Changes in physical activity in people with idiopathic pulmonary fibrosis before and after virtual pulmonary rehabilitation: a feasibility study.

BACKGROUND: Pulmonary rehabilitation (PR) is recommended for the treatment of people with idiopathic pulmonary fibrosis (IPF). Physical activity is an important health behaviour, closely linked to survival in people with IPF. Little is known about the impact of virtual (V) PR on physical activity in people with IPF. OBJECTIVE: To explore the feasibility of conducting a trial to explore effect of virtual PR on objectively measured physical activity in people with IPF. METHODS: All patients with a diagnosis of IPF in a stable phase of the disease were invited to participate in VPR: a 10 week exercise programme delivered twice-weekly for one hour. Data were collected at baseline (BL) and post VPR (10 weeks): Kings Brief Interstitial Lung Disease (K-BILD), Exercise capacity (6-minute walk test (6MWT) or 1-minute sit-to-stand (STS)) and Physical Activity. Physical activity was measured with a triaxial accelerometer for seven days. Screening, recruitment, adherence and safety data were collected. RESULTS: 68 people were screened for this study. N = 16 participants were recruited to the study. There was one dropout. N = 15 completed VPR. All results reported in mean (standard deviation) (SD). Participants attended 18.1(2.0) of the 20 sessions. No adverse events were detected. The mean age of participants was 71.5(11.5) years, range: 47-95 years; 7 M:9 F. Mean (SD) FEV1 2.3(0.3)L, FVC 2.8(0.7)L. No statistically significant changes were observed in outcome measures apart from exercise capacity. Light physical activity increased from 152(69.4) minutes per day (n = 16) to 161.9(88.7) minutes per day (n = 14), mean change (SD) (CI) p-value: 9.9 (39.8) [-12.3 to 30.9] p = 0.4. Moderate-to-vigorous physical activity increased from 19.1(18.6) minutes per day (n = 16) to 25.7(28.3) minutes per day (n = 14), mean change (SD) (CI) p-value: 6.7 (15.5) [-2.1 to 15.1] p = 0.1. Step count increased from 3838(2847) steps per day (n = 16) to 4537(3748) steps per day (n = 14), mean change (SD) (CI) p-value: 738 (1916) [-419.3 to 1734.6] p = 0.2. K-BILD (n = 15) increased from 55.1(7.4) at BL to 55.7(7.9) post VPR mean change (SD) [95% confidence interval] (CI) p-value: 1.7(6.5) [-1.7 to 5.3], p = 0.3. 6MWT (n = 5) increased from 361.5(127.1) to 452.2(136.1) meters, mean change (SD) (CI) p-value: 63.7 (48.2) [-3.8 to 123.6], p = 0.04 and 1-minute STS increased from 17.6(3.0) (n = 11) to 23.7(6.3) (n = 10), mean change (SD) (CI) p-value 5.8 (4.6) [2.6 to 9.1], p = 0.003. CONCLUSION: VPR can improve physical activity in people with IPF. A number of important feasibility issues included recruitment, retention, adherence and safety have been reported which are crucial for future research in this area. A fully powered trial is needed to determine the response of people with IPF to PR with regard to physical activity.

Bioaccumulation of mercury in Lake Michigan painted turtles (Chrysemys picta).

Mercury (Hg) contamination of aquatic environments can lead to bioaccumulation in organisms, but most previous work has focused on fish and not on semi-aquatic reptiles such as turtles that traverse both terrestrial and aquatic habitats. Here, we analyzed total Hg (THg) concentrations in 30 painted turtles (Chrysemys picta) collected from Lake Michigan (USA) coastal wetlands in 2013 to determine if (1) turtles bioaccumulated THg from the environment, (2) concentrations differed between turtle liver and muscle tissue, and (3) tissue concentrations were related to environmental concentrations (e.g., sediment THg). All individual turtles had detectable THg concentrations in both liver and muscle tissue. On average, THg concentrations were over three times higher in liver tissue compared to muscle tissue. We found a positive linear relationship between muscle THg concentrations and turtle body mass, a proxy for age, suggesting bioaccumulation in this species. Neither liver nor muscle THg concentrations followed the sediment contaminant gradient in the wetlands. Despite this, location was a strong predictor of tissue concentration in a linear model suggesting that other site-specific characteristics may be important. Overall, our results demonstrate that painted turtles accumulate mercury in liver and muscle tissues at different rates, which may be constrained by local conditions. Further research is needed to better understand the relationship between environmental mercury concentrations and body burdens in animals like turtles that traverse habitats. In addition, long-lived turtles could be incorporated into pollution monitoring programs to provide a more holistic picture of food web contamination and ecosystem health.

The potential role of veterinary technicians in promoting antimicrobial stewardship.

BACKGROUND: A core principle of antimicrobial stewardship (AMS) in veterinary settings is the need for engagement of all stakeholders; however, no studies have addressed the role of veterinary technicians in AMS specifically. The objective of this study was to qualitatively assess knowledge, opinions, and practices related to AMS among technicians. Semi-structured interviews were conducted with 33 veterinary technicians with varied backgrounds, experience and roles. Interviews centered on participants work experience and interactions with their employer, perceptions of antimicrobial resistance and overuse in veterinary medicine, observed application of AMS principles, opinions on potential opportunities for technicians to contribute to AMS and concomitant potential barriers to these opportunities. Transcripts of interviews were coded thematically by two authors, then organized into a hierarchical framework, and the characterization of codes was compared across different categories of respondents. RESULTS: Most veterinary technicians were knowledgeable about antimicrobial drugs but could not provide a complete definition of antimicrobial resistance or AMS. Most veterinary technicians could identify examples of antimicrobial misuse. Participants identified areas of client education and discussion with veterinarians as potential areas to contribute to AMS. Barriers identified included hierarchical structures of veterinary practices and time-constraints. Most participants expressed a personal interest in participating in AMS. CONCLUSIONS: There is a possible appetite among some veterinary technicians to participate in AMS and they already play applicable roles in practices. Barriers such as educational needs, hierarchical structures of veterinary practices and time constraints will need to be addressed if technicians are included in AMS efforts.

Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Baseline knee extension may be associated with volumetric cartilage loss in the anterolateral tibia: data from the Osteoarthritis Initiative.

OBJECTIVES: Animal studies suggest regional unloading of the knee due to flexion contracture (FC) results in cartilage loss in the anterior tibia. We looked for an association between the range of knee extension and articular cartilage thickness in the tibia of patients with knee OA, using quantitative MRI data from the OA Initiative. METHODS: Baseline knee extension was measured using a goniometer. Cartilage thickness was measured using 3-Tesla coronal MRI images of the knee. The tibia articular cartilage was segmented into medial and lateral regions, then further divided into anterior, central and posterior subregions. We evaluated differences between participants with and without a knee FC and associations between knee extension and cartilage thickness, including percentage denudation of bones (0 mm thickness), using linear models. RESULTS: A total of 596 participants were included. Participants with a knee FC had a larger percentage of denuded bone in the anterolateral tibia vs participants without FC (2.2 ± 0.7% vs 0.4 ± 0.1%; P = 0.006), and knee extension was associated with anterolateral tibia denuded bone (r = 0.16, P < 0.001). After correcting for demographics, knee alignment, and OA severity, presence of FC and lost knee extension were associated with the percentage of denuded bone in the anterolateral tibia [ß = 1.702 (0.634-2.770) and ß = 0.261 (95% CI 0.134, 0.388), respectively]. CONCLUSION: While causation cannot be determined in this study, limitation in knee extension was statistically associated with the percentage of denuded bone in the anterolateral tibia. These novel data support that maintaining range of motion over the entire joint surface may help preserve articular cartilage health.

Estimating the national carbon footprint of inhalers in healthcare.

BACKGROUND: Metered dose inhalers (MDIs) contain greenhouse gases which have a disproportionate effect on the carbon footprint of healthcare. There are more environmentally friendly alternatives such as dry powder inhalers (DPIs) or soft mist inhalers (SMIs). AIMS: This study aims to approximate the carbon footprint of inhalers dispensed in Irish healthcare. METHODS: Health Market Research data was used to examine the number of inhalers sold in Ireland in 2019 via dispensing data from pharmacy IT systems. The carbon footprint per inhaler data was then used to calculate the total carbon footprint of each drug class, and an estimate for the total carbon footprint of inhalers sold in Ireland was generated. RESULTS: 4,427,287 inhalers were dispensed in Ireland in 2019 of which 2,608,433 (59%) were MDIs and 1,818,854 were DPIs/SMIs (41.1%). The total carbon equivalent of these inhalers was estimated to be 54,765 tCO2. MDIs account for 59% of inhaler units dispensed but account for 97% of inhaler-related carbon emissions. CONCLUSION: Targeting inhaler prescribing offers the potential to significantly improve the carbon footprint of Irish healthcare. Establishing the current carbon footprint of the inhalers that are prescribed, dispensed, and disposed in Ireland is a necessary baseline to inform moving towards a net zero health service.

A qualitative exploration of people living with idiopathic pulmonary fibrosis experience of a virtual pulmonary rehabilitation programme.

BACKGROUND: Pulmonary rehabilitation (PR) is recommended in the treatment of people with idiopathic pulmonary fibrosis (IPF). Little is known about the experiences of people with IPF of PR. Due to Covid-19 there has been a rapid shift of PR services to remote/virtual delivery. OBJECTIVE: To explore people living with IPFs experience of a virtual PR (VPR) programme. METHODS: All patients with a diagnosis of IPF in a stable phase of the disease were invited to participate in virtual PR: a 10 week exercise programme delivered twice-weekly for one hour. One-to-one semi- structured interviews were conducted within one week following the programme. All interviews were recorded, transcribed and analysed using Braun and Clarke thematic analysis by two independent assessors. RESULTS: N=13 participants took part in the semi-structured interviews, mean (standard deviation (SD)) age 69.5(10.4) years; 7M:6F. Mean (SD) FEV1 2.6(0.3)L, FVC 2.9(0.4)L. Four key themes were identified: 1) The impact of VPR on health and outlook, (2) The reality of VPR, (3) Being active after VPR and (4) Living with IPF during the COVID-19 Pandemic. Participants reported high levels of enjoyment and engagement with the programme regardless of the health benefits experienced. Most participants expressed a desire for a longer programme. Participants expressed different levels of maintenance with exercise since finishing the programme, specific motivators and strategies for maintenance included lung transplant, the maintenance of benefits from the programme and social support. COVID-19 and the restrictions imposed had some negative impacts on some participants lives, engaging with PR helped overcome some of these. CONCLUSION: Despite the progressive nature of IPF, all participants expressed high levels of enjoyment with the programme. Future research should explore strategies for maintenance post PR and the optimum duration of PR for people with IPF.

Design of Spiral-Cable Forearm Exoskeleton to Assist Supination for Hemiparetic Stroke Subjects.

We present the development of a cable-based passive forearm exoskeleton that is designed to assist supination for hemiparetic stroke survivors. Our device uniquely provides torque sufficient for counteracting spasticity within a below-elbow apparatus. The mechanism consists of a spiral single-tendon routing embedded in a rigid forearm brace and terminated at the hand and upper-forearm. A spool with an internal releasable-ratchet mechanism allows the user to manually retract the tendon and rotate the hand to counteract involuntary pronation synergies due to stroke. We characterize the mechanism with benchtop testing and five healthy subjects, and perform a preliminary assessment of the exoskeleton with a single chronic stroke subject having minimal supination ability. The mechanism can be integrated into an existing active hand-opening orthosis to enable supination support during grasping tasks, and also allows for a future actuated supination strategy.

Flexion contracture is associated with knee joint degeneration on magnetic resonance imaging: data from the Osteoarthritis Initiative.

OBJECTIVES: Knee osteoarthritis (OA) is often accompanied by a flexion contracture (FC), resulting in worse clinical outcomes. Our objective was to determine associations between knee FC and specific regional and/or structural alterations on magnetic resonance imaging (MRI) using the Osteoarthritis Initiative (OAI). METHODS: 600 knees from the Foundation for the National Institutes of Health sub-study of the OAI were included. Knee extension was measured with a goniometer and FC was defined as inability to extend the knee to 0°. Structural alterations within the MRI Osteoarthritis Knee Score (MOAKS)-assessed regions that could potentially obstruct knee extension were primarily analysed. Multivariable linear regression models evaluated the effect size of MRI outcomes on knee extension. RESULTS: One-third (33.4%) of all participants had knee FC: 155 mild (1-5°, 26.0%), 44 moderate-severe (≥6°, 7.4%). Mean knee alignment was 0.3±3.7° valgus. Cartilage morphology and bone marrow lesion (BML) scores on the femoral side of the lateral patellofemoral joint were associated with lost knee extension (ß=0.709, p<0.001, and ß=0.666, p<0.001, respectively) as were higher osteophyte scores in multiple regions, worse meniscal score in the medial meniscal body (ß=0.164, p<0.040) and posterior horn (ß=0.400, p<0.001), and a worse effusion score (ß=0.711, p<0.001). CONCLUSIONS: Knee flexion contractures were associated with non-specific, widespread MRI degenerative changes including cartilage loss and BMLs in the lateral patellofemoral joint, osteophytes, meniscal alterations and whole-joint effusion. Loss of knee extension in OA is likely a structurally-multifactorial outcome.

Mixed methods protocol to examine the acceptability and clinical characteristics of a remote monitoring programme for delivery of COVID-19 care, among healthcare staff and patients.

INTRODUCTION: The use of remote monitoring technology to manage the care of patients with COVID-19 has been implemented to help reduce the burden placed on healthcare systems during the pandemic and protect the well-being of both staff and patients. Remote monitoring allows patients to record their signs and symptoms remotely (eg, while self-isolating at home) rather than requiring hospitalisation. Healthcare staff can, therefore, continually monitor their symptoms and be notified when the patient is showing signs of clinical deterioration. However, given the recency of the COVID-19 outbreak, there is a lack of research regarding the acceptance of remote monitoring interventions to manage COVID-19. This study will aim to evaluate the use of remote monitoring for managing COVID-19 cases from the perspective of both the patient and healthcare staff. METHODS AND ANALYSIS: Discharged patients from a large urban teaching hospital in Ireland, who have undergone remote monitoring for COVID-19, will be recruited to take part in a cross-sectional study consisting of a quantitative survey and a qualitative interview. A mixed methods design will be used to understand the experiences of remote monitoring from the perspective of the patient. Healthcare staff who have been involved in the provision of remote monitoring of patients with COVID-19 will be recruited to take part in a qualitative interview to understand their experiences with the process. Structural equation modelling will be used to examine the acceptance of the remote monitoring technology. Latent class analysis will be used to identify COVID-19 symptom profiles. Interview data will be examined using thematic analysis. ETHICS AND DISSEMINATION: Ethical approval has been granted by the ethical review boards at University College Dublin and the National Research Ethics Committee for COVID-19-related Research. Findings will be disseminated via publications in scientific journals, policy briefs, short reports and social media.

Routine Hematological Parameters May Be Predictors of COVID-19 Severity.

To date, coronavirus disease 2019 (COVID-19) has affected over 100 million people globally. COVID-19 can present with a variety of different symptoms leading to manifestation of disease ranging from mild cases to a life-threatening condition requiring critical care-level support. At present, a rapid prediction of disease severity and critical care requirement in COVID-19 patients, in early stages of disease, remains an unmet challenge. Therefore, we assessed whether parameters from a routine clinical hematology workup, at the time of hospital admission, can be valuable predictors of COVID-19 severity and the requirement for critical care. Hematological data from the day of hospital admission (day of positive COVID-19 test) for patients with severe COVID-19 disease (requiring critical care during illness) and patients with non-severe disease (not requiring critical care) were acquired. The data were amalgamated and cleaned and modeling was performed. Using a decision tree model, we demonstrated that routine clinical hematology parameters are important predictors of COVID-19 severity. This proof-of-concept study shows that a combination of activated partial thromboplastin time, white cell count-to-neutrophil ratio, and platelet count can predict subsequent severity of COVID-19 with high sensitivity and specificity (area under ROC 0.9956) at the time of the patient's hospital admission. These data, pending further validation, indicate that a decision tree model with hematological parameters could potentially form the basis for a rapid risk stratification tool that predicts COVID-19 severity in hospitalized patients.

COVID-19 induces a hyperactive phenotype in circulating platelets.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.

Bone replaces unloaded articular cartilage during knee immobilization. A longitudinal study in the rat.

BACKGROUND: Joint immobility results in deleterious changes such as capsule shortening, bone loss and articular cartilage damage. Immobilization of rat knees in flexion for 32 weeks resulted in the distinctive feature of well-established replacement of articular cartilage by bone. Determining the time of onset of bone replacement is critical for the prevention of this likely irreversible complication of joint immobilization. OBJECTIVES: To determine the onset and progression of bone replacement in the anterior tibial articular cartilage following knee immobilization in flexion. METHODS: One hundred forty-nine adult male Sprague-Dawley rats were used. The experimental groups had one knee immobilized at 135°of flexion for durations of 2, 4, 8, 16 or 32 weeks and were compared to age-matched controls. The knees were evaluated histologically for the presence and cross-sectional area of bone within the articular cartilage of the tibia. Distance between the anterior aspect of the tibia and intact articular cartilage and cross-sectional bone area of the tibial epiphysis were also measured. RESULT: Bone replacement in the articular cartilage was observed in 14%, 75%, 95%, 100% and 100% of knees after 2, 4, 8, 16 and 32 weeks of immobilization, respectively. No bone replacement was seen in the control knees. The mean area of bone replacement increased from 0.004 ± 0.007 mm2 after 2 weeks to 0.041 ± 0.036 mm2; 0.085 ± 0.077 mm2; 0.092 ± 0.056 mm2 and 0.107 ± 0.051 mm2 after 4, 8, 16 and 32 weeks of immobilization, respectively, (p < 0.001) largely restricted to the anterior tibial articular cartilage. Mean distance to intact articular cartilage increased from 0.89 ± 0.69 mm at 2 weeks to 1.10 ± 0.35 mm; 1.65 ± 0.77 mm; 1.48 ± 0.63 mm; and 1.78 ± 0.58 mm after 4, 8, 16 and 32 weeks of immobilization, respectively (p = 0.001). Epiphyseal bone cross-sectional area was significantly reduced following 4, 8, and 16 weeks of immobilization compare to controls (all 3 p < 0.05). CONCLUSION: Knee immobilization in flexion resulted in bone replacement in the anterior tibial articular cartilage that began after 2 weeks and was prevalent after 4 weeks of immobilization. The bone replacement progressed in an anterior-to-posterior direction and stopped at the area of contact between tibia and femur. These findings stress the importance of mobility to maintain joint health.

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Time taken from primary care referral to a specialist centre diagnosis of idiopathic pulmonary fibrosis: an opportunity to improve patient outcomes?

For patients with IPF, length of time in healthcare systems prior to review in an ILD clinic reflects disease severity and may impact upon patient outcome https://bit.ly/2TkO26r.

Choice of Methodology Impacts Outcome in Indirect Comparisons of Drugs for Idiopathic Pulmonary Fibrosis.

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a chronic condition leading to lung damage and deterioration in lung function. Following the availability of two new drugs, nintedanib and pirfenidone, a number of network meta-analyses (NMAs) of randomised controlled trials have been published which have conducted indirect comparisons on the two drugs. Differing recommendations from these studies are potentially confusing to clinicians and decision-makers. We aimed to systematically review published NMAs of IPF treatments, to compare their findings and summarise key recommendations. Materials and Methods: We systematically reviewed (PROSPERO: CRD42017072876) six eligible NMAs and investigated the differences in their findings with respect to key endpoints. We focused on differences in head-to-head comparisons between nintedanib and pirfenidone. Results: The NMAs were broadly consistent, with most differences being explained by model choice, endpoint definitions, inclusion of different studies, different follow-up durations, and access to unpublished data. A substantive difference remained, however, in the change from baseline forced vital capacity (FVC). One NMA favoured nintedanib, another found no statistical difference, whilst others did not conduct the analysis. These differences can be attributed to the choice of methodology, the use of the standardised mean difference (SMD) scale, and population heterogeneity. Conclusions: NMA methods facilitated the comparison of nintedanib and pirfenidone in the absence of a head-to-head trial. However, further work is needed to determine whether the trial populations are homogeneous and whether the SMD is appropriate in this population. Differences in patient characteristics may obscure the difference in treatment effects. To assist decision-makers, an exploration of efficacy in real-world populations may be prudent.

Using a Knee Arthrometer to Evaluate Tissue-specific Contributions to Knee Flexion Contracture in the Rat.

Normal knee range of motion (ROM) is critical to well-being and allows one to perform basic activities such as walking, climbing stairs and sitting. Lost ROM is called a joint contracture and results in increased morbidity. Due to the difficulty of reversing established knee contractures, early detection is important, and hence, knowing risk factors for their development is essential. The rat represents a good model with which the effect of an intervention can be studied due to the similarity of rat knee anatomy to that of humans, the rat's ability to tolerate long durations of knee immobilization in flexion, and because mechanical data can be correlated with histologic and biochemical analysis of knee tissue. Using an automated arthrometer, we demonstrate a validated, precise, reproducible, user-independent method of measuring the extension ROM of the rat knee joint at specific torques. This arthrometer can be used to determine the effects of interventions on knee joint ROM in the rat.

Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis.

Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis; however, pathologic changes in extracellular matrix (ECM) that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue, we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with increased stiffness, reduced swelling ratio, and reduced diameter. In ex vivo and animal models of lung fibrosis, dual inhibition of lysyl oxidase-like (LOXL) 2 and LOXL3 was sufficient to normalise collagen fibrillogenesis, reduce tissue stiffness, and improve lung function in vivo. Thus, in human fibrosis, altered collagen architecture is a key determinant of abnormal ECM structure-function, and inhibition of pyridinoline cross-linking can maintain mechano-homeostasis to limit the self-sustaining effects of ECM on progressive fibrosis.

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.