Computed tomography-based radiomics decodes prognostic and molecular differences in interstitial lung disease related to systemic sclerosis.

BACKGROUND: Radiomic features calculated from routine medical images show great potential for personalised medicine in cancer. Patients with systemic sclerosis (SSc), a rare, multiorgan autoimmune disorder, have a similarly poor prognosis due to interstitial lung disease (ILD). Here, our objectives were to explore computed tomography (CT)-based high-dimensional image analysis ("radiomics") for disease characterisation, risk stratification and relaying information on lung pathophysiology in SSc-ILD. METHODS: We investigated two independent, prospectively followed SSc-ILD cohorts (Zurich, derivation cohort, n=90; Oslo, validation cohort, n=66). For every subject, we defined 1355 robust radiomic features from standard-of-care CT images. We performed unsupervised clustering to identify and characterise imaging-based patient clusters. A clinically applicable prognostic quantitative radiomic risk score (qRISSc) for progression-free survival (PFS) was derived from radiomic profiles using supervised analysis. The biological basis of qRISSc was assessed in a cross-species approach by correlation with lung proteomic, histological and gene expression data derived from mice with bleomycin-induced lung fibrosis. RESULTS: Radiomic profiling identified two clinically and prognostically distinct SSc-ILD patient clusters. To evaluate the clinical applicability, we derived and externally validated a binary, quantitative radiomic risk score (qRISSc) composed of 26 features that accurately predicted PFS and significantly improved upon clinical risk stratification parameters in multivariable Cox regression analyses in the pooled cohorts. A high qRISSc score, which identifies patients at risk for progression, was reverse translatable from human to experimental ILD and correlated with fibrotic pathway activation. CONCLUSIONS: Radiomics-based risk stratification using routine CT images provides complementary phenotypic, clinical and prognostic information significantly impacting clinical decision making in SSc-ILD.

Staphylococcus aureus impairs dermal fibroblast functions with deleterious effects on wound healing.

Chronic wounds are a major disease burden worldwide. The breach of the epithelial barrier facilitates transition of skin commensals to invasive facultative pathogens. Therefore, we investigated the potential effects of Staphylococcus aureus (SA) on dermal fibroblasts as key cells for tissue repair. In co-culture systems combining live or heat-killed SA with dermal fibroblasts derived from the BJ-5ta cell line, healthy individuals, and patients with systemic sclerosis, we assessed tissue repair including pro-inflammatory cytokines, matrix metalloproteases (MMPs), myofibroblast functions, and host defense responses. Only live SA induced the upregulation of IL-1ß/-6/-8 and MMP1/3 as co-factors of tissue degradation. Additionally, the increased cell death reduced collagen production, proliferation, migration, and contractility, prerequisite mechanisms for wound closure. Intracellular SA triggered inflammatory and type I IFN responses via intracellular dsDNA sensor molecules and MyD88 and STING signaling pathways. In conclusion, live SA affected various key tissue repair functions of dermal fibroblasts from different sources to a similar extent. Thus, SA infection of dermal fibroblasts should be taken into account for future wound management strategies.

Application of metabolic modeling for targeted optimization of high seeding density processes.

Process intensification by application of perfusion mode in pre-stage bioreactors and subsequent inoculation of cell cultures at high seeding densities (HSD) has the potential to meet the increasing requirements of future manufacturing demands. However, process development is currently restrained by a limited understanding of the cell's requirements under these process conditions. The goal of this study was to use extended metabolite analysis and metabolic modeling for targeted optimization of HSD cultivations. The metabolite analysis of HSD N-stage cultures revealed accumulation of inhibiting metabolites early in the process and flux balance analysis led to the assumption that reactive oxygen species (ROS) were contributing to the fast decrease in cell viability. Based on the metabolic analysis an optimized feeding strategy with lactate and cysteine supplementation was applied, resulting in an increase in antibody titer of up to 47%. Flux balance analysis was further used to elucidate the surprisingly strong synergistic effect of lactate and cysteine, indicating that increased lactate uptake led to reduced ROS formation under these conditions whilst additional cysteine actively reduced ROS via the glutathione pathway. The presented results finally demonstrate the benefit of modeling approaches for process intensification as well as the potential of HSD cultivations for biopharmaceutical manufacturing.

The societal burden of haemophilia A. I - A snapshot of haemophilia A in Australia and beyond.

INTRODUCTION: Few studies, both in Australia and overseas, have examined the social impacts of living with haemophilia A (HA) or the economic costs associated with the disorder. The purpose of this paper is to examine the epidemiology and societal burden of people with HA (PwHA) in Australia, with a particular focus on men with this disorder. METHODS: The epidemiology and societal burden of HA in Australia, with a particular focus on men with this disorder, were assessed, using data available in the Australian and international literature and publicly available data. RESULTS: The mean annual prevalence of HA is approximately 1-2 per 10 000 males. Prophylactic treatment is used in one-quarter (25.1%) of people with moderate HA, and 82.2% of people with severe HA. Within the latter group, 16.1% have inhibitors for Factor VIII, predisposing them to worse morbidity, mortality and quality of life when compared to the non-inhibitor population. Joint pain and joint disease occur commonly in PwHA, with up to 70% of adults with HA experiencing joint problems. HA is associated with poor physical health, and PwHA miss school and work due to bleeding-related events. CONCLUSION: HA is associated with substantial economic burden; with large differences in costs reported between countries. Overall, HA imposes a significant burden of disease on PwHA, their families and the community at large.

The societal burden of haemophilia A. II - The cost of moderate and severe haemophilia A in Australia.

INTRODUCTION: Although the costs for people with haemophilia A (PwHA) in Europe and the United States have been well characterized, to date, there are no cost estimates for PwHA in Australia. The purpose of this study was to estimate direct and indirect costs of moderate and severe haemophilia A (HA) in Australia under current treatment practices. METHODS: The number of Australian males with moderate or severe HA was projected from Australian Bleeding Disorders Registry (ABDR) data. We estimated the prevalence in 2018 of adults with moderate HA to be 159 people, severe to be 416; and 68 and 283, respectively, in the paediatric (aged < 18 years) population. We used a 'bottom-up prevalence based cost of illness approach' to estimate costs; that is, we estimated the per capita cost for different groups of PwHA; for example, by age and disease severity, and these per capita costs were scaled up to the estimated population with HA. Costs were estimated based on publicly available secondary data and literature review. RESULTS: The treatment-related costs, direct and indirect costs, of moderate to severe HA are significant, totalling over AUD$111M in 2018, equating to a yearly per patient cost of approximately AUD$120 000 (equivalent to ~EUR€74 000 or ~USD$85 000). CONCLUSION: Although HA affects a relatively small number of people within the Australian population, it is associated with high aggregate costs and imposes a high economic burden.

The societal burden of haemophilia A. III - The potential impact of emicizumab on costs of haemophilia A in Australia.

INTRODUCTION: Emicizumab is a humanized monoclonal modified IgG4 antibody with bispecific antibody structure bridging Factor IXa and Factor X. Emicizumab has demonstrated efficacy and safety in adults, adolescents and paediatrics with HA, with or without inhibitors to Factor VIII (FVIII). There is currently no evidence that reports on the potential impact of the introduction of emicizumab on the societal costs of haemophilia A (HA). The purpose of this study was to explore the cost impact associated with the introduction of emicizumab on the current societal costs of people with HA (PwHA) in Australia. METHODS: We conducted an analysis of the impact of emicizumab on societal costs, based on changes in the direct and indirect costs incurred by PwHA. Potential impacts of emicizumab on outcomes in PwHA were modelled based on HAVEN 1, HAVEN 2 and HAVEN 3 studies. We assumed that eligible PwHA commenced use of emicizumab on 1 January 2018. The impact of emicizumab on costs of HA in Australia males was then estimated for the 12-month period to 31 December 2018. RESULTS: Overall, uptake of emicizumab in its first year of use reduces annual costs associated with moderate/severe HA by AUD$69.197M (62.3%). This reflects 64.2% reduction in the cost of FVIII blood products and 92% reduction in cost of bypassing agents. CONCLUSION: The cost of emicizumab is likely to offset some or all of the projected reductions in treatment costs. However, we also found 30.7% reduction in non-treatment direct costs (AUD$3.771M) and 19.1% reduction in indirect costs (AUD$2.732M).

Visualisation of interstitial lung disease by molecular imaging of integrin αvß3 and somatostatin receptor 2.

OBJECTIVE: To evaluate integrin αvß3 (alpha-v-beta-3)-targeted and somatostatin receptor 2 (SSTR2)-targeted nuclear imaging for the visualisation of interstitial lung disease (ILD). METHODS: The pulmonary expression of integrin αvß3 and SSTR2 was analysed in patients with different forms of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. Single photon emission CT/CT (SPECT/CT) was performed on days 3, 7 and 14 after BLM instillation using the integrin αvß3-targeting 177Lu-DOTA-RGD and the SSTR2-targeting 177Lu-DOTA-NOC radiotracer. The specific pulmonary accumulation of the radiotracers over time was assessed by in vivo and ex vivo SPECT/CT scans and by biodistribution studies. RESULTS: Expression of integrin αvß3 and SSTR2 was substantially increased in human ILD regardless of the subtype. Similarly, in lungs of BLM-challenged mice, but not of controls, both imaging targets were stage-specifically overexpressed. While integrin αvß3 was most abundantly upregulated on day 7, the inflammatory stage of BLM-induced lung fibrosis, SSTR2 expression peaked on day 14, the established fibrotic stage. In agreement with the findings on tissue level, targeted nuclear imaging using SPECT/CT specifically detected both imaging targets ex vivo and in vivo, and thus visualised different stages of experimental ILD. CONCLUSION: Our preclinical proof-of-concept study suggests that specific visualisation of molecular processes in ILD by targeted nuclear imaging is feasible. If transferred into clinics, where imaging is considered an integral part of patients' management, the additional information derived from specific imaging tools could represent a first step towards precision medicine in ILD.

Atomic-accuracy models from 4.5-Å cryo-electron microscopy data with density-guided iterative local refinement.

We describe a general approach for refining protein structure models on the basis of cryo-electron microscopy maps with near-atomic resolution. The method integrates Monte Carlo sampling with local density-guided optimization, Rosetta all-atom refinement and real-space B-factor fitting. In tests on experimental maps of three different systems with 4.5-Å resolution or better, the method consistently produced models with atomic-level accuracy largely independently of starting-model quality, and it outperformed the molecular dynamics-based MDFF method. Cross-validated model quality statistics correlated with model accuracy over the three test systems.

Structural and Functional Characterization of the Bacterial Type III Secretion Export Apparatus.

Bacterial type III protein secretion systems inject effector proteins into eukaryotic host cells in order to promote survival and colonization of Gram-negative pathogens and symbionts. Secretion across the bacterial cell envelope and injection into host cells is facilitated by a so-called injectisome. Its small hydrophobic export apparatus components SpaP and SpaR were shown to nucleate assembly of the needle complex and to form the central "cup" substructure of a Salmonella Typhimurium secretion system. However, the in vivo placement of these components in the needle complex and their function during the secretion process remained poorly defined. Here we present evidence that a SpaP pentamer forms a 15 Å wide pore and provide a detailed map of SpaP interactions with the export apparatus components SpaQ, SpaR, and SpaS. We further refine the current view of export apparatus assembly, consolidate transmembrane topology models for SpaP and SpaR, and present intimate interactions of the periplasmic domains of SpaP and SpaR with the inner rod protein PrgJ, indicating how export apparatus and needle filament are connected to create a continuous conduit for substrate translocation.

Media photo-degradation in pharmaceutical biotechnology - impact of ambient light on media quality, cell physiology, and IgG production in CHO cultures.

BACKGROUND: Many vital components in bioprocess media are prone to photo-conversion or photo-degradation upon exposure to ambient light, with severe negative consequences for biomass yield and overall productivity. However, there is only limited awareness of light irradiation as a potential risk factor when working in transparent glass bioreactors, storage vessels or disposable bag systems. The chemical complexity of most media renders a root-cause analysis difficult. This study investigated in a novel, holistic approach how light-induced changes in media composition relate to alterations in radical burden, cell physiology, morphology, and product formation in industrial Chinese hamster ovary (CHO) bioprocesses. RESULTS: Two media formulations from proprietary and commercial sources were tested in a pre-hoc light exposure scenario prior to cultivation. Using fluorescence excitation/emission (EEM) matrix spectroscopy, a photo-sensitization of riboflavin was identified as a likely cause for drastically decreased IgG titers (up to -80%) and specific growth rates (-50% to -90%). Up to three-fold higher radical levels were observed in photo-degraded medium. On the biological side, this resulted in significant changes in cell morphology and aberrations in the normal IgG biosynthesis/secretion pathway. CONCLUSION: These findings clearly illustrate the underrated impact of room light after only short periods of exposure, occurring accidentally or knowingly during bioprocess development and scale- up. The detrimental effects, which may share a common mechanistic cause at the molecular level, correlate well with changes in spectroscopic properties. This offers new perspectives for online monitoring concepts, and improved detectability of such effects in future. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.

Investigation of the interactions of critical scale-up parameters (pH, pO2 and pCO2) on CHO batch performance and critical quality attributes.

Understanding process parameter interactions and their effects on mammalian cell cultivations is an essential requirement for robust process scale-up. Furthermore, knowledge of the relationship between the process parameters and the product critical quality attributes (CQAs) is necessary to satisfy quality by design guidelines. So far, mainly the effect of single parameters on CQAs was investigated. Here, we present a comprehensive study to investigate the interactions of scale-up relevant parameters as pH, pO2 and pCO2 on CHO cell physiology, process performance and CQAs, which was based on design of experiments and extended product quality analytics. The study used a novel control strategy in which process parameters were decoupled from each other, and thus allowed their individual control at defined set points. Besides having identified the impact of single parameters on process performance and product quality, further significant interaction effects of process parameters on specific cell growth, specific productivity and amino acid metabolism could be derived using this method. Concerning single parameter effects, several monoclonal antibody (mAb) charge variants were affected by process pCO2 and pH. N-glycosylation analysis showed positive correlations between mAb sialylation and high pH values as well as a relationship between high mannose variants and process pH. This study additionally revealed several interaction effects as process pH and pCO2 interactions on mAb charge variants and N-glycosylation pattern. Hence, through our process control strategy and multivariate investigation, novel significant process parameter interactions and single effects were identified which have to be taken into account especially for process scale-up.

Head swivel on the ribosome facilitates translocation by means of intra-subunit tRNA hybrid sites.

The elongation cycle of protein synthesis involves the delivery of aminoacyl-transfer RNAs to the aminoacyl-tRNA-binding site (A site) of the ribosome, followed by peptide-bond formation and translocation of the tRNAs through the ribosome to reopen the A site. The translocation reaction is catalysed by elongation factor G (EF-G) in a GTP-dependent manner. Despite the availability of structures of various EF-G-ribosome complexes, the precise mechanism by which tRNAs move through the ribosome still remains unclear. Here we use multiparticle cryoelectron microscopy analysis to resolve two previously unseen subpopulations within Thermus thermophilus EF-G-ribosome complexes at subnanometre resolution, one of them with a partly translocated tRNA. Comparison of these substates reveals that translocation of tRNA on the 30S subunit parallels the swivelling of the 30S head and is coupled to unratcheting of the 30S body. Because the tRNA maintains contact with the peptidyl-tRNA-binding site (P site) on the 30S head and simultaneously establishes interaction with the exit site (E site) on the 30S platform, a novel intra-subunit 'pe/E' hybrid state is formed. This state is stabilized by domain IV of EF-G, which interacts with the swivelled 30S-head conformation. These findings provide direct structural and mechanistic insight into the 'missing link' in terms of tRNA intermediates involved in the universally conserved translocation process.

Five-year outcome in immune-mediated scleritis.

BACKGROUND: Immune-mediated scleritis is a rare condition, and the information on the clinical course and complications is scarce. The aim of this study was to identify prognostic factors, complications, and therapeutic effects in patients with immune-mediated scleritis. METHODS: Patients with diagnosis of scleritis and a follow-up time of 5 years were identified. Systemic disease, laboratory investigations, type of scleritis, disease activity, therapy, and complications were recorded. The study design was a retrospective, non-comparative, interventional case series. RESULTS: Systemic disease was identified in 15 (37%) patients at presentation and in 18 (45%) after 5 years. Rheumatoid arthritis (15%), granulomatosis with polyangiitis (7.5%), and polychondritis (7.5%) were the most predominant disorders. Persistent scleritis (>5 years) was associated with systemic disease (66 vs. 6%; p < 0.05) and positive auto-antibodies (48 vs. 23%; p = 0.18). Control of ocular inflammation was achieved in 38 of 40 (95%). Prednisone (14 patients) and/or methotrexate (8) were the predominant drugs to control persistent disease. Complications included interstitial keratitis (2), inflammatory astigmatism (2), corneal melt (3), macular edema (6), and severe systemic disease (5). CONCLUSION: The presence of systemic disease and positive auto-antibodies are associated with persistent scleritis. Immunosuppressive agents allow control of scleritis, but may contribute to severe systemic complications.

Comparative Clinical Effectiveness and Cost-Effectiveness of the Cochlear Osia System and Baha Attract System in Patients with Conductive or Mixed Hearing Loss or Single-Sided Deafness.

The aim of this study was to evaluate the comparative clinical effectiveness and cost-utility of the active transcutaneous Osia® System versus the passive transcutaneous Baha® Attract System for patients with conductive or mixed hearing loss or single-sided deafness in an Australian healthcare setting. In the absence of direct comparative evidence, an indirect treatment comparison (ITC) of the clinical effectiveness and utility gains was needed. The ITC was informed by three studies identified through a systematic literature review. A Markov model was developed to evaluate the cost-utility of the Osia System. The literature review identified three studies suitable to inform an ITC: Mylanus et al. 2020 and Briggs et al. 2022 (Osia System) and den Besten et al. 2019 (Baha Attract System). The Osia System was found to be clinically superior to the Baha Attract System, across objective audiological outcomes resulting in a clinically meaningful utility benefit of 0.03 measured by the Health Utility Index with at least equivalent safety. In conclusion, the Osia System is more effective than the Baha Attract System, providing better hearing and health-related quality of life outcomes. In an Australian healthcare setting, the Osia System is cost-effective as demonstrated in a cost-utility analysis versus the Baha Attract System.

Radioproteomics stratifies molecular response to antifibrotic treatment in pulmonary fibrosis.

Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.

BRD3 Regulates the Inflammatory and Stress Response in Rheumatoid Arthritis Synovial Fibroblasts.

BACKGROUND: Individual functions of members of the bromodomain (BRD) and extra-terminal (BET) protein family underlying the anti-inflammatory effects of BET inhibitors in rheumatoid arthritis (RA) are incompletely understood. Here, we aimed to analyze the regulatory functions of BRD3, an understudied member of the BET protein family, in RA synovial fibroblasts (FLS). METHODS: BRD3 was silenced in FLS prior to stimulation with TNF. Alternatively, FLS were treated with I-BET. Transcriptomes were analyzed by RNA sequencing (RNAseq), followed by pathway enrichment analysis. We confirmed results for selective target genes by real-time PCR, ELISA, and Western blotting. RESULTS: BRD3 regulates the expression of several cytokines and chemokines in FLS, and positively correlates with inflammatory scores in the RA synovium. In addition, RNAseq pointed to a profound role of BRD3 in regulating FLS proliferation, metabolic adaption, and response to stress, including oxidative stress, and autophagy. CONCLUSIONS: BRD3 acts as an upstream regulatory factor that integrates the response to inflammatory stimuli and stress conditions in FLS and executes many functions of BET proteins that have previously been identified using pan-BET inhibitors.

Topology and organization of the Salmonella typhimurium type III secretion needle complex components.

The correct organization of single subunits of multi-protein machines in a three dimensional context is critical for their functionality. Type III secretion systems (T3SS) are molecular machines with the capacity to deliver bacterial effector proteins into host cells and are fundamental for the biology of many pathogenic or symbiotic bacteria. A central component of T3SSs is the needle complex, a multiprotein structure that mediates the passage of effector proteins through the bacterial envelope. We have used cryo electron microscopy combined with bacterial genetics, site-specific labeling, mutational analysis, chemical derivatization and high-resolution mass spectrometry to generate an experimentally validated topographic map of a Salmonella typhimurium T3SS needle complex. This study provides insights into the organization of this evolutionary highly conserved nanomachinery and is the basis for further functional analysis.

Transferability of radiomic signatures from experimental to human interstitial lung disease.

Background: Interstitial lung disease (ILD) defines a group of parenchymal lung disorders, characterized by fibrosis as their common final pathophysiological stage. To improve diagnosis and treatment of ILD, there is a need for repetitive non-invasive characterization of lung tissue by quantitative parameters. In this study, we investigated whether CT image patterns found in mice with bleomycin induced lung fibrosis can be translated as prognostic factors to human patients diagnosed with ILD. Methods: Bleomycin was used to induce lung fibrosis in mice (n_control = 36, n_experimental = 55). The patient cohort consisted of 98 systemic sclerosis (SSc) patients (n_ILD = 65). Radiomic features (n_histogram = 17, n_texture = 137) were extracted from microCT (mice) and HRCT (patients) images. Predictive performance of the models was evaluated with the area under the receiver-operating characteristic curve (AUC). First, predictive performance of individual features was examined and compared between murine and patient data sets. Second, multivariate models predicting ILD were trained on murine data and tested on patient data. Additionally, the models were reoptimized on patient data to reduce the influence of the domain shift on the performance scores. Results: Predictive power of individual features in terms of AUC was highly correlated between mice and patients (r = 0.86). A model based only on mean image intensity in the lung scored AUC = 0.921 ± 0.048 in mice and AUC = 0.774 (CI95% 0.677-0.859) in patients. The best radiomic model based on three radiomic features scored AUC = 0.994 ± 0.013 in mice and validated with AUC = 0.832 (CI95% 0.745-0.907) in patients. However, reoptimization of the model weights in the patient cohort allowed to increase the model's performance to AUC = 0.912 ± 0.058. Conclusion: Radiomic signatures of experimental ILD derived from microCT scans translated to HRCT of humans with SSc-ILD. We showed that the experimental model of BLM-induced ILD is a promising system to test radiomic models for later application and validation in human cohorts.

Societal costs of primary progressive multiple sclerosis in Australia and the economic impact of a hypothetical disease-modifying treatment that could delay disease progression.

AIMS: Primary progressive multiple sclerosis (PPMS) has a progressive course of disability with continuous neurological worsening. We investigated societal costs of PPMS in Australia and the economic impact of increasing the independence of people with PPMS through delaying disease progression. METHODS: This prevalence-based retrospective cost-of-illness analysis used observational data from publicly available secondary data sources and literature findings. Direct and indirect costs of PPMS were considered. A replica estimated population was created using the National Centre for Social and Economic Modelling (NATSEM) microsimulation model of the Australian tax and transfer system (STINMOD+). Using a budget impact analysis approach, we modelled the effect on PPMS costs of an effective hypothetical disease-modifying treatment (DMT) that delays disease progression by a year from mild to moderate and a further year from moderate to severe PPMS. RESULTS: An estimated 31,650 Australians have multiple sclerosis (MS) including 4,430 with PPMS. The proportion with PPMS was estimated to increase with age and disease severity. Overall 25% of males with MS, and 10% of females, were estimated to have PPMS. Societal cost of PPMS in Australia in 2018 was estimated at AU$418.1 million. Indirect costs contributed 67.5% of total costs, attributable to reduced workforce participation and need for informal care. The modelled DMT was estimated to create savings of AU$14.9 million (3.6%). Fewer people had moderate and severe PPMS resulting in major cost savings, partially offset by increased costs of treatment, care and support for a relative increase in the number of people with mild PPMS and their increased productivity losses. LIMITATIONS: Publicly available data may be incomplete. The potential cost of the DMT was not considered. CONCLUSIONS: The economic burden of PPMS was estimated at AU$418 million in 2018. An effective DMT that delayed progression from disease severity states by one year could provide significant cost savings.

Echinococcosis, toxocarosis and toxoplasmosis screening in a rural community in eastern Kazakhstan.

OBJECTIVE: To determine the extent of carnivore-transmitted parasitic zoonoses in a community in eastern Kazakhstan, a region where cystic echinococcosis (CE) re-emerged in recent years. METHODS: Cross sectional ultrasound study of 3126 human subjects to determine the extent of human cystic and alveolar echinococcosis (AE). Blood samples were taken from each subject and analysed for antibodies against Echinococcus, Toxocara and Toxoplasma spp. Each subject was questioned about possible risk factors that might be associated with zoonotic transmission. Analysis employed a mixed modelling approach based on the results of the ultrasound study, the serological results and the results of the questionnaire. Bayesian techniques were employed to estimate diagnostic performance. A helminthological study of the local dog population was also undertaken. RESULTS: A total of 23 subjects tested positive for CE on ultrasound and a further three individuals had strong serological evidence of infection. Another 24 reported treatment for CE. Ultrasound lesions or treatment for CE were associated with poverty. No ultrasound evidence of AE was found, but one individual had strong serological evidence of exposure to Echinococcus multilocularis. Toxoplasma seropositivity (16%; 504 individuals) increased with age. Household level Toxoplasma-seropositivity was associated with unsafe drinking water. Toxocara seropositivity (11%; 349 individuals) was more frequent in children and in individuals who disposed of dog faeces on the vegetable garden. A purgation study of dogs indicated that 13% of dogs in the community were infected with Echinococcus granulosus, 5% with E. multilocularis and 2% with Toxocara canis respectively. CONCLUSIONS: There is significant transmission of E. granulosus to humans in this community. Transmission may be associated with poverty. There is little evidence of E. multilocularis transmission to humans, despite the presence in the parasite in the domestic dog population. Toxoplasma is actively transmitted and there is evidence for transmission by the water supply. Children are at highest risk of exposure to Toxocara.