Mortality surrogates in combined pulmonary fibrosis and emphysema.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

Pregnancy in women with cystic fibrosis and diabetes: An audit of outcomes at two tertiary obstetric hospitals in Australia in the pre-cystic fibrosis transmembrane conductance regulator modulator era.

Background: Pregnancy in women with cystic fibrosis (CF) is becoming more common. Long-term metabolic issues such as diabetes are also becoming more common and have potentially important impacts on pregnancy outcomes. This study aimed to assess the impact of diabetes on pregnancy outcomes for women with CF. Methods: We undertook a retrospective chart audit of pregnancies to women with CF at the two tertiary obstetric hospitals in Southeast Queensland associated with CF and transplant management clinics between 2006 and 2016. Results: A total of 38 pregnancies among 26 women were identified. Four women (five pregnancies) had cystic fibrosis-related diabetes (CFRD) diagnosed prior to pregnancy, and 12 women (15 pregnancies) developed gestational diabetes (GDM) complicating pregnancy. CFRD and GDM were associated with higher rates of delivery complications, prematurity, and the need for neonatal intensive care unit admission. Conclusion: Diabetes is common during pregnancy in women with CF and impacts pregnancy outcomes.

Long-term exposure to low concentrations of air pollution and decline in lung function in people with idiopathic pulmonary fibrosis: Evidence from Australia.

BACKGROUND AND OBJECTIVE: Little is known about the association between ambient air pollution and idiopathic pulmonary fibrosis (IPF) in areas with lower levels of exposure. We aimed to investigate the impact of air pollution on lung function and rapid progression of IPF in Australia. METHODS: Participants were recruited from the Australian IPF Registry (n = 570). The impact of air pollution on changes in lung function was assessed using linear mixed models and Cox regression was used to investigate the association with rapid progression. RESULTS: Median (25th-75th percentiles) annual fine particulate matter (<2.5 µm, PM2.5 ) and nitrogen dioxide (NO2 ) were 6.8 (5.7, 7.9) µg/m3 and 6.7 (4.9, 8.2) ppb, respectively. Compared to living more than 100 m from a major road, living within 100 m was associated with a 1.3% predicted/year (95% confidence interval [CI] -2.4 to -0.3) faster annual decline in diffusing capacity of the lungs for carbon monoxide (DLco). Each interquartile range (IQR) of 2.2 µg/m3 increase in PM2.5 was associated with a 0.9% predicted/year (95% CI -1.6 to -0.3) faster annual decline in DLco, while there was no association observed with NO2 . There was also no association between air pollution and rapid progression of IPF. CONCLUSION: Living near a major road and increased PM2.5 were both associated with an increased rate of annual decline in DLco. This study adds to the evidence supporting the negative effects of air pollution on lung function decline in people with IPF living at low-level concentrations of exposure.

Multimodal Transplant-clinic-based Skin Cancer Prevention Education for Organ Transplant Recipients: Feasibility Study.

We studied the feasibility of transplant-clinic staff routinely providing primary prevention advice to lung transplant recipients at high risk of skin cancer. Methods: Patients enrolled by a transplant-clinic study nurse completed baseline questionnaires and received sun-safety brochures. For the 12-mo intervention, transplant physicians were alerted to provide standard sun-protection advice (use of hat, long sleeves, and sunscreen outdoors) by sun-advice prompt cards attached to participants' medical charts at each clinic visit. Patients indicated receiving advice from their physician and from study personnel via an exit-card postclinic, and at final study clinics, they also reported their sun behaviors by questionnaire. Feasibility of the intervention was measured by patients' and clinic staff's study engagement; effectiveness was assessed by calculating odds ratios (ORs) for improved sun protection, using generalized estimating equations. Results: Of 151 patients invited, 134 consented (89%), and 106 (79 %) (63% male, median age 56 y, 93% of European descent) completed the study. Odds of receiving sun advice from transplant physicians and study nurses rose after the intervention compared with baseline (ORs, 1.67; 95% confidence interval [CI], 0.96-2.96 and 3.56; 95% CI, 1.38-9.14, respectively). After 12 mo of regular transplant-clinic advice, odds of sunburn decreased (OR, 0.59; 95% CI, 0.13-2.60), and odds of applying sunscreen (OR, 1.93; 95% CI, 1.20-3.09) almost doubled. Conclusions: Encouragement of primary prevention of skin cancer among organ transplant recipients by physicians and nurses during routine transplant-clinic visits is feasible and appears to be effective.

High-risk Prognostic Tumor Features of Squamous Cell Carcinomas in Organ Transplant Recipients Compared With the General Population.

Importance: The extent to which major high-risk features of squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs) differ from SCCs in the general population is not known. Objective: To quantify the relative frequency of perineural invasion, invasion below the dermis, lack of cellular differentiation, and tumor diameter greater than 20 mm in SCCs in OTRs and the general population, by anatomic site. Design, Setting, and Participants: This dual-cohort study in Queensland, Australia, included a cohort of OTRs at high risk of skin cancer ascertained from 2012 to 2015 (Skin Tumours in Allograft Recipients [STAR] study) and a population-based cohort ascertained from 2011 (QSkin Sun and Health Study). The STAR study comprised population-based lung transplant recipients and kidney and liver transplant recipients at high risk of skin cancer recruited from tertiary centers and diagnosed with histopathologically confirmed SCC from 2012 to 2015. The QSkin participants were recruited from Queensland's general adult population, and primary SCCs diagnosed from 2012 to 2015 were ascertained through Medicare (national health insurance scheme) and linked with histopathology records. Data analysis was performed from July 2022 to April 2023. Main Outcomes and Measures: Prevalence ratio (PR) of head/neck location, perineural invasion, tumor invasion to/beyond subcutaneous fat, poor cellular differentiation, and tumor diameter greater than 20 mm among SCCs in OTRs vs the general population. Results: There were 741 SCCs excised from 191 OTRs (median [IQR] age, 62.7 [56.7-67.1] years; 149 [78.0%] male) and 2558 SCCs from 1507 persons in the general population (median [IQR] age, 63.7 [58.0-68.8] years; 955 [63.4%] male). The SCCs developed most frequently on the head/neck in OTRs (285, 38.6%), but on arms/hands in the general population (896, 35.2%) (P < .001). After adjusting for age and sex, perineural invasion was more than twice as common in OTRs as in population cases (PR, 2.37; 95% CI, 1.70-3.30), as was invasion to/beyond subcutaneous fat (PR, 2.37; 95% CI, 1.78-3.14). Poorly vs well-differentiated SCCs were more than 3-fold more common in OTRs (PR, 3.45; 95% CI, 2.53-4.71), and prevalence of tumors greater than 20 mm vs 20 mm or smaller was moderately higher in OTRs (PR, 1.52; 95% CI, 1.08-2.12). Conclusions and Relevance: In this dual-cohort study, SCCs in OTRs had significantly worse prognostic features than SCCs in the general population, reinforcing the necessity of early diagnosis and definitive management of SCCs in OTRs.

Contribution of skin cancer to overall healthcare costs of lung transplantation in Queensland, Australia.

BACKGROUND: Skin cancers are a major source of morbidity in lung transplant recipients, but the relative costs associated with their treatment are unknown. METHODS: We prospectively followed 90 lung transplant recipients from enrollment in the Skin Tumors in Allograft Recipients study in 2013-2015, until mid-2016. We undertook a cost analysis to quantify the health system costs relating to the index transplant episode and ongoing costs for 4 years. Linked data from surveys, Australian Medicare claims, and hospital accounting systems were used, and generalized linear models were employed. RESULTS: Median initial hospitalization costs of lung transplantation were AU$115,831 (interquartile range (IQR) $87,428-$177,395). In total, 57 of 90 (63%) participants were treated for skin cancers during follow-up at a total cost of AU$44,038. Among these 57, total government costs per person (mostly of pharmaceuticals) over 4 years were median AU$68,489 (IQR $44,682-$113,055) vs AU$59,088 (IQR $38,190-$94,906) among those without skin cancer, with the difference predominantly driven by more doctors' visits, and higher pathology and procedural costs. Healthcare costs overall were also significantly higher in those treated for skin cancers (cost ratio 1.50, 95%CI: 1.09, 2.06) after adjusting for underlying lung disease, age on enrollment, years of immunosuppression, and the number of treated comorbidities. CONCLUSIONS: Skin cancer care is a small component of overall costs. While all lung transplant recipients with comorbidities have substantial healthcare costs, those affected by skin cancer incur even greater healthcare costs than those without, highlighting the importance of skin cancer control.

Primary graft dysfunction following lung transplantation: From pathogenesis to future frontiers.

Lung transplantation is the treatment of choice for patients with end-stage lung disease. Currently, just under 5000 lung transplants are performed worldwide annually. However, a major scourge leading to 90-d and 1-year mortality remains primary graft dysfunction. It is a spectrum of lung injury ranging from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. This review aims to provide an in-depth analysis of the epidemiology, patho physiology, risk factors, outcomes, and future frontiers involved in mitigating primary graft dysfunction. The current diagnostic criteria are examined alongside changes from the previous definition. We also highlight the issues surrounding chronic lung allograft dysfunction and identify the novel therapies available for ex-vivo lung perfusion. Although primary graft dysfunction remains a significant contributor to 90-d and 1-year mortality, ongoing research and development abreast with current technological advancements have shed some light on the issue in pursuit of future diagnostic and therapeutic tools.

Mycoplasma hominis and Ureaplasma urealyticum infections in the immediate post-lung transplant period: A case series and literature review.

Mycoplasma hominis and Ureaplasma species infections in the post-transplant setting are believed to be donor-derived and can be associated with poor outcomes. Difficulty in culturing and identifying these organisms is a significant barrier to diagnosis and early intervention. Tetracyclines, macrolides and fluoroquinolones are the mainstay treatments to cure these infections; however, there are increasing reports of antibiotic resistance. In this case series, we report our single-centre experience with M. hominis and U. urealyticum infection after lung transplantation (9 recipients, all men, mean age 56 years). Delayed diagnosis was common. Young donor age (mean age 23 yrs) and high-risk donor social history (67%) were repeatedly noted in these cases, and all infections were associated with significant morbidity (anastomosis and sternal wound infection, empyema, mediastinitis, pericarditis). Two patients died; with one directly related to Ureaplasma urealyticum infection. In conclusion post lung transplant M. hominis, and U. urealyticum infections are challenging and carry high morbidity. More prospective studies are required to assess the true prevalence, full spectrum of complications and utility of molecular diagnostics to aid early diagnosis and identify antibiotic susceptibility of Mycoplasma and Ureaplasma infections in the post-lung transplant setting.

Mapping EQ5D utilities from forced vital capacity and diffusing capacity in fibrotic interstitial lung disease.

OBJECTIVES: Fibrotic interstitial lung disease (ILD) includes a large group of conditions that lead to scarring of the lungs. The lack of available 5-level EuroQol 5D (EQ5D) data has limited the ability to conduct economic evaluations in ILD. The purpose of this study was to develop and validate a mapping algorithm that predicts EQ5D utilities from commonly collected pulmonary function measurements (forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]) in fibrotic ILDs. METHODS: EQ5D utility and pulmonary function measurements from the Canadian Registry for Pulmonary Fibrosis were included. Ordinary least squares (OLS), beta regression, two-part, and tobit models were used to map EQ5D utilities from FVC or DLCO. Model performance was assessed by comparing the predicted and observed utilities. Subgroup analyses were also conducted to test how well models performed across different patient characteristics. The models were then externally validated in the Australian Idiopathic Pulmonary Fibrosis Registry. RESULTS: The OLS model performed as well as other more complex models (root mean squared error: 0.17 for FVC and 0.16 for DLCO). As with the other models, the OLS algorithm performed well across the different subgroups (except for EQ5D utilities < 0.5) and in the external validation cohort. CONCLUSION: We developed a mapping algorithm that predicts EQ5D utilities from FVC and DLCO, with the intent that this algorithm can be applied to clinical trial populations and real-world cohorts that have not prioritized collection of health-related utilities. The mapping algorithm can be used in future economic evaluations of potential ILD therapies.

Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

Laparoscopic fundoplication after lung transplantation does not appear to alter lung function trajectory.

BACKGROUND: The primary aim of this study was to determine if allograft function in lung transplant (LTx) recipients improves or stabilizes after laparoscopic fundoplication (LF). The secondary aim was to examine the differences in forced expiratory volume in 1 second (FEV1) before and after LF for various subgroups to identify patients who obtained a superior respiratory outcome after LF, and potential predictive factors for this outcome. METHODS: Retrospective analysis of consecutive LTx recipients undergoing LF at a single centre in Brisbane, Australia between 2004 and 2018. 149/431 proceeded to LF after clinical review and pH study. Regular pre- and post-fundoplication pulmonary function tests were collected from participants. Data were analyzed with linear mixed models, random intercept models, the Reliable Change Index (RCI), and graphical and visual analysis of the trajectory of FEV1. RESULTS: There was 100% follow-up. After Bonferroni adjustment for multiple comparison was performed, none of the models demonstrated statistical significance. The Reliable Change Index showed one patient had a significant improvement in lung function across that time period, while nine had a significant reduction. The rate of change before and after LF was similar for the 132/149 patients for whom the first and last pre- and post-LF FEV1 values were available. A subset of patients had a considerable reduction in their FEV1 in the peri-operative period (i.e., a large difference between the first measurement post-LF and the final measurement pre-LF). CONCLUSION: In the largest published cohort to date, LF performed in a high-volume center did not appear to alter the reduction in allograft function seen with time.

The relative contribution of co-morbidities to health-related quality of life of people with idiopathic pulmonary fibrosis using the Assessment of Quality of Life-8-Dimension multi-attribute utility instrument.

PURPOSE: Little is known about the impact of co-morbidities on health-related quality of life (HRQoL) for people with idiopathic pulmonary fibrosis (IPF). We aimed to investigate the relative contribution of co-morbidities to HRQoL of people with IPF. METHODS: N = 157 participants were recruited from the Australian IPF Registry (AIPFR). Health state utilities (HSUs), and the super-dimensions of physical and psychosocial scores were measured using the Assessment of Quality of Life-8-Dimensions (AQoL-8D). The impact of co-morbidities on HRQoL was investigated using linear regression and general dominance analyses. RESULTS: A higher number of co-morbidities was associated with lower HSUs (p trend = 0.002). Co-morbidities explained 9.1% of the variance of HSUs, 16.0% of physical super-dimensional scores, and 4.2% of psychosocial super-dimensional scores. Arthritis was associated with a significant reduction on HSUs (ß = - 0.09, 95% confidence interval [CI] - 0.16 to - 0.02), largely driven by reduced scores on the physical super-dimension (ß = - 0.13, 95% CI - 0.20 to - 0.06). Heart diseases were associated with a significant reduction on HSUs (ß = - 0.09, 95% CI - 0.16 to - 0.02), driven by reduced scores on physical (ß = - 0.09, 95% CI - 0.16 to - 0.02) and psychosocial (ß = -0.10, 95% CI - 0.17 to - 0.02) super-dimensions. CONCLUSIONS: Co-morbidities significantly impact HRQoL of people with IPF, with markedly negative impacts on their HSUs and physical health. A more holistic approach to the care of people with IPF is important as better management of these co-morbidities could lead to improved HRQoL in people with IPF.

Assessment of health-related quality of life in Australian patients with idiopathic pulmonary fibrosis: a comparison of the EQ-5D-5L and the AQoL-8D.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating chronic lung disease with a high symptom burden, which has a substantial impact on health-related quality of life (HRQoL). Our study aimed to assess the suitability of the EuroQol five-dimension (EQ-5D-5L) and the Assessment of Quality of Life- eight-dimension (AQoL-8D) questionnaires in measuring HRQoL as health state utility values (HSUVs) in an Australian IPF cohort. METHODS: Data for estimation of health state utility values (HSUVs) were collected from participants of the Australian IPF Registry (AIPFR) using self-administered surveys which included the EQ-5D-5L and the AQoL-8D. Data on lung function and disease specific HRQoL instruments were collected from the AIPFR. Performance of the two instruments was evaluated based on questionnaire practicality, agreement between the two instruments and test performance (internal and construct validity). RESULTS: Overall completion rates for the EQ-5D-5L and AQoL-8D were 96% and 85%, respectively. Mean (median) HSUVs were 0.65 (0.70) and 0.69 (0.72) for the EQ-5D-5L and AQoL-8D, respectively. There was reasonable agreement between the two instruments based on the Bland-Altman plot mean difference (-0.04) and intraclass correlation coefficient (0.84), however there were some fundamental differences. A larger range of values was observed with the EQ-5D-5L (-0.57-1.00 vs 0.16-1.00). The EQ-5D-5L had a greater divergent sensitivity and efficacy in relation to assessing HSUVs between clinical groupings. The AQoL-8D ,however, had a higher sensitivity to measure psychosocial aspects of HRQoL in IPF. CONCLUSION: The EQ-5D-5L demonstrated superior performance when compared to AQoL-8D in persons with IPF. This may be attributable to the high symptom burden which is physically debilitating to which the EQ-5D-5L may be more sensitive.

Basal cell carcinomas in organ transplant recipients versus the general population: clinicopathologic study.

Organ transplant recipients (OTRs) are at greater risk of basal cell carcinomas (BCCs) than non-OTRs, but histopathologic differences between BCCs in OTRs and the general population are largely unknown. We compared clinicopathologic features of BCCs in OTRs vs the general population in Queensland, Australia. Details of BCC tumors (site, size, level of invasion, subtype, biopsy procedure) were collected from histopathology reports in two prospective skin cancer studies, one in OTRs and one general-population-based. We used log-binomial regression models to estimate age- and sex-adjusted prevalence ratios (PR) with 95% confidence intervals (CIs) for BCC features. Overall, there were 702 BCCs in 200 OTRs and 1725 BCCs in 804 population cases. Of these, 327 tumors in 128 OTRs were higher risk BCCs (any head and neck BCC; ≥ 2 cm on trunk/extremities), more per person than 703 higher risk BCCs in 457 cases in the general population (chi-square p = 0.008). Among head/neck BCCs, OTRs were more likely than general population cases to have BCCs on scalp/ear than on face/lip/neck (PR = 1.5, 95%CI 1.2-1.8). Although aggressive subtypes were less common among higher risk BCCs in OTRs, BCCs invading beyond the dermis were almost twice as prevalent in OTRs (PR = 1.8, 95% CI 1.3-2.6) than the general population.

The economic burden of idiopathic pulmonary fibrosis in Australia: a cost of illness study.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease found mostly in elderly persons, characterized by a high symptom burden and frequent encounters with health services. This study aimed to quantify the economic burden of IPF in Australia with a focus on resource utilization and associated direct costs. METHODS: Participants were recruited from the Australian IPF Registry (AIPFR) between August 2018 and December 2019. Data on resource utilization and costs were collected via cost diaries and linked administrative data. Clinical data were collected from the AIPFR. A "bottom up" costing methodology was utilized, and the costing was performed from a partial societal perspective focusing primarily on direct medical and non-medical costs. Costs were standardized to 2021 Australian dollars ($). RESULTS: The average annual total direct costs per person with IPF was $31,655 (95% confidence interval (95% CI): $27,723-$35,757). Extrapolating costs based on prevalence estimates, the total annual costs in Australia are projected to be $299 million (95% CI: $262 million-$338 million). Costs were mainly driven by antifibrotic medication, hospital admissions and medications for comorbidities. Disease severity, comorbidities and antifibrotic medication all had varying impacts on resource utilization and costs. CONCLUSION: This cost-of-illness study provides the first comprehensive assessment of IPF-related direct costs in Australia, identifies the key cost drivers and provides a framework for future health economic analyses. Additionally, it provided insight into the major cost drivers which include antifibrotic medication, hospital admissions and medications related to comorbidities. Our findings emphasize the importance of the appropriate management of comorbidities in the care of people with IPF as this was one of the main reasons for hospitalizations.

Quantitative computed tomography predicts outcomes in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Prediction of disease course in patients with progressive pulmonary fibrosis remains challenging. The purpose of this study was to assess the prognostic value of lung fibrosis extent quantified at computed tomography (CT) using data-driven texture analysis (DTA) in a large cohort of well-characterized patients with idiopathic pulmonary fibrosis (IPF) enrolled in a national registry. METHODS: This retrospective analysis included participants in the Australian IPF Registry with available CT between 2007 and 2016. CT scans were analysed using the DTA method to quantify the extent of lung fibrosis. Demographics, longitudinal pulmonary function and quantitative CT metrics were compared using descriptive statistics. Linear mixed models, and Cox analyses adjusted for age, gender, BMI, smoking history and treatment with anti-fibrotics were performed to assess the relationships between baseline DTA, pulmonary function metrics and outcomes. RESULTS: CT scans of 393 participants were analysed, 221 of which had available pulmonary function testing obtained within 90 days of CT. Linear mixed-effect modelling showed that baseline DTA score was significantly associated with annual rate of decline in forced vital capacity and diffusing capacity of carbon monoxide. In multivariable Cox proportional hazard models, greater extent of lung fibrosis was associated with poorer transplant-free survival (hazard ratio [HR] 1.20, p < 0.0001) and progression-free survival (HR 1.14, p < 0.0001). CONCLUSION: In a multi-centre observational registry of patients with IPF, the extent of fibrotic abnormality on baseline CT quantified using DTA is associated with outcomes independent of pulmonary function.

Deep Learning-based Outcome Prediction in Progressive Fibrotic Lung Disease Using High-Resolution Computed Tomography.

Rationale: Reliable outcome prediction in patients with fibrotic lung disease using baseline high-resolution computed tomography (HRCT) data remains challenging. Objectives: To evaluate the prognostic accuracy of a deep learning algorithm (SOFIA [Systematic Objective Fibrotic Imaging Analysis Algorithm]), trained and validated in the identification of usual interstitial pneumonia (UIP)-like features on HRCT (UIP probability), in a large cohort of well-characterized patients with progressive fibrotic lung disease drawn from a national registry. Methods: SOFIA and radiologist UIP probabilities were converted to Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)-based UIP probability categories (UIP not included in the differential, 0-4%; low probability of UIP, 5-29%; intermediate probability of UIP, 30-69%; high probability of UIP, 70-94%; and pathognomonic for UIP, 95-100%), and their prognostic utility was assessed using Cox proportional hazards modeling. Measurements and Main Results: In multivariable analysis adjusting for age, sex, guideline-based radiologic diagnosis, anddisease severity (using total interstitial lung disease [ILD] extent on HRCT, percent predicted FVC, DlCO, or the composite physiologic index), only SOFIA UIP probability PIOPED categories predicted survival. SOFIA-PIOPED UIP probability categories remained prognostically significant in patients considered indeterminate (n = 83) by expert radiologist consensus (hazard ratio, 1.73; P < 0.0001; 95% confidence interval, 1.40-2.14). In patients undergoing surgical lung biopsy (n = 86), after adjusting for guideline-based histologic pattern and total ILD extent on HRCT, only SOFIA-PIOPED probabilities were predictive of mortality (hazard ratio, 1.75; P < 0.0001; 95% confidence interval, 1.37-2.25). Conclusions: Deep learning-based UIP probability on HRCT provides enhanced outcome prediction in patients with progressive fibrotic lung disease when compared with expert radiologist evaluation or guideline-based histologic pattern. In principle, this tool may be useful in multidisciplinary characterization of fibrotic lung disease. The utility of this technology as a decision support system when ILD expertise is unavailable requires further investigation.

Markers of rejection of a lung allograft: state of the art.

Chronic lung allograft dysfunction (CLAD) affects approximately 50% of all lung transplant recipients by 5 post-operative years and is the leading cause of death in lung transplant recipients. Early CLAD diagnosis or ideally prediction of CLAD is essential to enable early intervention before significant lung injury occurs. New technologies have emerged to facilitate biomarker discovery, including epigenetic modification and single-cell RNA sequencing. This review examines new and existing technologies for biomarker discovery and the current state of research on biomarkers for identifying lung transplant rejection.

Incidence, prevalence and mortality of idiopathic pulmonary fibrosis in Australia.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung diseases. While studies have been conducted in other countries to determine the epidemiological burden of IPF, there is limited information in Australia. Our study aimed to address this gap and generate the first estimates for the mortality, incidence and prevalence of IPF in Australia. METHODS: Estimates were generated by utilizing the novel Mortality Incidence Analysis Model (MIAMOD) method and software based on the illness-death model. Data inputs included population estimates and mortality data from the Australian Bureau of Statistics (ABS) for the period 1997-2015 and participant data from the Australian IPF Registry (AIPFR). Projections were estimated for a 10-year period up to 2025. RESULTS: Overall crude and age-standardized estimates for mortality were 5.9 and 6.3 per 100,000 population; incidence, 10.4 and 11.2 per 100,000 population; and prevalence, 32.6 and 35.1 per 100,000 population. Crude and age-standardized mortality, incidence and prevalence increased over the study period; however, they demonstrated a decreasing trend over the projected period. Persons older than 70 years constituted 9% of the population; however, they accounted for approximately 82%-83% of all deaths, incident and prevalent cases. All estimates were higher in males than in females. CONCLUSION: Our study provides the first estimates for incidence, prevalence and mortality of IPF in Australia. By reporting national estimates for IPF, our study addresses an information gap important for policy, planning and to help optimize the allocation of resources for the management of patients with IPF.

Nb/a-Si/Nb-junction Josephson arbitrary waveform synthesizers for quantum information.

We demonstrate Josephson arbitrary waveform synthesizers (JAWS) with increased operating temperature range for temperatures below 4 K. These JAWS synthesizers were fabricated with externally-shunted Nb/a-Si/Nb junctions whose critical current exhibits improved temperature stability compared to the self-shunted Nb/Nb0.15Si0.85/Nb junctions typically used. Vertical stud resistors made of 230 nm of PdAu were developed to provide the milliohm shunt resistance required for junction overdamping while maintaining a small footprint suitable for high-density series arrays embedded in a coplanar waveguide. We evaluated the performance of these resistors from 3.8 K down to 20 mK. We designed, fabricated and tested a JAWS circuit with 4650 externally shunted Nb/a-Si/Nb JJs with a critical current density (Jc) of 0.12 mA∕µm2 and critical current (Ic) of 3 mA. This circuit was designed to be mounted to the 3 K stage of a dilution refrigerator and used to control and calibrate a qubit mounted at the 10 mK stage. To increase the circuit density of the JAWS circuits we made arrays of two-junction vertical stacks. Current-voltage (I-V) curves of this JAWS circuit with stacked junctions under microwave excitation show Shapiro steps with quantum-locking ranges similar to those of JAWS circuits used for qubit control.