96), but were higher during omicron wave (aOR =

Developing O2-selective adsorbents that can produce high-purity oxygen from air remains a significant challenge. Here, we show that chemically reduced metal-organic framework materials of the type AxFe2(bdp)3 (A = Na+, K+; bdp2- = 1,4-benzenedipyrazolate; 0 < x ≤ 2), which feature coordinatively saturated iron centers, are capable of strong and selective adsorption of O2 over N2 at ambient (25 °C) or even elevated (200 °C) temperature. A combination of gas adsorption analysis, single-crystal X-ray diffraction, magnetic susceptibility measurements, and a range of spectroscopic methods, including 23Na solid-state NMR, Mössbauer, and X-ray photoelectron spectroscopies, are employed as probes of O2 uptake. Significantly, the results support a selective adsorption mechanism involving outer-sphere electron transfer from the framework to form superoxide species, which are subsequently stabilized by intercalated alkali metal cations that reside in the one-dimensional triangular pores of the structure. We further demonstrate O2 uptake behavior similar to that of AxFe2(bdp)3 in an expanded-pore framework analogue and thereby gain additional insight into the O2 adsorption mechanism. The chemical reduction of a robust metal-organic framework to render it capable of binding O2 through such an outer-sphere electron transfer mechanism represents a promising and underexplored strategy for the design of next-generation O2 adsorbents.

Background: Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans. Methods: A phase three, randomised, double-blind, placebo-controlled trial was done at eight paediatric cystic fibrosis centres in Australia and New Zealand. Infants (aged 3–6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Exclusion criteria included prolonged mechanical ventilation in the first 3 months of life, clinically significant medical disease or comorbidities other than cystic fibrosis, or macrolide hypersensitivity. Participants were randomly assigned (1:1) to receive either azithromycin (10 mg/kg bodyweight orally three times per week) or matched placebo until age 36 months. Randomisation was done with a permuted block strategy and an interactive web-based response system, stratified by study site. Unblinding was done once all participants completed the trial. The two primary outcomes were the proportion of children with radiologically defined bronchiectasis, and the percentage of total lung volume affected by disease. Secondary outcomes included clinical outcomes and exploratory outcomes were inflammatory markers. Analyses were done with the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT01270074). Findings: Between June 15, 2012, and July 10, 2017, 281 patients were screened, of whom 130 were enrolled, randomly assigned, and received first study dose. 68 participants received azithromycin and 62 received placebo. At 36 months, 88% (n=50) of the azithromycin group and 94% (n=44) of the placebo group had bronchiectasis (odds ratio 0·49, 95% CI 0·12 to 2·00; p=0·32), and total airways disease did not d

Respiratory illness is the leading cause of mortality in children with cerebral palsy (CP). Although risk factors for developing chronic respiratory illness have been identified, comprehensive clinical care recommendations for the prevention and management of respiratory illness do not currently exist. We invited over 200 clinicians and researchers from multiple disciplines with expertise in the management of respiratory illness in children with CP to develop care recommendations using a modified Delphi method on the basis of the RAND Corporation–University of California Los Angeles Appropriateness Method. These recommendations are intended for use by the wide range of practitioners who care for individuals living with CP. They provide a framework for recognizing multifactorial primary and secondary potentially modifiable risk factors and for providing coordinated multidisciplinary care. We describe the methods used to generate the consensus recommendations, and the overall perspective on assessment, prevention, and treatment of respiratory illness in children with CP. What this paper adds: The first consensus statement for preventing and managing respiratory disease in cerebral palsy (CP). Risk factors for respiratory disease in CP should be identified early. Individuals with CP at risk of respiratory disease require regular assessment of risk factors. Effective partnerships between multidisciplinary teams, individuals with CP, and families are essential. Treatment of respiratory disease in individuals with CP must be proactive.

Despite the urgent case for bringing new energy technologies to the marketplace, the delivery of these innovations has been frustratingly slow, often taking several decades to develop even the most promising ideas into novel technologies that achieve a significant amount of market penetration. The pathway for delivering new energy technologies is frequently discussed in the literature in a vague and aggregated way, but innovation tends to consist of a series of partially overlapping processes consisting of: (1) the production of scientific and technological knowledge, (2) the translation of that knowledge into working technologies or artifacts, and (3) the introduction of the artifacts into the marketplace, where they are matched with users’ requirements. However, relatively little data are available showing how long each of these processes takes for energy technologies. Here we combine information from patent applications with bibliographic data to shine light on the second process—that is, the translation of scientific knowledge into working prototypes. Our results show that energy technologies take an average of approximately 10 years to pass through this phase. These findings will help policymakers to devise more effective mechanisms and strategies for accelerating the overall rate of technological change in this domain.

Mei Chan,1 Melinda Gray,2 Christine Burns,2 Louisa Owens,1,2 Adam Jaffe,1,2 Nusrat Homaira1,2 1Discipline of Paediatrics, School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2031, Australia; 2Respiratory Department, Sydney Children’s Hospital, Randwick, Sydney, NSW, AustraliaCorrespondence: Nusrat HomairaDiscipline of Paediatrics, School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2031, AustraliaTel +612 93825526Email n.homaira@unsw.edu.auPurpose: To evaluate potential variation in care management pathways following hospital discharge for children with asthma in New South Wales, Australia.Methods: A cross-sectional web-based survey was conducted in emergency departments (EDs) and paediatric units of public hospitals with more than five paediatric beds within New South Wales, Australia, between July 2018 and March 2019. Nursing and medical staff in EDs and paediatric units who had cared for children aged under 18 years with asthma in the preceding 12 months were invited to participate in this study. Outcome measures included use of clinical practice guidelines and asthma action plan (AAP); advice on post-hospitalization follow-up; provision of asthma education for parents/carers; availability of community-based asthma services; communication with schools/childcare services.Results: A total of 502 participants (236 nursing and 266 medical staff, response rate=22%) from 37 hospitals were included. Overall, the use of AAP was not universal (median=90%; IQR=81– 96%) with significant difference across local health districts (LHDs) (88.6%, 95% CI=85.4– 91.3) and between EDs and paediatric wards (p=9.4× 10− 9); and a range of asthma clinical practice guidelines were used. Post-hospitalization follow-up within 2– 3 days was recommended by 70% of the respondents, but only 8% reported that hospitals had a system in place to ensure follow-up compliance

Cellular stress has long been acknowledged as a component of disease. More recently, several cellular stress related exosome and lncRNA-based functional mechanisms have been identified in two different disease models. Importantly, the thesis concludes by investigating methods to address and modulate cellular stress as a possible therapeutic treatment to disease.In this project, the cooperative functional role of lncRNAs and exosomes in two disease models was investigated. In chapter 1, we hypothesised that exosomal lncRNAs can modulate cellular signalling and micro-environments in cancer. This was extended by exploring the relationship between exosomes and lncRNAs and the disease cystic fibrosis in chapter 2. Cellular stress and the potential impact of exosomes and lncRNAs on the disease at the cellular level served as the connection between the two different disease models. Our experiments in chapter 3 highlighted the functional capacity of lncRNAs to modulate cellular stress in disease states. Using transcriptome profiling of heat shocked cells, I discovered that the lncRNA retro-EIF2S2 has the ability to modulate cell adherence in response to heat shock. Interestingly, I then demonstrated that exosomes isolated from cancer cells can transfer functional lncRNAs to their recipient cells in chapter 4. Examination of these cancer cell exosomes identified several highly expressed exosomal lncRNA sequences that modulated cell viability. The ubiquity of modulating cellular stress via exosomal transfer in diseased cells was confirmed in cells isolated from CF patients in chapter 5. In these experiments, using primary patient epithelial cells and exosomes, I demonstrate that serum-derived exosomes induce NETosis, modulate wound healing and up regulate inflammation. The potential for moderating cellular stress as a therapeutic strategy was explored in the final experimental chapter (chapter 6). In this approach, I create an oxidative stress model of CF by challenging diffe

Gastrointestinal disease in cystic fibrosis (CF) begins In Utero and continues throughout life. Intestinal dysbiosis and inflammation have been observed in children with CF, however, the mechanisms linking them, and clinical implications are poorly understood. The intestinal tract as a therapeutic target is relatively underexplored. The overarching hypothesis is the intestinal milieu (bacteria, viruses and host-expressed proteins) is altered in children with CF compared to healthy controls (HC), and these changes have implications for intestinal inflammation and clinical outcomes. This thesis presents a series of observational studies characterising alterations in the intestinal milieu in children with CF, with a focus on identifying mechanisms for inflammation, disease, influences on clinical outcomes and potential therapeutic strategies. This thesis presents a novel research program commenced to address the limitations of current microbiome research and explore the gut-lung and gut-brain axes. This thesis demonstrates that in children with CF: (i) the intestinal milieu is structurally and functionally altered compared to HC, (ii) pro-inflammatory microbiota and bacteriophage lysins are increased in abundance, (iii) Ruminococcaceae may be beneficial for growth and lung function, (iv) upstream regulators for intestinal inflammation include interferon gamma, tumour necrosis factor (TNF) 5 and transglutaminase 2, and (v) xanthine dehydrogenase/oxidase (generates reactive oxygen species) negatively correlate with growth measures. Several potential strategies warranting further investigation for intestinal disease in children with CF include: (i) probiotics, (ii) short-chain fatty acid sources, (iii) antioxidants (e.g. glutathione), (iv) lactotransferrin, (v) TNF inhibitors, and (vi) amino acids (e.g. phenylalanine). A systematic review of probiotics for people with CF revealed low-quality evidence suggestive that probiotics may be beneficial to the health of children a

Background and aims: Surface electromyography (sEMG) recording of the inspiratory muscles is a potential non-invasive method of assessing neural respiratory drive (NRD) in children. This thesis explored the application of inspiratory muscle sEMG to assess NRD in healthy children and in children with sleep-disordered breathing. The relationship between sEMG and lung function variables of volume and pressure, and other factors affecting interpretation of sEMG were also evaluated. Method: The reliability of a developed method to quantitatively assess sEMG of the diaphragm (sEMGdi) recorded using a commercial sleep study set up was examined. Surface EMG of the diaphragm recorded from snoring children with and without obstructive sleep apnoea, and also from children with sleep-disordered breathing before and after treatment with pressure support were compared. Inspiratory muscle (scalene, parasternal intercostal, and diaphragm) sEMG recorded from healthy children during tidal breathing and maximal inspiratory ramps were evaluated. Variability in peak inspiratory muscle sEMG recorded during different maximal inspiratory manoeuvres were assessed. Linear mixed models were used to assess factors affecting sEMG magnitude. Results: A reliable method using sEMGdi to assess NRD was developed and demonstrated that NRD was significantly higher in children with obstructive sleep apnoea and increased work of breathing compared to healthy snorers. Provision of positive airway pressure support decreased NRD as reflected by decreased sEMGdi from baseline in children with sleep-disordered breathing. Inspiratory muscle sEMG had a curvilinear/linear relationship with increasing lung volume and pressure. Inspiratory muscle tidal sEMG had a negative linear relationship with age and body mass index (BMI), but not biological sex. Postural changes can affect inspiratory muscle sEMG. Peak sEMG of the inspiratory muscles were recorded from the majority of the children when performing the maximal

The U.S. government invests more than $50 billion per year in R&D procurement but we know little about the outcomes of these investments. We have traced all the patents arising from government funding since the year 2000. About 1.5 percent of all R & D procurement contracts have led to at least one patent for a total of about 13,000 patents. However, contracts connected to patents account for 36 per cent of overall contract value. The gestation lag from the signing date of the contract to the patent filing is on average 33 months and does not depend on the type of R & D performed. Patents that are produced faster also seem to be more valuable. We find strong decreasing returns to contract size. Conditional on generating at least one patent, a 1-percent increase in the size of an R & D contract is associated with 0.12 percent more patents.

Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. Objective: To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. Setting: An Australian paediatric hospital and health consumer organisations. Methods: Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. Results: Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary

The diffusion of knowledge through society proceeds like an invisible ripple that moves between agents through multiple information channels. However, some types of knowledge are recorded, systematised and digitised for the benefit of everyone. Patents and academic articles are examples of such codified knowledge. These documents also contain a common element that is utilised for linking new and established knowledge: citations. This thesis harnesses citations in patents and scientific articles as proxies for signifying the existence of knowledge flows between cited and citing documents, focusing primarily on the dynamics of citation accumulation and the mechanisms governing these dynamics. For this purpose, it is helpful to think of patents and their citations as nodes and links, respectively, in a network where new nodes join the network and distribute their citations among existing nodes. This mode of thinking leads directly to the question: How does the citation network grow? This thesis addresses that question both empirically and theoretically. Two mechanisms that can explain much of the observed citation dynamics are preferential attachment and node ageing. The former mechanism reflects the tendency for successful nodes (by citation count) to become even more successful, while the latter captures the propensity for knowledge to become obsolete over time. The independence of these phenomena is nontrivial, but has generally been assumed. We put this assumption to the test for both patent and scientific-article citation networks and found it to be generally true if precautions are taken to account for important context surrounding the meaning of citations. Achieving a clear separation of these mechanisms is found to be very useful both mathematically and empirically, as they can now be studied independently. Patents are particularly sophisticated documents, with various components holding specific legal meanings. Associating certain properties of these component

We report the first high-pressure single-crystal structures of hybrid perovskites. The crystalline semiconductors (MA)PbX3 (MA = CH3NH3 (+), X = Br(-) or I(-)) afford us the rare opportunity of understanding how compression modulates their structures and thereby their optoelectronic properties. Using atomic coordinates obtained from high-pressure single-crystal X-ray diffraction we track the perovskites' precise structural evolution upon compression. These structural changes correlate well with pressure-dependent single-crystal photoluminescence (PL) spectra and high-pressure bandgaps derived from density functional theory. We further observe dramatic piezochromism where the solids become lighter in color and then transition to opaque black with compression. Indeed, electronic conductivity measurements of (MA)PbI3 obtained within a diamond-anvil cell show that the material's resistivity decreases by 3 orders of magnitude between 0 and 51 GPa. The activation energy for conduction at 51 GPa is only 13.2(3) meV, suggesting that the perovskite is approaching a metallic state. Furthermore, the pressure response of mixed-halide perovskites shows new luminescent states that emerge at elevated pressures. We recently reported that the perovskites (MA)Pb(Br x I1-x )3 (0.2 < x < 1) reversibly form light-induced trap states, which pin their PL to a low energy. This may explain the low voltages obtained from solar cells employing these absorbers. Our high-pressure PL data indicate that compression can mitigate this PL redshift and may afford higher steady-state voltages from these absorbers. These studies show that pressure can significantly alter the transport and thermodynamic properties of these technologically important semiconductors.

Background:Long-term health, development and wellbeing and related predictors in resettled refugee children are unknown. Aims:This work aims to (1) understand barriers to accessing health care in refugee children and families (2) measure access to timely post-arrival screening (3) assess physical health, development and social-emotional wellbeing longitudinally over three years post-arrival (4) identify risk and protective factors for social-emotional wellbeing, and (5) determine the impact of detention on social-emotional wellbeing.Methods:A literature review on the barriers to healthcare in refugee families informed the design and implementation of a population based screening program, from which a longitudinal cohort of refugee children was created and followed for three years. Physical health, development and social-emotional wellbeing were assessed using standardised measures. Risk and protective factors were collected and analysed to predict social-emotional wellbeing. The impact of detention on wellbeing was explored by comparing the non-detained longitudinal cohort with detained asylum seeker children. Results:The screening program provided highly accessible and timely health assessments to newly-arrived refugee children (n=367, 97%; average of 20 days post-arrival). Sixty-one children were enrolled in the longitudinal study. Retention was 100% at year two and 85% at year three. Fifteen per cent had a chronic disease and 13% were overweight. In preschool children, 27% had mild developmental problems in year two; all were normal by year three. Most children (>87%) improved in social-emotional wellbeing over time. Protective factors for normal social-emotional wellbeing (at year three) were: originating from Africa, a father present on arrival, and reduced stressful life events in the past year. Cumulatively, four or more protective factors predicted better social-emotional wellbeing (p<0.006). Modifiable protective factors included stability in the child’s sc

Public research is critical to the economy and society. However, tangible economic and social impact only occurs when research outputs are combined, used and reused with other elements and capabilities, to deliver a product, practice, or service. Assessing the context and influence of scholarship during the dynamic process of innovation rather than measuring ex post impact, may improve performance. With this aim, we integrated and interconnected scholarly citations with global patent literature, and here we offer new tools enabling diverse stakeholders to freely evaluate the influence published research has on the generation and potential use of inventions as reflected by the patent system. We outline an evolving toolkit, Lens Influence Mapping, that allows assessment of individual scholarly works and aggregated outputs of authors for influence on industry and enterprise as measured by citations within patents. This performance measure, applied at many levels and normalized by either research disciplines or technology fields of use, may expose and highlight institutional strength and practices, and guide their future partnerships

When registries collect accurate clinical data over time, they can act as fundamental support structures for patients and their families and powerful cost-effective instruments to support clinical trials and translational research to improve quality of care, quality of life and survival. Registries are critical for rare diseases (RD) with low prevalence and propensity for variation in treatment and outcomes. Rare Voices Australia is leading a call for action to the research and clinical community to prioritise RD data collection and develop an integrated RD Registry strategy for Australia. Financial, operational and governance challenges exist for establishing and maintaining RD registries. As a multidisciplinary team whose interests converge on RD, we highlight the need for the establishment of an Australian RD Registry Alliance. This ‘umbrella’ organisation will: (i) bring together existing RD registries across Australia; (ii) establish National RD Registry Standards to support interoperability and cohesion across registries; (iii) develop strategies to attract sustainable funding from government and other sources to maximise the utility of existing RD registries and support the development of new RD registries. The most important role for the Alliance would be to use the RD registries for translational research to address current knowledge gaps about RD and to improve the care for the over 1.4 million Australians estimated to live with RD.

The United States patent system has become sand rather than lubricant in the wheels of American progress. Such is the premise behind this provocative and timely book by two of the nation's leading experts on patents and economic innovation. Innovation and Its Discontents tells the story of how recent changes in patenting--an institutional process that was created to nurture innovation--have wreaked havoc on innovators, businesses, and economic productivity. Jaffe and Lerner, who have spent the past two decades studying the patent system, show how legal changes initiated in the 1980s converted the system from a stimulator of innovation to a creator of litigation and uncertainty that threatens the innovation process itself. In one telling vignette, Jaffe and Lerner cite a patent litigation campaign brought by a a semi-conductor chip designer that claims control of an entire category of computer memory chips. The firm's claims are based on a modest 15-year old invention, whose scope and influenced were broadened by secretly manipulating an industry-wide cooperative standard-setting body. Such cases are largely the result of two changes in the patent climate, Jaffe and Lerner contend. First, new laws have made it easier for businesses and inventors to secure patents on products of all kinds, and second, the laws have tilted the table to favor patent holders, no matter how tenuous their claims. After analyzing the economic incentives created by the current policies, Jaffe and Lerner suggest a three-pronged solution for restoring the patent system: create incentives to motivate parties who have information about the novelty of a patent; provide multiple levels of patent review; and replace juries with judges and special masters to preside over certain aspects of infringement cases. Well-argued and engagingly written, Innovation and Its Discontents offers a fresh approach for enhancing both the nation's creativity and its economic growth.

The most common form of childhood diabetes is type 1 diabetes mellitus, resulting from autoimmune destruction of pancreatic beta-cells. However, other types of diabetes have different pathophysiology and treatment requirements. Two under-recognised forms are monogenic diabetes and cystic fibrosis related diabetes (CFRD). This thesis details three studies which improve understanding of the pathophysiology, detection and treatment of these conditions.Monogenic diabetes may be misdiagnosed as type I diabetes and may respond better to oral medications than insulin. The first publication successfully used the persistent absence of autoantibodies, followed by genetic testing, to detect undiagnosed monogenic diabetes, permitting genetic counselling and improved therapy. It also identified only 3 patients known to have CFRD at Sydney Children’s Hospital. This prompted a systematic assessment of glucose abnormalities in CF patients at the hospital.CF is a common autosomal recessive disease, causing early death through respiratory failure. Progressive insulin deficiency causes hyperglycaemia and catabolism, culminating in CFRD. Late diagnosis of CFRD increases morbidity and may occur due to inadequate screening. Using 30-minutely oral glucose tolerance testing and continuous glucose monitoring, the second publication identified high rates of glucose abnormalities. CFRD is diagnosed according to criteria adopted from type 2 diabetes. This work documented the earliest glucose abnormalities (prior to meeting the currentcriteria for CFRD) that are associated with weight and lung function decline (predictors of early mortality in CF). This raised the possibility of intervention with insulin therapy earlier than current practice, to prevent clinical deterioration.The subsequent work in this thesis demonstrated that a simple, minimally-burdensome, once-daily injection regimen of long-acting insulin detemir improved weight and lung function in children with either CFRD, or earlier gl

Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory hospitalization all over the world. There are several potential vaccine candidates and antivirals targeting RSV in different phases of clinical trials. Once an effective vaccine or therapy becomes available, country-specific burden of disease data are likely to be needed to prioritize and/or target the intervention to the highest risk groups. Data on burden of childhood severe RSV disease from Australia are limited. I aimed to quantify the burden of severe RSV disease and identify risk factors at a population level.Three studies were conducted. In the first I performed a retrospective analysis of linked administrative population based datasets comprising a birth cohort of almost one million children born in NSW between 2001-2010. The incidence of RSV hospitalization/1000 children-year among children aged <5 years was 11.0 for Indigenous children, 81.5 for children with bronchopulmonary dysplasia, 10.2 for preterm children with gestational age (GA) 32-36 weeks, 27.0 for children with GA 28-31 weeks, 39.0 for children with GA <28weeks and 6.7 for term children with low birth weight. Severe RSV disease was also found to incur a substantial direct health care cost amounting to more than AUD nine million in NSW. Having confirmed that preterm infants suffer a high incidence of severe RSV disease, I conducted a prospective study into the risk of these infants acquiring nosocomial RSV infection in the neonatal intensive care unit (NICU) during their birth hospitalization. The findings suggested that with optimal implementation of hand hygiene, the risk of neonates acquiring nosocomial RSV infection from environmental sources within NICU, in the absence of an outbreak, is low. Finally, I assessed the comparable risk factors for severe RSV disease in the birth cohort of the first study and estimated the population attributable risk of each to quantify the burden of disease potentially preventable

Our insight into cystic fibrosis (CF) and diseases associated with CF gene mutations has changed. Cystic fibrosis now includes a wide spectrum of phenotypes ranging from patients affected by the historical multi-system disease to patients with single-organ manifestations of CF such as chronic sinopulmonary disease and recurrent acute or chronic pancreatitis. This heterogeneity is largely but not completely explained by the large number of CFTR mutations, which are associated with different functional and clinical consequences on different CF-affected organs. The overarching hypothesis is disease manifestation in CF-affected organs begin to develop when a specific threshold of CFTR ion channel function is lost. This threshold varies considerably between organs that are affected by CF disease and may lead to diagnostic challenges. Furthermore, this threshold can be defined by ion channel measurements and correlating the CF-phenotype and CFTR genotype. The thesis is based on studies of symptomatic individuals who present with single organ manifestations of CF and the genotype-phenotype study of acute pancreatitis. This thesis demonstrated the following: (1) The wide spectrum of CF phenotypes has resulted in difficulties in diagnosing CF and discrepancies in diagnosticterminology and criteria, which in turn has resulted in risk of patients receiving different diagnostic outcomes; (2) Diagnostic uncertainty may remain in a subset of patients who present with single-organ manifestations of CF despite comprehensive evaluation by sweat test, nasal potential difference (NPD) and extensive genotyping – with issues of discordance between sweat test and NPD and extensive genotyping providing the lowest diagnostic yield; (3) A combined ion channel measurement based on more than one CF-affected end-organ epithelia, may improve the diagnostic performance for CF by incorporating the variations in organ specific penetrance of ion channel defects; and (4) The risk of pancreatitis in

Background: Immigration is increasingly common worldwide and its impact on neonatal intensive care unit outcomes is uncertain. Aims: To determine the outcomes of children of immigrant mothers admitted to NICUs in New South Wales (NSW), Australia, between

Unrecognised airway infection and inflammation may begin early in life in children with cystic fibrosis (CF). This may lead to lung function decline and irreversible lung disease before conventional investigations such as chest x-rays and spirometry become abnormal. Bronchoalveolar lavage (BAL), the current standard for assessing airway infection and inflammation in young children, is invasive, resource-intensive and not easily repeated. Sensitive, non-invasive measures to detect and monitor early CF lung disease are required. The main aim of this thesis was to determine whether the lung clearance index (LCI), a measure of ventilation inhomogeneity reflecting peripheral airway disease, the neutrophilic S100 proteins, S100A8/A9 (calprotectin) and S100A12 measured in serum and urinary desmosine, a measure of (lung) elastin breakdown, were sensitive, non-invasive markers of airway infection and inflammation in newborn-screened infants and young children with CF. A secondary aim was to determine whether distal gastro-oesophageal reflux and BAL pepsin were associated with early lung disease.The LCI was measured in sedated infants and young children with CF and healthy children of the same age using a multiple breath washout method and a portable, commercially available ultrasonic flowmeter. S100A8/A9 and S100A12 were measured by a commercially available and an “in-house” assay respectively. Urinary desmosine was measured by a modified high performance liquid chromatography technique and pepsin activity by fluorometric assay.This thesis has shown for the first time that the LCI is elevated in CF infants and young children especially in the presence of P. aeruginosa infection and airway inflammation. Further, the LCI was assessed to have good within and between test repeatability. The S100 proteins were elevated in BAL fluid and serum in the presence of infection and inflammation but serum levels were insufficiently sensitive to be useful non-invasive markers of

As patent data become more available in machine-readable form, an increasing number of researchers have begun to use measures based on patents and their citations as indicators of technological output and information flow. This paper explores the economic meaning of these citation-based patent measures using the financial market valuation of the firms that own the patents. Using a new and comprehensive dataset containing over 4800 U. S. Manufacturing firms and their patenting activity for the past 30 years, we explore the contributions of R&D spending, patents, and citation-weighted patents to measures of Tobin's Q for the firms. We find that citation-weighted patent stocks are more highly correlated with market value than patent stocks themselves and that this fact is due mainly to the high valuation placed on firms that hold very highly cited patents. We also find that self-citations are worth about twice as much as ordinary citations, especially to smaller firms.

Lacaze, P., Millis, N., Fookes, M., Zurynski, Y., Jaffe, A., Bellgard, M., ... & Bittles, A. H. (2017). Rare disease registries: a call to action. Internal Medicine Journal, 47(9), 1075-1079. Available here.