Interstitial lung disease incidence and mortality in the United Kingdom and the European Union: an observational study, 2001-2017

Objective: To compare the trends in age-standardised incidence and mortality from interstitial lung diseases (ILD) in the United Kingdom (UK) and the European Union (EU). Design: Observational study using data obtained from the Global Burden of Disease Study. Setting and Participants: Residents of the UK and of the twenty-seven EU countries. Main outcome measures: ILD age-standardised incidence rates per 100 000 (ASIR), age-standardised death rates per 100 000 (ASDR), and mortality-to-incidence ratio (MIRs) are presented for males and females separately for each country, for the years 2001–2017. Trends were analysed using Joinpoint regression analysis. Results: For men, in 2017, the median incidence of ILD was 7.22 (IQR 5.57–8.96) per 100 000 population. For women, in 2017, the median incidence of ILD was 4.34 (IQR 3.36–6.29) per 100 000 population. For men, in 2017, the median ASDR attributed to ILD was 2.04 (IQR 1.13–2.71) per 100 000 population. For women, the median ASDR in 2017 for ILD was 1.02 (0.68–1.37) per 100 000 population. There was an overall increase in ASDR during the observation period with a median change of +20.42% (IQR 5.44–31.40) for men and an increase of +15.44% (IQR −1.01–31.52) for women. Despite increases in mortality over the entire observation period, there were decreasing mortality trends in the majority of countries at the end of the observation period (75% for men and 86% for women). Conclusion: Over the past two decades, there have been increases in the incidence and mortality of interstitial lung diseases in Europe. The most recent trends, however, demonstrate decreases in mortality from ILD in the majority of European countries for both men and women. These data support the ongoing improvements in the diagnosis and management of ILD

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Effect of interchain separation on the photoinduced absorption spectra of polycarbazolyldiacetylenes

The photoinduced absorption spectra of a novel polycarbazolyldiacetylene with long aliphatic chains on the carbazolyl side groups are measured and compared with those of the unsubstituted polyDCHD. The two polymers in the blue form exhibit very similar electronic absorption spectra and Raman frequencies. This fact indicates that the conjugation length of the polydiacetylene backbone is not too affected by the long substituents. In contrast, the near steady-state photoinduced absorption spectra show that different photogeneration mechanisms are involved in the two polymers. This result can be ascribed to the role played by the interchain distance in the dynamics of the relaxation processes in polydiacetylenes

Long-lived photoexcited states in polydiacetylenes with different molecular and supramolecular organization

With the aim of determining the importance of the molecular and supramolecular organization on the excited states of polydiacetylenes, we have studied the photoinduced absorption spectra of the red form of poly[1,6-bis(3,6-didodecyl-N-carbazolyl)-2,4-hexadiyne] (polyDCHD-S) and the results compared with those of the blue form of the same polymer. An interpretation of the data is given in terms of both the conjugation length and the interbackbone separation also in relation to the photoinduced absorption spectra of both blue and red forms of poly[1,6-bis(N-carbazolyl)-2,4-hexadiyne] (polyDCHD), which does not carry the alkyl substituents on the carbazolyl side groups. Information on the above properties is derived from the analysis of the absorption and Raman spectra of this class of polydiacetylenes

Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort.

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF. Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p  0 vs. LOW slope, slope < =0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p = 0.080); PINP (HR 0.76, p = 0.309); PRO-C6 (HR 1.14, p = 0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR = 1.84, CI 1.03–3.27, p = 0.038, HR = 2.44, CI 1.39–4.31, p = 0.002; HR = 2.19, CI 1.25–3.82, p = 0.006; HR = 2.13 CI 1.21–3.75, p = 0.009 respectively). Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00787-015-0777-2) contains supplementary material, which is available to authorized users

Dipeptidyl Peptidase-4 Inhibitors as a Third-Line Oral Antihyperglycaemic Agent in Patients with Type 2 Diabetes Mellitus: The Impact of Ethnicity

Aims. The aim of this study is to examine the efficacy of adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to patients with type 2 diabetes inadequately controlled by metformin and sulphonylurea combination treatment. The response of Asian and non-Asian patients to this regimen was also examined. Methods. The medical and computerized records of 80 patients were examined. These patients had baseline HbA1c levels ranging from 7.0 to 12.5% and had a DPP-4 inhibitor add-on therapy for a minimum period of 12 weeks. The primary endpoint was the change in HbA1c level before and after DPP-4 inhibitor treatment. Results. During oral triple therapy, there was a reduction of HbA1c from 8.3% (7.7–8.9) to 7.2% (6.8–7.6) and 26 patients (32.5%) achieved an HbA1c <7%. Poor baseline glycaemic control, lower BMI, and younger age were associated with a better response, but duration of diabetes and gender did not affect outcome. The HbA1c reduction was not different between Asians and non-Asians group [−1.00% (0.6–1.3) vs −0.90% (0.4–1.6)]. Conclusions. DPP-4 inhibitor as a third-line add-on therapy can achieve significant glycaemic improvement in patients with type 2 diabetes inadequately controlled on the combination of metformin and sulphonylurea. The improvement in HbA1c was similar between Asian and non-Asian patients

The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study

Background: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related. Methods: A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. Results: GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04–2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997–1.000; p=0.245). Conclusions: We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects

Using Simulation Models to Evaluate Ape Nest Survey Techniques

BACKGROUND: Conservationists frequently use nest count surveys to estimate great ape population densities, yet the accuracy and precision of the resulting estimates are difficult to assess. METHODOLOGY/PRINCIPAL FINDINGS: We used mathematical simulations to model nest building behavior in an orangutan population to compare the quality of the population size estimates produced by two of the commonly used nest count methods, the 'marked recount method' and the 'matrix method.' We found that when observers missed even small proportions of nests in the first survey, the marked recount method produced large overestimates of the population size. Regardless of observer reliability, the matrix method produced substantial overestimates of the population size when surveying effort was low. With high observer reliability, both methods required surveying approximately 0.26% of the study area (0.26 km(2) out of 100 km(2) in this simulation) to achieve an accurate estimate of population size; at or above this sampling effort both methods produced estimates within 33% of the true population size 50% of the time. Both methods showed diminishing returns at survey efforts above 0.26% of the study area. The use of published nest decay estimates derived from other sites resulted in widely varying population size estimates that spanned nearly an entire order of magnitude. The marked recount method proved much better at detecting population declines, detecting 5% declines nearly 80% of the time even in the first year of decline. CONCLUSIONS/SIGNIFICANCE: These results highlight the fact that neither nest surveying method produces highly reliable population size estimates with any reasonable surveying effort, though either method could be used to obtain a gross population size estimate in an area. Conservation managers should determine if the quality of these estimates are worth the money and effort required to produce them, and should generally limit surveying effort to 0.26% of the study area, unless specific management goals require more intensive sampling. Using site- and time- specific nest decay rates (or the marked recount method) are essential for accurate population size estimation. Marked recount survey methods with sufficient sampling effort hold promise for detecting population declines