Dual inhibition of airway inflammation and fibrosis by common ß cytokine receptor blockade.

BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common ß (ßc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation. OBJECTIVE: To determine the pathogenesis of ßc receptor-mediated inflammation and remodeling in severe asthma and to investigate ßc antagonism as a therapeutic strategy for mixed granulocytic airway disease. METHODS: ßc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human ßc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of ßc was used to block ßc signaling. RESULTS: ßc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. CONCLUSIONS: ßc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-ßc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

Early-life house dust mite aeroallergen exposure augments cigarette smoke-induced myeloid inflammation and emphysema in mice.

BACKGROUND: Longitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow limitation can develop more aggressively. However, a causal link between childhood asthma and COPD/ACO remains to be established. Our study aimed to model the natural history of childhood asthma and COPD and to investigate the cellular/molecular mechanisms that drive disease progression. METHODS: Allergic airways disease was established in three-week-old young C57BL/6 mice using house dust mite (HDM) extract. Mice were subsequently exposed to cigarette smoke (CS) and HDM for 8 weeks. Airspace enlargement (emphysema) was measured by the mean linear intercept method. Flow cytometry was utilised to phenotype lung immune cells. Bulk RNA-sequencing was performed on lung tissue. Volatile organic compounds (VOCs) in bronchoalveolar lavage-fluid were analysed to screen for disease-specific biomarkers. RESULTS: Chronic CS exposure induced emphysema that was significantly augmented by HDM challenge. Increased emphysematous changes were associated with more abundant immune cell lung infiltration consisting of neutrophils, interstitial macrophages, eosinophils and lymphocytes. Transcriptomic analyses identified a gene signature where disease-specific changes induced by HDM or CS alone were conserved in the HDM-CS group, and further revealed an enrichment of Mmp12, Il33 and Il13, and gene expression consistent with greater expansion of alternatively activated macrophages. VOC analysis also identified four compounds increased by CS exposure that were paradoxically reduced in the HDM-CS group. CONCLUSIONS: Early-life allergic airways disease worsened emphysematous lung pathology in CS-exposed mice and markedly alters the lung transcriptome.

Severe weather events and cryptosporidiosis in Aotearoa New Zealand: A case series of space-time clusters.

Occurrence of cryptosporidiosis has been associated with weather conditions in many settings internationally. We explored statistical clusters of human cryptosporidiosis and their relationship with severe weather events in New Zealand (NZ). Notified cases of cryptosporidiosis from 1997 to 2015 were obtained from the national surveillance system. Retrospective space-time permutation was used to identify statistical clusters. Cluster data were compared to severe weather events in a national database. SaTScan analysis detected 38 statistically significant cryptosporidiosis clusters. Around a third (34.2%, 13/38) of these clusters showed temporal and spatial alignment with severe weather events. Of these, nearly half (46.2%, 6/13) occurred in the spring. Only five (38%, 5/13) of these clusters corresponded to a previously reported cryptosporidiosis outbreak. This study provides additional evidence that severe weather events may contribute to the development of some cryptosporidiosis clusters. Further research on this association is needed as rainfall intensity is projected to rise in NZ due to climate change. The findings also provide further arguments for upgrading the quality of drinking water sources to minimize contamination with pathogens from runoff from livestock agriculture.

Mitigating imported fuel dependency in agricultural production: Case study of an island nation's vulnerability to global catastrophic risks.

A major global catastrophe would likely disrupt trade in liquid fuels. Countries dependent on imported oil products might struggle to sustain industrial agriculture. Island nations importing 100% of refined fuels are particularly vulnerable. Our case study aimed to estimate the agricultural land area and biofuel volumes needed to feed the population of New Zealand in the absence of trade. Results showed that stored diesel would quickly be exhausted with ordinary use (weeks) and even with strict rationing (months). To preserve fuel, we found that farming wheat (requiring as little as 5.4 million liters [L] of diesel per annum) was more fuel-efficient than potatoes (12.3) or dairy (38.7) to feed the national population under a climate-as-usual scenario. In a nuclear winter scenario, with reduced agricultural yields, proportionately greater diesel is needed. The wheat would require 24% of current grain-cropped land, and the canola crop used as feedstock for the required biofuel would occupy a further 1%-7%. Investment in canola biodiesel or renewable diesel refineries could ensure supply for the bare minimum agricultural liquid fuel needs. Were subsequent analysis to favor this option as part of a fuels resilience response and as a tradeoff for routine food use, expansion in refining and canola cropping before a catastrophe could be encouraged through market mechanisms, direct government investment, or a combination of these. Logistics of biofuel refining scale-up, post-catastrophe, should also be analyzed. Further, biodiesel produced in normal times would help the nation meet its emissions reduction targets. Other countries should conduct similar analyses.

The rise and fall of excess winter mortality in New Zealand from 1876 to 2020.

Excess winter mortality (EWM) has been used as a measure of how well populations and policy moderate the health effects of cold weather. We aimed to investigate long-term changes in the EWM of Aotearoa New Zealand (NZ), and potential drivers of change, and to test for structural breaks in trends. We calculated NZ EWM indices from 1876 (4,698 deaths) to 2020 (33,310 deaths), total and by age-group and sex, comparing deaths from June to September (the coldest months) to deaths from February to May and October to January. The mean age and sex-standardised EWM Index (EWMI) for the full study period, excluding 1918, was 1.22. However, mean EWMI increased from 1.20 for 1886 to 1917, to 1.34 for the 1920s, then reduced over time to 1.14 in the 2010s, with excess winter deaths averaging 4.5% of annual deaths (1,450 deaths per year) in the 2010s, compared to 7.9% in the 1920s. Children under 5 years transitioned from a summer to winter excess between 1886 and 1911. Otherwise, the EWMI age-distribution was J-shaped in all time periods. Structural break testing showed the 1918 influenza pandemic strain had a significant impact on trends in winter and non-winter mortality and winter excess for subsequent decades. It was not possible to attribute the post-1918 reduction in EWM to any single factor among improved living standards, reduced severe respiratory infections, or climate change.

CSL324, a granulocyte colony-stimulating factor receptor antagonist, blocks neutrophil migration markers that are upregulated in hidradenitis suppurativa.

BACKGROUND: Neutrophils have been shown to contribute to the pathophysiology of hidradenitis suppurativa (HS), a chronic, painful and debilitating inflammatory skin disease, yet their exact role remains to be fully defined. Granulocyte colony-stimulating factor (G-CSF), a major regulator of neutrophil development and survival, can be blocked by the novel, fully human anti-G-CSF receptor (G-CSFR) monoclonal antibody CSL324. OBJECTIVES: We investigated the activation and migration of neutrophils in HS and the impact of blocking G-CSFR with CSL324. METHODS: Biopsy and peripheral blood samples were taken from participants of two studies: 2018.206, a noninterventional research study of systemic and dermal neutrophils and inflammatory markers in patients with neutrophilic skin diseases, and CSL324_1001 (ACTRN12616000846426), a single-dose ascending and repeated dose, randomized, double-blind, placebo-controlled study to assess the safety, pharmacokinetics and pharmacodynamics of CSL324 in healthy adult subjects. Ex vivo experiments were performed, including neutrophil enumeration and immunophenotyping, migration, receptor occupancy and transcriptome analysis. RESULTS: The number of cells positive for the neutrophil markers myeloperoxidase (MPO) and neutrophil elastase (NE) was significantly higher in HS lesions compared with biopsies from healthy donors (HDs) (P < 0.0001 and P = 0.0223, respectively). In peripheral blood samples, mean neutrophil counts were significantly higher in patients with HS than in HDs (2.98 vs. 1.60 × 109 L-1, respectively; P = 8.8 × 10-4). Neutrophil migration pathways in peripheral blood were increased in patients with HS and their neutrophils demonstrated an increased migration phenotype, with higher mean CXCR1 on the surface of neutrophils in patients with HS (24453.20 vs. 20798.47 for HD; P = 0.03). G-CSF was a key driver of the transcriptomic changes in the peripheral blood of patients with HS and was elevated in serum from patients with HS compared with HDs (mean 6.61 vs. 3.84 pg mL-1, respectively; P = 0.013). Administration of CSL324 inhibited G-CSF-induced transcriptional changes in HDs, similar to those observed in the HS cohort, as highlighted by expression changes in genes related to neutrophil migratory capacity. CONCLUSIONS: Data suggest that neutrophils contribute to HS pathophysiology and that neutrophils are increased in lesions due to an increase in G-CSF-driven migration. CSL324 counteracted G-CSF-induced transcriptomic changes and blocked neutrophil migration by reducing cell-surface levels of chemokine receptors.

Disease-Related Loss to Government Funding: Longitudinal Analysis of Individual-Level Health and Tax Data for an Entire Country.

OBJECTIVES: The objective of this longitudinal analysis was to estimate funding loss in terms of tax revenue to the New Zealand (NZ) government from disease and injury among working age adults. METHODS: Linked national health and tax data sets of the usually resident population between 2006 and 2016 were used to model 40 disease states simultaneously in a fixed-effects regression analysis to estimate population-level tax loss from disease and injury. To estimate tax revenue loss to the NZ government, we modeled a counterfactual scenario where all disease/injury was cause deleted. RESULTS: The estimated tax paid by all 25- to 64-year-olds in the eligible NZ population was $15 773 million (m) per annum (US dollar 2021), or $16 446 m for a counterfactual as though no one had any disease disease-related income loss (a 4.3% or $672.9 m increase in tax revenue per annum). The disease that-if it had no impact on income-generated the greatest impact was mental illness, contributing 34.7% ($233.3 m) of all disease-related tax loss, followed by cardiovascular (14.7%, $99.0 m) and endocrine (10.2%, $68.8 m). Tax revenue gains after deleting all disease/injury increased up to 65 years of age, with the largest contributor occurring among 60- to 64-year-olds ($131.7 m). Varied results were also observed among different ethnicities and differing levels of deprivation. CONCLUSIONS: This study finds considerable variation by disease on worker productivity and therefore tax revenue in this high-income country. These findings strengthen the economic and government case for prevention, particularly the prevention of mental health conditions and cardiovascular disease.

Prioritization of intervention domains to prevent cardiovascular disease: a country-level case study using global burden of disease and local data.

AIM: We aimed to combine Global Burden of Disease (GBD) Study data and local data to identify the highest priority intervention domains for preventing cardiovascular disease (CVD) in the case study country of Aotearoa New Zealand (NZ). METHODS: Risk factor data for CVD in NZ were extracted from the GBD using the "GBD Results Tool." We prioritized risk factor domains based on consideration of the size of the health burden (disability-adjusted life years [DALYs]) and then by the domain-specific interventions that delivered the highest health gains and cost-savings. RESULTS: Based on the size of the CVD health burden in DALYs, the five top prioritized risk factor domains were: high systolic blood pressure (84,800 DALYs; 5400 deaths in 2019), then dietary risk factors, then high LDL cholesterol, then high BMI and then tobacco (30,400 DALYs; 1400 deaths). But if policy-makers aimed to maximize health gain and cost-savings from specific interventions that have been studied, then they would favor the dietary risk domain (e.g., a combined fruit and vegetable subsidy plus a sugar tax produced estimated lifetime savings of 894,000 health-adjusted life years and health system cost-savings of US$11.0 billion; both 3% discount rate). Other potential considerations for prioritization included the potential for total health gain that includes non-CVD health loss and potential for achieving relatively greater per capita health gain for Maori (Indigenous) to reduce health inequities. CONCLUSIONS: We were able to show how CVD risk factor domains could be systematically prioritized using a mix of GBD and country-level data. Addressing high systolic blood pressure would be the top ranked domain if policy-makers focused just on the size of the health loss. But if policy-makers wished to maximize health gain and cost-savings using evaluated interventions, dietary interventions would be prioritized, e.g., food taxes and subsidies.

Perceptions of Illicit Tobacco Sources Following a Proposed Reduction in Tobacco Availability: A Qualitative Analysis of New Zealanders Who Smoke.

INTRODUCTION: Tobacco companies claim that substantially reducing tobacco retail outlets in Aotearoa New Zealand will increase illicit tobacco trade and crime. However, we know little about whether people who smoke anticipate using illicit tobacco once this measure is implemented. Exploring current illicit tobacco use and expected market development would clarify the likely scale of this potential problem. AIMS AND METHODS: We undertook online in-depth interviews with 24 adults who smoke and explored their experiences of illicit tobacco, perceptions of illicit market growth once legal tobacco became less available, intentions to engage in this market, and potential measures that could curb illicit market development. We interpreted the data using a qualitative descriptive approach. RESULTS: Few participants had purchased illegally imported or stolen tobacco. While most did not know how to access illicit tobacco products, many expected illicit trade and crime would increase, if legal tobacco became difficult to access. While cheaper tobacco appealed to many, most perceived illicit supply routes as unsafe and saw products obtained via these sources as likely to be of poor quality. Few suggested measures to control illicit markets, though a minority called for social reforms to reduce poverty, which they thought fueled illegal practices. CONCLUSIONS: Although illicit trade may appear to threaten new policy initiatives, participants' limited knowledge of these markets and concerns regarding product safety suggest illegal tobacco may pose less of a threat than tobacco companies have claimed. Policy makers should not be deterred from reducing tobacco availability by industry arguments. IMPLICATIONS: Although participants believed illicit trade would increase if the number of tobacco retailers was substantially reduced, few anticipated purchasing illegal tobacco. They viewed supply routes as unsafe and product quality as likely to be low. Industry predictions that illicit tobacco trade will grow if tobacco becomes less available do not reflect how people who smoke expect to engage with these markets and should not deter the introduction of retail reduction measures.

The potential human health hazard of nitrates in drinking water: a media discourse analysis in a high-income country.

BACKGROUND: Recent studies linking low levels of nitrate in drinking water to colorectal cancer have raised public concerns over nitrate contamination. The aim of this study was to analyze the media discourse on the potential human health hazard of nitrates in drinking water in a high-income country with a large livestock industry: New Zealand (NZ). METHODS: Searches of media sources ("major newspapers") held by the Factiva database for the NZ setting in the five-year period 17 December 2016 to 20 December 2021. RESULTS: The largest number of media items was observed for 2017 (n = 108), the year of a NZ general election, with a notable decrease in 2020 (n = 20) that was likely due to the Covid-19 pandemic, which dominated health media. However, the percentage of these media items with a health focus steadily increased over time, from 11.1% of all articles in 2017 to 51.2% in 2021. The most commonly mentioned health hazard was colorectal cancer, followed by methemoglobinemia. The temporal pattern of media items suggests that the release of scientific studies and scholarly blogs was associated with the publication of subsequent media items. Major stakeholders involved in the discourse included representatives of local and central government, environmental and recreational interest groups, researchers, local residents, agricultural interest groups, and health organizations. Maori (Indigenous New Zealanders) values or perspectives were rarely mentioned. CONCLUSIONS: Analysis of major newspapers for a five-year period indicated that a wide range of expert comment and opinions were made available to the public and policy makers on the issue of nitrates in water. While many different stakeholder views were captured in the media discourse, there is scope for the media to better report the views of Maori on this topic. There is also a need for articles detailing the health issues to also refer to the environmental, recreational, and cultural aspects of protecting water quality to ensure that the public, policy makers, and regulators are aware of co-benefits.

Economic effects for citizens and the government of a country-level tobacco endgame strategy: a modelling study.

BACKGROUND: Aotearoa-New Zealand (A/NZ) was the first country to pass a comprehensive commercial tobacco endgame strategy into law. Key components include the denicotinisation of smoked tobacco products and a major reduction in tobacco retail outlets. Understanding the potential long-term economic impacts of such measures is important for government planning. DESIGN: A tobacco policy simulation model that evaluated the health impacts of the A/NZ Smokefree Action Plan was extended to evaluate the economic effects from both government and citizen perspectives. Estimates were presented in 2021 US$, discounted at 3% per annum. RESULTS: The modelled endgame policy package generates considerable growth in income for the A/NZ population with a total cumulative gain of US$31 billion by 2050. From a government perspective, increased superannuation payments and reduced tobacco excise tax revenue result in a negative net financial position and a cumulative shortfall of US$11.5 billion by 2050. In a sensitivity analysis considering future labour force changes, the government's cumulative net position remained negative by 2050, but only by US$1.9 billion. CONCLUSIONS: A policy such as the A/NZ Smokefree Action Plan is likely to produce substantial economic benefits for citizens, and modest impacts on government finances related to reduced tobacco tax and increases in aged pensions due to increased life expectancy. Such costs can be anticipated and planned for and might be largely offset by future increases in the size of the labour force and the proportion of people 65+ years old working in the formal economy.

Tobacco endgame intervention impacts on health gains and Maori:non-Maori health inequity: a simulation study of the Aotearoa/New Zealand Tobacco Action Plan.

BACKGROUND: The Aotearoa/New Zealand Government is aiming to end the tobacco epidemic and markedly reduce Maori:non-Maori health inequalities by legislating: (1) denicotinisation of retail tobacco, (2) 95% reduction in retail outlets and (c) a tobacco free-generation whereby people born after 2005 are unable to legally purchase tobacco. This paper estimates future smoking prevalence, mortality inequality and health-adjusted life year (HALY) impacts of these strategies. METHODS: We used a Markov model to estimate future yearly smoking and vaping prevalence, linked to a proportional multistate life table model to estimate future mortality and HALYs. RESULTS: The combined package of strategies (plus media promotion) reduced adult smoking prevalence from 31.8% in 2022 to 7.3% in 2025 for Maori, and 11.8% to 2.7% for non-Maori. The 5% smoking prevalence target was forecast to be achieved in 2026 and 2027 for Maori males and females, respectively.The HALY gains for the combined package over the population's remaining lifespan were estimated to be 594 000 (95% uncertainty interval (UI): 443 000 to 738 000; 3% discount rate). Denicotinisation alone achieved 97% of these HALYs, the retail strategy 19% and tobacco-free generation 12%.By 2040, the combined package was forcat to reduce the gap in Maori:non-Maori all-cause mortality rates for people 45+ years old by 22.9% (95% UI: 19.9% to 26.2%) for females and 9.6% (8.4% to 11.0%) for males. CONCLUSION: A tobacco endgame strategy, especially denicotinisation, could deliver large health benefits and dramatically reduce health inequities between Maori and non-Maori in Aotearoa/New Zealand.

Comparing COVID-19 pandemic health responses in two high-income island nations: Iceland and New Zealand.

AIMS: We aimed to compare COVID-19 control measures, epidemiological characteristics and economic performance measures in two high-income island nations with small populations, favorable border control options, and relatively good outcomes: Iceland and New Zealand (NZ). METHODS: We examined peer-reviewed journal articles, official websites, reports, media releases and press articles for data on pandemic preparedness and COVID-19 public health responses from 1 January 2020 to 1 June 2022 in Iceland and NZ. We calculated epidemiological characteristics of the COVID-19 pandemic, as well as measures of economic performance. RESULTS: Both nations had the lowest excess mortality in the OECD from the start of the pandemic up to June 2022. Iceland pursued a mitigation strategy, never used lockdowns or officially closed its border to foreign nationals, and instead relied on extensive testing and contact tracing early in the pandemic. Meanwhile, NZ pursued an elimination strategy, used a strict national lockdown to stop transmission, and closed its international border to everyone except citizens and permanent residents going through quarantine and testing. Iceland experienced a larger decrease in gross domestic product in 2020 (relative to 2019) than NZ (-8·27% vs. -1·22%, respectively). In late 2021, NZ announced a shift to a suppression strategy and in 2022 began to reopen its border in stages, while Iceland ended all public restrictions on 25 February 2022. CONCLUSIONS: Many of Iceland's and NZ's pandemic control measures appeared successful and features of the responses in both countries could potentially be adopted by other jurisdictions to address future disease outbreaks and pandemic threats.

Island refuges for surviving nuclear winter and other abrupt sunlight-reducing catastrophes.

Some island nations in the Southern Hemisphere might survive a severe sun-reducing catastrophe such as nuclear winter and be well placed to help reboot-collapsed human civilization. Such islands must be resilient to the cascading effects abrupt sunlight reduction scenarios (ASRS) would impose beyond the impacts on agricultural systems. We aimed to identify island nations whose societies are most likely to survive nuclear winter or other ASRS. We also aimed to conduct a case study of one island nation to consider how it might enhance its resilience and therefore its chance of aiding a global reboot of complex technological society. We performed a threshold analysis on food self-sufficiency under severe nuclear winter conditions to identify islands. We then profiled each island across global macroindices representing resilience factors reported in the literature. We undertook a case study of the island nation of New Zealand. The island nations of Australia, New Zealand, Iceland, the Solomon Islands, and Vanuatu appear most resilient to ASRS. However, our case-study island nation of New Zealand is threatened in scenarios of no/low trade, has precarious aspects of its energy supply, and shortcomings in manufacturing of essential components. Therefore, inadequate preparations and critical failures in these systems could see rapid societal breakdown. Despite some islands' favorable baseline conditions and apparent food security even in a severe ASRS, cascading impacts through other socioecological systems threaten complex functioning. We identified specific resilience measures, many with cobenefits, which may protect island nodes of sustained complexity in ASRS.

Assumptions, uncertainty, and catastrophic/existential risk: National risk assessments need improved methods and stakeholder engagement.

Two key shortcomings of national risk assessments (NRAs) are: (1) lack of justification and transparency around important foundational assumptions of the process, (2) omission of almost all the largest scale risks. Using a demonstration set of risks, we illustrate how NRA process assumptions around time horizon, discount rate, scenario choice, and decision rule impact on risk characterization and therefore any subsequent ranking. We then identify a neglected set of large-scale risks that are seldom included in NRAs, namely global catastrophic risks and existential threats to humanity. Under a highly conservative approach that considers only simple probability and impact metrics, the use of significant discount rates, and harms only to those currently alive at the time, we find these risks have likely salience far greater than their omission from national risk registers might suggest. We highlight the substantial uncertainty inherent in NRAs and argue that this is reason for more engagement with stakeholders and experts. Widespread engagement with an informed public and experts would legitimize key assumptions, encourage critique of knowledge, and ease shortcomings of NRAs. We advocate for a deliberative public tool that can support informed two-way communication between stakeholders and governments. We outline the first component of such a tool for communication and exploration of risks and assumptions. The most important factors for an "all hazards" approach to NRA are ensuring license for key assumptions and that all the salient risks are included before proceeding to ranking of risks and considering resource allocation and value.

Coagulation factor-XII induces interleukin-6 by primary lung fibroblasts: a role in idiopathic pulmonary fibrosis?

The mechanisms driving idiopathic pulmonary fibrosis (IPF) remain undefined, however it is postulated that coagulation imbalances may play a role. The impact of blood-derived clotting factors, including factor XII (FXII) has not been investigated in the context of IPF. Plasma levels of FXII were measured by ELISA in patients with IPF and in age-matched healthy donors. Expression of FXII in human lung tissue was quantified using multiplex immunohistochemistry and Western blotting. Mechanistic investigation of FXII activity was assessed in vitro on primary lung fibroblasts using qPCR and specific receptor/FXII inhibition. The functional outcome of FXII on fibroblast migration was examined by high-content image analysis. Compared with 35 healthy donors, plasma levels of FXII were not higher in patients with IPF (n = 27, P > 0.05). Tissue FXII was elevated in IPF (n = 11) and increased numbers of FXII+ cells were found in IPF (n = 8) lung tissue compared with nondiseased controls (n = 6, P < 0.0001). Activated FXII induced IL6 mRNA and IL-6 protein in fibroblasts that was blocked by anti-FXII antibody, CSL312. FXII induced IL-6 production via PAR-1 and NF-κB. FXII induced migration of fibroblasts in a concentration-dependent manner. FXII is normally confined to the circulation but it leaks from damaged vessels into the lung interstitium in IPF where it 1) induces IL-6 production and 2) enhances migration of resident fibroblasts, critical events that drive chronic inflammation and therefore, contribute to fibrotic disease progression. Targeting FXII-induced fibroblastic processes in IPF may ameliorate pulmonary fibrosis.

Disaggregating proportional multistate lifetables by population heterogeneity to estimate intervention impacts on inequalities.

BACKGROUND: Simulation models can be used to quantify the projected health impact of interventions. Quantifying heterogeneity in these impacts, for example by socioeconomic status, is important to understand impacts on health inequalities. We aim to disaggregate one type of Markov macro-simulation model, the proportional multistate lifetable, ensuring that under business-as-usual (BAU) the sum of deaths across disaggregated strata in each time step returns the same as the initial non-disaggregated model. We then demonstrate the application by deprivation quintiles for New Zealand (NZ), for: hypothetical interventions (50% lower all-cause mortality, 50% lower coronary heart disease mortality) and a dietary intervention to substitute 59% of sodium with potassium chloride in the food supply. METHODS: We developed a disaggregation algorithm that iteratively rescales mortality, incidence and case-fatality rates by time-step of the model to ensure correct total population counts were retained at each step. To demonstrate the algorithm on deprivation quintiles in NZ, we used the following inputs: overall (non-disaggregated) all-cause mortality & morbidity rates, coronary heart disease incidence & case fatality rates; stroke incidence & case fatality rates. We also obtained rate ratios by deprivation for these same measures. Given all-cause and cause-specific mortality rates by deprivation quintile, we derived values for the incidence, case fatality and mortality rates for each quintile, ensuring rate ratios across quintiles and the total population mortality and morbidity rates were returned when averaged across groups. The three interventions were then run on top of these scaled BAU scenarios. RESULTS: The algorithm exactly disaggregated populations by strata in BAU. The intervention scenario life years and health adjusted life years (HALYs) gained differed slightly when summed over the deprivation quintile compared to the aggregated model, due to the stratified model (appropriately) allowing for differential background mortality rates by strata. Modest differences in health gains (HALYs) resulted from rescaling of sub-population mortality and incidence rates to ensure consistency with the aggregate population. CONCLUSION: Policy makers ideally need to know the effect of population interventions estimated both overall, and by socioeconomic and other strata. We demonstrate a method and provide code to do this routinely within proportional multistate lifetable simulation models and similar Markov models.

Comparing health gains, costs and cost-effectiveness of 100s of interventions in Australia and New Zealand: an online interactive league table.

BACKGROUND: This study compares the health gains, costs, and cost-effectiveness of hundreds of Australian and New Zealand (NZ) health interventions conducted with comparable methods in an online interactive league table designed to inform policy. METHODS: A literature review was conducted to identify peer-reviewed evaluations (2010 to 2018) arising from the Australia Cost-Effectiveness research and NZ Burden of Disease Epidemiology, Equity and Cost-Effectiveness Programmes, or using similar methodology, with: health gains quantified as health-adjusted life years (HALYs); net health system costs and/or incremental cost-effectiveness ratio; time horizon of at least 10 years; and 3% to 5% discount rates. RESULTS: We identified 384 evaluations that met the inclusion criteria, covering 14 intervention domains: alcohol; cancer; cannabis; communicable disease; cardiovascular disease; diabetes; diet; injury; mental illness; other non-communicable diseases; overweight and obesity; physical inactivity; salt; and tobacco. There were large variations in health gain across evaluations: 33.9% gained less than 0.1 HALYs per 1000 people in the total population over the remainder of their lifespan, through to 13.0% gaining > 10 HALYs per 1000 people. Over a third (38.8%) of evaluations were cost-saving. CONCLUSIONS: League tables of comparably conducted evaluations illustrate the large health gain (and cost) variations per capita between interventions, in addition to cost-effectiveness. Further work can test the utility of this league table with policy-makers and researchers.

Updated Health and Cost Impacts of Electronic Nicotine Delivery Systems, Using Recent Estimates of Relative Harm for Vaping Compared to Smoking.

BACKGROUND: Measuring population health and costs effects of liberalizing access to electronic nicotine delivery systems (ENDS) is an evolving field with high persisting uncertainty. A critical area of uncertainty for policy-makers are estimates of net harms from ENDS relative to cigarettes, therefore, we model these harms using updated estimates incorporating disease specificity. METHODS: We use updated estimates of relative harm of vaping vs smoking, based upon relevant biomarker studies to model the impact of liberalizing access to ENDS in New Zealand (NZ), relative to a ban (where ENDS are not legally available), in an existing proportional multi-state life-table model of 16 tobacco-related diseases. RESULTS: This modeling suggests that ENDS liberalization results in an expected gain of 195 000 quality-adjusted life-years (QALYs) over the remainder of the NZ population's lifespan. There was wide uncertainty in QALYs gained (95% uncertainty interval [UI] = -8000 to 406 000) with a 3.2% probability of net health loss (based upon the number of simulation runs returning positive QALY gains). The average per capita health gain was 0.044 QALYs (equivalent to an extra 16 days of healthy life). Health system cost-savings were expected to be NZ$2.8 billion (US$2.1 billion in 2020 US$; 95%UI: -0.3 to 6.2 billion [2011 NZ$]), with an estimated 3% chance of a net increase in per capita cost. CONCLUSIONS: This updated modeling around liberalizing ENDs in NZ, still suggests likely net health and cost-saving benefits-but of lesser magnitude than previous work and with a small possibility of net harm to population health. IMPLICATIONS: This study found evidence using updated biomarker studies that ENDS liberalization could result in QALY gains across the New Zealand population lifespan that are also cost-saving to the health system. Governments should include the information from these types of modeling studies in their decision-making around potentially improving access to ENDS for existing smokers, while at the same further reducing access to tobacco.

Going 'Super Value' in New Zealand: cigarette pricing strategies during a period of sustained annual excise tax increases.

BACKGROUND: Between 2010 and 2020, the New Zealand (NZ) Government increased tobacco excise tax by inflation plus 10% each year. We reviewed market structure changes and examined whether NZ tobacco companies shifted excise tax increases to maintain the affordability of lower priced cigarette brands. METHODS: We cluster-analysed market data that tobacco companies supply to the NZ Ministry of Health, created four price partitions and examined the size and share of these over time. For each partition, we analysed cigarette brand numbers and market share, calculated the volume-weighted real stick price for each year and compared this price across different price partitions. We calculated the net real retail price (price before tax) for each price partition and compared these prices before and after plain packaging took effect. RESULTS: The number and market share of Super Value and Budget brands increased, while those of Everyday and Premium brands decreased. Differences between the price of Premium and Super Value brands increased, as did the net retail price difference for these partitions. Following plain packaging's implementation, Super Value brand numbers more than doubled; contrary to industry predictions, the price difference between these and higher priced brands did not narrow. CONCLUSIONS: Between 2010 and 2020, NZ tobacco companies introduced more Super Value cigarette brands and shifted excise tax increases to reduce the impact these had on low-priced brands. Setting a minimum retail price for cigarettes could curtail tobacco companies' ability to undermine tobacco taxation policies designed to reduce smoking.