To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis.
An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 ...immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.
In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures.
On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.
To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis.
An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists ...representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.
Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures.
On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.
Objectives
To describe the long‐term effects of ivacaftor (Kalydeco®) in individuals with cystic fibrosis (CF) on body mass index (BMI), body composition (BC), pulmonary function (PF), resting energy ...expenditure (REE), and exercise capacity (EC) after ≥12 months of treatment.
Working Hypothesis
BMI, lean and fat mass, PF, and EC will increase and REE will decrease after treatment.
Study Design
Observational study.
Methodology
Seven individuals with CF (mean age 15.4 ± 5.8 years) heterozygous for S1251N mutation, starting with ivacaftor, were included. Paired t tests were performed to assess the effects of ivacaftor. Height and weight were used to calculate BMI and BMI Z‐scores. Dual‐energy X‐ray absorptiometry was used to assess BC. Spirometry and body plethysmography were used to assess PF. Indirect calorimetry was used to measure REE and cardiopulmonary exercise testing (CPET) was used to measure oxygen uptake (VO2peak), peak work rate (Wpeak), and other CPET variables.
Results
After a median of 15 (interquartile range: 13‐16) months of treatment, BMI increased significantly (P = .03), but not BMI Z‐score (P = .23) or BC. Significant improvements were found for several PF variables, especially measures of hyperinflation (P = .02). Absolute VO2peak (P = .01), VO2peak related to body weight (P = .00), and oxygen cost of work (P = .01) decreased. Absolute Wpeak (P = .59) and Wpeak related to body weight (P = .31) remained stable.
Conclusions
The results showed that long‐term treatment of ivacaftor is associated with improvement of BMI and PF, but not of BC and REE. Oxygen uptake reduced after treatment, which may be due to a decrease in work of breathing.
•We implemented a high-throughput 384-wells version of the functional FIS assay to screen a large number of PDIOs for compounds that enhance CFTR function.•We found that PDE4 inhibitors are potent ...CFTR function inducers when residual CFTR function is either present or created by additional compound exposure.•We show that CFTR modulators can be beneficial for CF patients with CFTR mutations that are not eligible for CFTR modulators at present-day.•Our study demonstrates how preclinical studies using PDIOs can be used to initiate drug repurposing efforts, paving the way for patient stratification in the upcoming era of personalized medicine.
Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF.
We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators.
In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy.
This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies.
We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.
Carbonated hydroxyapatite (CHA) coatings were applied onto titanium implants by using a biomimetic precipitation method. Different antibiotics were incorporated into the CHA coatings and their ...release and efficacy against bacteria growth were studied in vitro. The following antibiotics were used within this study: cephalothin, carbenicillin, amoxicillin, cefamandol, tobramycin, gentamicin and vancomycin. Increased concentrations of antibiotics in the coating solution led to a higher quantity of antibiotic incorporated into the CHA coating. Some antibiotics were better incorporated than others depending on their chemical structure. Antibiotics, containing carboxylic groups such as cephalothin, carbenicillin and cefamandol, were better incorporated than antibiotics lacking these groups. A bacterial inhibition test on
Staphylococcus aureus bacteria showed inhibition of growth for all antibiotics that were released from the CHA coating. A release test was conducted in phosphate buffer saline PBS at pH 7.4 and 37 °C and showed that antibiotics containing carboxylic groups like cephalothin were slower released from the CHA coating than others. These results suggest that certain antibiotics are able to bind/chelate with calcium, resulting in a better incorporation into the CHA coating and a slower release. Antibiotics incorporated in CHA coatings on titanium implants might be used to prevent post-surgical infections and to promote bone-bonding of orthopedic devices.
The past half century has seen explosive growth in the use of medical implants. Orthopedic, cardiac, oral, maxillofacial and plastic surgeons are examples of medical specialists treating millions of ...patients each year by implanting devices varying from pace makers, artificial hip joints, breast and dental implants, to implantable hearing aids. All such medical implants make use of special materials, known as biomaterials, defined as “materials intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ, or function of the body” D.F. Williams, The Williams Dictionnary of Biomaterials, Liverpool University Press, Liverpool, 1999. While the priority for the first generation of biomaterials was inertness with living tissues, the field is shifting towards biologically active systems in order to improve their performance and to expand their use. Biomaterials can be combined as scaffolds with cells (i.e. tissue engineering), growth factors or genetic material in order to trigger tissue regeneration. In addition, recent reports have shown the possibility to design biomaterials that can activate cellular processes and tissue formation solely by their intrinsic physicochemical and three dimensional spatial properties. This article reviews the recent developments in the design of biomaterials that integrate our understanding of cellular and molecular mechanisms with materials science. After an overview of the physicochemical and biological processes occurring at the interface between the biomaterials and biological milieu, we will address the biological principles contributing to the design and engineering of advanced biomaterials for application towards recent therapeutic strategies for tissue regeneration. Finally, future directions for the design of advanced biomaterials will be discussed.
•Until 2016, Dutch NBS for CF, as implemented in 2011, showed a sensitivity of 90%.•In 2016, NBS for CF algorithm was modified, resulting in a sensitivity of 95%.•Sensitivity improved by changing PAP ...cut-off values.•Costs per screened child and PPV did not change substantially.•With every twelve CF patients Dutch NBS refers one CRMS/CFSPID and three carriers.
Dutch newborn screening (NBS) for Cystic Fibrosis (CF) introduced in 2011 showed a sensitivity of 90% and a positive predictive value (PPV) of 63%. We describe a study including an optimization phase and evaluation of the modified protocol.
Dutch protocol consists of four steps: determination of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP), DNA analysis by INNO-LiPA and extended gene analysis (EGA).
For the optimization phase we used results of 556,952 newborns screened between April 2011 and June 2014 to calculate effects of 13 alternative protocols on sensitivity, specificity, PPV, ratios of CF to other diagnoses, and costs. One alternative protocol was selected based on calculated sensitivity, PPV and costs and was implemented on 1st July 2016. In this modified protocol DNA analysis is performed in samples with a combination of IRT ≥60 µg/l and PAP ≥3.0 µg/l, IRT ≥100 µg/l and PAP ≥1.2 µg/l or IRT ≥124 µg/l and PAP not relevant. Results of 599,137 newborns screened between 1st July 2016 and 31st December 2019 were similarly evaluated as in the optimization phase.
The modified protocol showed a sensitivity of 95%, PPV of 76%, CF to CF transmembrane conductance regulator-related metabolic syndrome/CF screen positive, inconclusive diagnoses (CRMS/CFSPID) ratio 12/1, CF/CF carrier ratio 4/1. Costs per screened newborn were slightly higher. Eleven children, of whom five with classic CF, would not have been referred with the previous protocol.
The modified protocol results in acceptable sensitivity (95%) and good PPV of 76% with minimal increase in costs.
Calcium phosphate coatings containing an antibiotic were produced on titanium alloy (Ti6Al4V) implants using a biomimetic approach. Thin, amorphous calcium phosphate (ACP) coatings were first ...deposited onto Ti6Al4V plates by immersion in 5 times concentrated simulated body fluid (SBF), for 24
h at 37°C. The ACP-coated implants were then immersed in a supersaturated calcium phosphate (SCP) solution containing 0, 100, 200, 400, 600 or 800
mg/l of tobramycin for 48
h at 37°C. A carbonated hydroxyapatite (CHA) layer, approximately 40
μm thick, was formed. Approximately 3
μg/mg of tobramycin was co-precipitated with the CHA crystals onto titanium alloy plates, using 800
mg/l tobramycin in the coating solution. For comparison, plasma-sprayed calcium phosphate coatings were also immersed in solutions containing 100, 200, 400 or 1000
mg/l of tobramycin for 10, 40
min, or 48
h. A maximum of about 0.3
μg/mg could be adsorbed onto the plasma-sprayed calcium phosphate coating with the comparable concentration of 800
mg/l in solution. The dissolution of coating and release of tobramycin were also measured in vitro using saline solution buffered at pH 5.0 or 7.3 at 37°C. The release rate of tobramycin was faster at pH 7.3 than at pH 5, with 50 and 4
μg/ml/min, respectively. Tobramycin released from the biomimetic-coated plates could inhibit growth of
Staphylococcus aureus bacteria. The result of this study, therefore, indicates that the biomimetic CHA coatings containing antibiotics could be used to prevent post-surgical infections in orthopaedic or trauma.
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