Design of a randomized controlled trial to evaluate effectiveness of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study

Background: Treatment of pulmonary sarcoidosis is recommended in case of significant symptoms, impaired or deteriorating lung function. Evidence-based treatment recommendations are limited and largely based on expert opinion. Prednisone is currently the first-choice therapy and leads to short-term improvement of lung function. Unfortunately, prednisone often has side-effects and may be associated with impaired quality of life. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects. Objective: The primary objective of this trial is to investigate the effectiveness and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared with prednisone. The primary endpoint of this study will be the change in hospital-measured Forced Vital Capacity (FVC) between baseline and 24 weeks. Secondary objectives are to gain more insights in response to therapy in individual patients by home spirometry and patient-reported outcomes. Blood biomarkers will be examined to find predictors of response to therapy, disease progression and chronicity, and to improve our understanding of the underlying disease mechanism. Methods/design: In this prospective, randomized, non-blinded, multi-center, non-inferiority trial, we plan to randomize 138 treatment-naïve patients with pulmonary sarcoidosis who are about to start treatment. Patients will be randomized in a 1:1 ratio to receive either prednisone or methotrexate in a predefined schedule for 24 weeks, after which they will be followed up in regular care for up to 2 years. Regular hospital visits will include pulmonary function assessment, completion of patient-reported outcomes, and blood withdrawal. Additionally, patients will be asked to perform weekly home spirometry, and record symptoms and side-effects via a home monitoring application for 24 weeks. Discussion: This study will be the first randomized controlled trial comparing first-line treatment of prednisone and methotrexate and provide valuable data on efficacy, safety, quality of life and biomarkers. If this study confirms the hypothesis that methotrexate is as effective as prednisone as first-line treatment for sarcoidosis but with fewer sideeffects, this will lead to improvement in care and initiate a change in practice. Furthermore, insights into the immunological mechanisms underlying sarcoidosis pathology might reveal new therapeutic targets

The importance of local factors and management in determining wheat yield variability in on-farm experimentation in Tigray, northern Ethiopia

Low crop yield in Tigray is one of the causes of food insecurity. Intervention work to increase yields, however, had only limited success and farmers often hesitated to adopt recommended practices. Considering this, we used participatory on-farm experimentation to arrive at best practices matching local preferences, complexity and context. Outcomes were evaluated at meta level and at site level, respectively to identify major sources of yield variability and direct relationships between yield and treatment, location and soil properties. About 56% of the total grain yield variability in our experiments was explained by a linear regression model with management, altitude and N-fertilizer input. When management was excluded, still 49% of the grain yield variability was explained by altitude, N-fertilizer input, N-total, organic-C, rainfall and K-exchangeable of the soil. This indicated that grain yield was very location specific and related, next to treatment effects, to local climate and soil conditions. Excluding management, straw yield variability was explained for approximately 38% by including N-fertilizer input, the soil stoniness, soil P-content and the slope of the field as predictors. This indicated strong location dependent variability. Again excluding management, fertilizer responses were mainly explained by soil characteristics, which together with the inputs explained almost half of the total response variability. Focusing specifically on the relation between soil properties (N-total, P-available and K-exchangeable) and response to recommended fertilizer application we found this relation indeterminate, except for N. Differences in yields between recommended application and farmer managed fields were limited and non-significant. We concluded that (1) defining best practices is a location specific and tailor-made task which requires the involvement of farmers to deal with local preferences and context and (2) on-farm experimentation includes such local environment and farmer-related variability. Our participatory approach using on-farm experimentation demonstrated why a one-size-fits-all strategy, i.e. blanket recommendations, will not work unconditionally in Tigray. Both grain and straw yield were determined by the complex local interplay of farmer management, soil properties, landscape and fertilizer input

Identifying crop productivity constraints and opportunities using focus group discussions : A case study with farmers from Tigray

Crop productivity in many places in Sub Saharan Africa is low. This affects food security and rural livelihoods. Identification of constraints and opportunities is a first and essential step in development processes aiming at improving crop productivity. Macro- and meso-level diagnostic methods frequently point to soil fertility and agronomic practices as major constraints. In Tigray, our study area in Northern Ethiopia, we applied focus group discussion in four locations to identify productivity constraints and opportunities. Outcomes in the form of “mind maps” were quantified to allow comparison between the locations. We found that, apart from some similarities, outcomes demonstrated much diversity. Location specific conditions and agronomic factors were considered main constraints by farmer groups in all locations. Soil fertility measures were considered a main opportunity. However, other categories of constraints and opportunities, like economic factors and irrigation, were diverse for the locations involved. Observed outcome variability was supported by descriptive biophysical and socio-economic data. We concluded that superficial identification of constraints and opportunities neglected contextual diversity. Making such diversity visible is essential in understanding and addressing this complexity. Applying approaches like focus group discussion, therefore, offers important opportunities at grassroots-level to give farmers a mandate and responsibility at early stages of development processes.</p

Simultaneous testing of immunological sensitization to multiple antigens in sarcoidosis reveals an association with inorganic antigens specifically related to a fibrotic phenotype

Organic and inorganic antigens were studied simultaneously in the same cohort of sarcoidosis patients to investigate whether correlations between clinical characteristics and immunological sensitization could reveal new phenotypes. Sensitization to antigens of mycobacteria, Propionibacterium acnes catalase and vimentin was investigated in 201 sarcoidosis and 51 obstructive sleep apnoea patients, serving as control group. Sensitization to aluminium, beryllium, silica and zirconium was also studied in 105 of the sarcoidosis patients and in 24 of the controls. A significantly higher percentage of sarcoidosis patients (27·6%) than controls (4·2%) had an immunological response to metals or silica (P = 0·014). A higher percentage of these sarcoidosis patients showed fibrosis on chest X-ray 5 years after the diagnosis (69·2 versus 30·3%, P = 0·016). No significant differences in mycobacterial or vimentin enzyme-linked immunospot (ELISPOT) assay results were observed between sarcoidosis and control patients. A significantly lower percentage of sarcoidosis patients (3·5%) than control patients (15·7%) had a positive ELISPOT for P. acnes catalase (P = 0·003). However, sarcoidosis patients sensitized to P. acnes catalase were more likely to have skin involvement, while sarcoidosis patients sensitized to mycobacterial antigens were more likely to have cardiac involvement. Our study suggests a more prominent role for inorganic triggers in sarcoidosis pathogenesis than previously thought. Immunological sensitization to inorganic antigens was associated with development of fibrotic sarcoidosis. No association was found between sensitization to bacterial antigens or vimentin and sarcoidosis in Dutch patients. However, our data suggest that trigger-related phenotypes can exist in the heterogeneous population of sarcoidosis patients

Cast-OFF Trial: One Versus 4 to 5 Weeks of Plaster Cast Immobilization for Nonreduced Distal Radius Fractures: A Randomized Clinical Feasibility Trial

BACKGROUND: Distal radius fracture is a common fracture of which the incidence appears to be increasing worldwide. This pilot study investigated whether 1 week of plaster cast is feasible for nonreduced (stable fractures including nondisplaced and displaced fractures) distal radius fractures. METHODS: The study was a multicenter randomized clinical feasibility trial including patients from regional acute care providers. Patients with a nonreduced distal radius fracture were included in the study. Nonreduced fractures meant intra-articular or extra-articular fractures and including nondisplaced and minimal displaced fractures (dorsal angulation less than 5°-10°, maximum radial shortening of 2 mm, and maximum radial shift of 2 mm) not needing a reduction. Forty Patients were included and randomized. After 1 week of plaster cast, patients were randomized to 1 of the 2 treatment groups: plaster cast removed (intervention group) versus 4 to 5 weeks of plaster cast (control group). RESULTS: The analysis shows no significant differences between the 2 groups in having less pain, better function after 6 weeks, and better overall patient satisfaction. No difference was shown in secondary displacement between the 2 groups (control 1 vs intervention 0). CONCLUSION: One week of plaster cast treatment for nonreduced distal radius fracture is feasible, preferred by patients, with at least the same functional outcome and pain scores. LEVEL OF EVIDENCE: According to the Oxford 2011 level of evidence, the level of evidence of this study is 2