Changes in the physical and affective dimensions of dyspnoea after a home-based pulmonary rehabilitation in fibrotic idiopathic interstitial pneumonias.

Background: Our objective was to evaluate the short-, medium- and long-term benefits of home-based pulmonary rehabilitation (PR) on the physical and affective components of dyspnoea in people with fibrotic idiopathic interstitial pneumonias (f-IIPs). Anxiety and depressive symptoms, fatigue, health-related quality of life and exercise tolerance were also assessed. Methods: Data on 166 individuals with f-IIPs who enrolled in an 8-week home-based PR programme (weekly supervised 90-min session) were retrospectively analysed. Assessments included the Dyspnoea-12 (D-12) questionnaire, Hospital Anxiety and Depression Scale, Fatigue Assessment Scale, Visual Simplified Respiratory Questionnaire and 6-min stepper test, and were performed at home at short, medium (6 months) and long (12 months) term. Results: Among the 166 individuals with f-IIPs who enrolled in PR, 75 (45%) and 91 (55%) participants had a diagnosis of idiopathic pulmonary fibrosis and fibrosing non-specific interstitial pneumonia, respectively, and 87 (52%) participants concluded a full year of follow-up. In the total group, both physical and affective components of dyspnoea were improved, at short, medium and long term, after PR. Overall, half of the participants reached the minimally important difference of 3 points of the D-12 questionnaire at the end of PR, and at the 6- and 12-month follow-ups. Anxiety and depressive symptoms, fatigue and health-related quality of life were also improved, while the short-term benefits in exercise tolerance were not maintained 1 year after PR. Conclusion: An individualised home-based PR programme resulted in short-, medium- and long-term improvements in both physical and affective components of dyspnoea assessed by the D-12 questionnaire.

Frequency and characteristics of refractory dyspnea in idiopathic fibrosing interstitial pneumonia.

Patients with idiopathic fibrosing interstitial pneumonias (f-IIPs) mainly suffer from dyspnea. Refractory dyspnea, defined as persistent dyspnea despite optimal treatment, could be the signal to prescribe dyspnea relievers. We aimed to examine the prevalence and characteristics of refractory dyspnea in consecutive patients with f-IIPs. Refractory dyspnea was defined by an mMRC≥3 and also by a VAS dyspnea score≥2 at rest. The sensory and affective characteristics of refractory dyspnea (mMRC≥3) and associated quality of life (QoL) anxiety and depression were compared with non-refractory dyspnea (mMRC1-2) using the Multidimensional Dyspnea Profile (MDP), King's Brief Interstitial Lung Disease (KBILD) and Hospital Anxiety and Depression scale (HADs). We included 40 patients (24 men), aged 72 [68-79], FVC of 71 % [59-86] and DLCO 47 % [40-49]. Refractory dyspnea, was found in 38 % (95%CI:23-54) when defined by mMRC≥3 and in 67 % (95%CI:50-81) using a resting VAS dyspnea score ≥2. The agreement between the two definitions was low. Patients with refractory dyspnea (mMRC≥3) were more often women (60 % vs.28 %, p = 0.046), had a lower DLCO (24 % [22-43] vs.47 % [43-51], p = 0.014) and more frequently used oxygen (60 % vs.12 %, p = 0.003); they experience more intense air hunger (5/10 [3-6] vs.2/10 [0-5], p = 0.018)). No significant differences were observed in VAS, MDP, KBILD, or HADs scores between refractory and non-refractory dyspnea patients. Our results indicate a significant frequency of refractory dyspnea in patients with f-IIPs and an association with air hunger but no impact on the affective dimension of dyspnea, anxiety, depression and QoL, suggesting that the mMRC score might not accurately identify patients distressed by their breathlessness.

Cationic amino-acid functionalized polymethacrylamide vectors for siRNA transfection based on modification of poly(2-isopropenyl-2-oxazoline).

Poly(2-isopropenyl-2-oxazoline) (PiPOx) is a functional polymer showing great potential for the development of smart biomaterials. The straightforward synthesis and post-polymerization functionalization of PiPOx offers many opportunities for tailoring the properties of the polymer towards biomaterials. In this study we report for the first time PiPOx-based cationic charged polymethacrylamides with amino acid side chains that can complex siRNA and promote transfection in vitro. Therefore, PiPOx was fully modified via ring opening addition reactions with the carboxylic acid groups of a series of N-Boc-L-amino acids and their reaction kinetics were investigated. Based on the determined kinetic constants, another series of PiPOx-based copolymers with balanced hydrophilic/hydrophobic content of N-Boc-L-amino acids were obtained via one-pot modification reaction with two different N-Boc-L-amino acids. The N-Boc protected homopolymers and related copolymers were deprotected to obtain (co)polymers with the targeted side chain cationic charged units. The (co)polymers' structures were fully investigated via FT-IR and 1H NMR spectroscopy, size exclusion chromatography (SEC), and TGA-DSC-MS analysis. The polarimetry measurements revealed that the homopolymers retain their chiroptical properties after post-modification, and a sign inversion is noticed from (L) N-Boc-protected analogues to (D) for the TFA cationic charged homopolymers. Generally, cationically charged homopolymers with hydrophilic amino acids on the side chain showed efficient complexation of siRNA, but poor transfection while cationic copolymers having both tryptophan and valine or proline side chains revealed moderate siRNA binding, high transfection efficiency (> 90% of the cells) and potent gene silencing with IC50 values down to 5.5 nM. Particularly, these cationic copolymers showed higher gene silencing potency as compared to the commercial JetPRIME® reference, without reducing cell viability in the concentration range used for transfection, making this a very interesting system for in vitro siRNA transfection.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. METHODS: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. FINDINGS: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. INTERPRETATION: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

Poly(N-allyl acrylamide) as a Reactive Platform toward Functional Hydrogels.

The synthesis of poly(N-allyl acrylamide) (PNAllAm) as a platform for the preparation of functional hydrogels is described. The PNAllAm was synthesized via organocatalyzed amidation of poly(methyl acrylate) (PMA) with allylamine and characterized by 1H NMR spectroscopy, size exclusion chromatography (SEC), and turbidimetry, which allowed an estimation of the lower critical solution temperature of ∼26 °C in water. The PNAllAm was then used to make functional hydrogels via photoinitiated thiol-ene chemistry, where dithiothreitol (DTT) was used to cross-link the polymer chains. In addition, mercaptoethanol (ME) was added as a functional thiol to modulate the hydrogel properties. A decrease of the volume-phase transition temperature of the resulting hydrogels was observed with increasing ME content. Altogether this work introduces a straightforward way for the preparation of PNAllAm from PMA and demonstrates its value as a reactive polymer platform for the generation of functional hydrogels.

Interstitial pneumonia with autoimmune features: Evaluation of connective tissue disease incidence during follow-up.

OBJECTIVES: Among interstitial pneumonia with autoimmune features (IPAF) patients, identifying those at risk to develop a connective tissue disease (CTD) during the disease course is a key issue. The aim of this study was to evaluate the incidence of definite CTD diagnosis in IPAF patients during follow-up. METHODS: We performed a multicentric cohort study of interstitial lung disease (ILD) from 2010 to 2017 in pneumology and immunology departments of tertiary care centers. Patients with a known cause of ILD (including established CTD) at diagnosis were excluded. Among patients with idiopathic ILD and at least three years of follow-up, two groups (IPAF and non-IPAF) were retrospectively analyzed at time of diagnosis. RESULTS: A total of 249 patients with ILD were enrolled, including 70 IPAF and 179 non-IPAF patients. After a mean follow-up time of 77 ± 44 months, 18/70 IPAF patients (26%) had a CTD diagnosis - 9 antisynthetase syndrome, 8 systemic sclerosis and 1 overlap myositis - compared with 4/179 non-IPAF patients (2%). IPAF patients were at higher risk of CTD occurrence at 3 years of follow-up compared to non-IPAF patients (HR 10.1, 95% CI 3.1-33.1, p < 0. 01). IPAF patients progressing to CTD tended to be younger, more often female and have more frequently puffy fingers, capillaroscopy abnormalities and antisynthetase antibodies at diagnosis. CONCLUSIONS: We found that a significant proportion of IPAF patients had associated CTD diagnosis during follow-up. Prospective studies are needed to confirm baseline predictive factors of CTD occurrence in IPAF patients.

Advances and opportunities in the exciting world of azobenzenes.

Azobenzenes are archetypal molecules that have a central role in fundamental and applied research. Over the course of almost two centuries, the area of azobenzenes has witnessed great achievements; azobenzenes have evolved from simple dyes to 'little engines' and have become ubiquitous in many aspects of our lives, ranging from textiles, cosmetics, food and medicine to energy and photonics. Despite their long history, azobenzenes continue to arouse academic interest, while being intensively produced for industrial purposes, owing to their rich chemistry, versatile and straightforward design, robust photoswitching process and biodegradability. The development of azobenzenes has stimulated the production of new coloured and light-responsive materials with various applications, and their use continues to expand towards new high-tech applications. In this Review, we highlight the latest achievements in the synthesis of red-light-responsive azobenzenes and the emerging application areas of photopharmacology, photoswitchable adhesives and biodegradable materials for drug delivery. We show how the synthetic versatility and adaptive properties of azobenzenes continue to inspire new research directions, with limits imposed only by one's imagination.

Bioinspired double network hydrogels: from covalent double network hydrogels via hybrid double network hydrogels to physical double network hydrogels.

The design and synthesis of double network (DN) hydrogels that can mimic the properties and/or structure of natural tissue has flourished in recent years, overcoming the bottlenecks of mechanical performance of single network hydrogels and extending their potential applications in various fields. In recent years, such bioinspired DN hydrogels with extraordinary mechanical performance, excellent biocompatibility, and considerable strength have been demonstrated to be promising candidates for biomedical applications, such as tissue engineering and biomedicine. In this minireview, we provide an overview of the recent developments of bioinspired DN hydrogels defined as DN hydrogels that mimic the properties and/or structure of natural tissue, ranging from, e.g., anisotropically structured DN hydrogels, via ultratough energy dissipating DN hydrogels to dynamic, reshapable DN hydrogels. Furthermore, we discuss future perspectives of bioinspired DN hydrogels for biomedical applications.

In Vitro Assessment of the Hydrolytic Stability of Poly(2-isopropenyl-2-oxazoline).

Poly(2-isopropenyl-2-oxazoline) (PiPOx) is emerging as a promising, versatile polymer platform to design functional materials and particularly biomaterials that rely on the hydrophilic character of the 2-oxazoline side units. To be able to assess the applicability of PiPOx in a biomedical context, it is essential to understand its stability and degradation behavior in physiological conditions. In the present work, the hydrolytic stability of PiPOx was systematically investigated as a function of pH during incubation in various buffers. PiPOx was found to be stable in deionized water (pH 6.9), to have good stability in basic conditions (pH 8 and 9), to be satisfactorily stable in neutral conditions (pH 7.4), and to have moderate to low stability in acidic conditions (decreases drastically from pH 6 to pH 1.2). At pH 4, PiPOx formed a crosslinked network in a timeframe of hours, while at pH 1.2, PiPOx was transformed to a water-soluble poly(N-(2-hydroxyethyl)methacrylamide) type of structure over the course of 2 weeks. In vitro stability assays were performed in phosphate-buffered saline (pH 7.4), simulated body fluid (SBF) (pH 7.4), simulated saliva (pH 6.4), simulated intestinal fluid (pH 6.8), and plasma (pH 7.4) revealing that PiPOx is stable in these SBFs up to 1 week of incubation. When incubated in simulated gastric fluid (pH 1.2), PiPOx exhibited a similar degradation behavior to that observed in the buffer at pH 1.2, rendering a water-soluble structure. The presented results on the stability of PiPOx will be important for future use of PiPOx for the development of drug-delivery systems and biomedical applications, such as hydrogels.

[2 × 2] metallo-supramolecular grids based on 4,6-bis((1H-1,2,3-triazol-4-yl)-pyridin-2-yl)-2-phenylpyrimidine ligands: from discrete [2 × 2] grid structures to star-shaped supramolecular polymeric architectures.

The self-assembly of bis-tridentate ligands leads to the spontaneous formation of [2 × 2] grid-like metal complexes. However, the synthesis of such ligands is rather cumbersome. In the work, we demonstrate a straightforward synthesis route to prepare bis-tridentate 4,6-bis((1H-1,2,3-triazol-4-yl)-pyridin-2-yl)-2-phenylpyrimidine ligands through double CuAAC click chemistry with 4,6-bis(6-ethynylpyridin-2-yl)-2-phenylpyrimidine as well as their self-assembly into [2 × 2] grid-like metal complexes. In addition, four macromolecular ligands were synthesized starting from azido-end-functionalized poly(2-ethyl-2-oxazoline) (PEtOx) or poly(ethylene glycol) (PEG). These macromolecular ligands were used in the construction of star-shaped supramolecular polymers through complexation with transition metal ions (e.g., Fe2+ or Zn2+). The successful fabrication of complexes and star-shaped polymers was confirmed by UV-vis titration measurements and MALDI-TOF mass spectrometry. However, the chemical structure of the polymer was found to have a strong influence on the [2 × 2] grid formation, which was successful with the PEG-ligands but not with the PEtOx-ligands, while the molecular weight of the PEG did not interfere with grid formation.

Filamin A Mutations: A New Cause of Unexplained Emphysema in Adults?

Emphysema is a chronic respiratory disorder characterized by destruction of alveoli, usually due to cigarette smoking or exposure to noxious particles or gases. Dysfunction of proteins that are involved in lung development and maintenance, such as alpha-1 antitrypsin, also contributes to emphysema. Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton reorganization. Mutations in the FLNA gene classically lead to abnormal neuronal migration and connective and vascular tissue anomalies. Pulmonary manifestations consist of a wide range of pulmonary disorders that occur during infancy. We report the first familial case of emphysema in non- and very low-smoking adults who carry a loss-of-function mutation of the FLNA gene. The identification of this new risk factor for emphysema encourages (1) screening, prevention and monitoring of pulmonary disorders in patients with FLNA mutation and (2) screening for FLNA mutation in patients with early-onset emphysema that is associated with low-smoking or vascular or connective tissue anomalies.

Reduction-Responsive Molecularly Imprinted Poly(2-isopropenyl-2-oxazoline) for Controlled Release of Anticancer Agents.

Trigger-responsive materials are capable of controlled drug release in the presence of a specific trigger. Reduction induced drug release is especially interesting as the reductive stress is higher inside cells than in the bloodstream, providing a conceptual controlled release mechanism after cellular uptake. In this work, we report the synthesis of 5-fluorouracil (5-FU) molecularly imprinted polymers (MIPs) based on poly(2-isopropenyl-2-oxazoline) (PiPOx) using 3,3'-dithiodipropionic acid (DTDPA) as a reduction-responsive functional cross-linker. The disulfide bond of DTDPA can be cleaved by the addition of tris(2-carboxyethyl)phosphine (TCEP), leading to a reduction-induced 5-FU release. Adsorption isotherms and kinetics for 5-FU indicate that the adsorption kinetics process for imprinted and non-imprinted adsorbents follows two different kinetic models, thus suggesting that different mechanisms are responsible for adsorption. The release kinetics revealed that the addition of TCEP significantly influenced the release of 5-FU from PiPOx-MIP, whereas for non-imprinted PiPOx, no statistically relevant differences were observed. This work provides a conceptual basis for reduction-induced 5-FU release from molecularly imprinted PiPOx, which in future work may be further developed into MIP nanoparticles for the controlled release of therapeutic agents.

Structural Diversification of Pillar[n]arene Macrocycles.

Despite the fact that pillar[n]arenes receive major interest as building blocks for supramolecular chemistry and advanced materials, their functionalization is generally limited to the modification of the hydroxy or alkoxy units present on the rims. This limited structural freedom restricts further developments and has very recently been overcome. In this article, we highlight three very recent studies demonstrating further structural diversification of pillar[n]arenes by partial removal of the alkoxy substituents on the rims, which can be considered as the next generation of pillar[n]arenes.

Self-Healing Metallo-Supramolecular Hydrogel Based on Specific Ni2+ Coordination Interactions of Poly(ethylene glycol) with Bistriazole Pyridine Ligands in the Main Chain.

In this study, a supramolecular hydrogel formed by incorporating the 2,6-bis(1,2,3-triazol-4-yl)-pyridine (btp) ligand in the backbone of a polymer prepared by copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) "click" polyaddition reaction of 2,6-diethynylpyridine and diazido-poly(ethylene glycol) is reported. The hydrogelation is selectively triggered by the addition of Ni2+ ions to aqueous copolymer solutions. The gelation and rheological properties could be tuned by the change of metal to ligand ratio and polymer concentration. Interestingly, the hydrogel exhibits a fast (within 2 min) and excellent repeatable autonomic healing capacity without external stimuli. This self-healing behavior may find potential applications for the repairing of metal coatings, in the future.

Metal Ion Selective Self-Assembly of a Ligand Functionalized Polymer into [1+1] Macrocyclic and Supramolecular Polymer Structures via Metal-Ligand Coordination.

The design and synthesis of polymer-based metallomacrocycles relying on metal-ligand interactions remain a challenge in the polymer field. Instead of utilizing chemical reactions to synthesize macrocycles, a general approach is proposed to construct metallomacrocyclic structures through supramolecular self-assembly of a specific macroligand with suitable transition metal ions. Therefore, a new ditopic macroligand (L) consisting of PEG end-capped with 2,6-bis(1,2,3-triazol-4-yl)pyridine derivatives is prepared via CuAAC "click" reaction. Four types of metal (Fe2+ , Zn2+ , Ni2+ , and Cu2+ ) complexes are obtained by simply mixing a solution of metal ions and L in appropriate concentrations. The investigation of the coordination chemistry suggests that coordination of L with Cu2+ results in the formation of a [1+1] metallomacrocycle, while the other metal complexes exclusively lead to the formation of linear metallopolymers and/or larger aggregates. This work provides new insights into designing metallomacrocycles and may have potential application in the synthesis of catenanes and other cyclic or cycle-based topological architectures.

Influence of the Aliphatic Side Chain on the Near Atmospheric Pressure Plasma Polymerization of 2-Alkyl-2-oxazolines for Biomedical Applications.

Plasma polymerization is gaining popularity as a technique for coating surfaces due to the low cost, ease of operation, and substrate-independent nature. Recently, the plasma polymerization (or deposition) of 2-oxazoline monomers was reported resulting in coatings that have potential applications in regenerative medicine. Despite the structural versatility of 2-oxazolines, only a few monomers have been subjected to plasma polymerization. Within this study, however, we explore the near atmospheric pressure plasma polymerization of a range of 2-oxazoline monomers, focusing on the influence of the aliphatic side-chain length (methyl to butyl) on the plasma polymerization process conditions as well as the properties of the obtained coatings. While side-chain length had only a minor influence on the chemical composition, clear effects on the plasma polymerization conditions were observed, thus gaining valuable insights in the plasma polymerization process as a function of monomer structure. Additionally, cytocompatibility and cell attachment on the coatings obtained by 2-oxazoline plasma polymerization was assessed. The coatings displayed strong cell interactive properties, whereby cytocompatibility increased with increasing aliphatic side-chain length of the monomer, reaching up to 93% cell viability after 1 day of cell culture compared to tissue culture plates. As this is in stark contrast to the antifouling behavior of the parent polymers, we compared the properties and composition of the plasma-polymerized coatings to the parent polymers revealing that a significantly different coating structure was obtained by plasma polymerization.

Performance of Endobronchial Ultrasound Elastography in the Differentiation of Malignant and Benign Mediastinal Lymph Nodes: Results in Real-life Practice.

BACKGROUND: Little data exists regarding the performance of elastography in EBUS-TBNA. The aim of the study was to evaluate the elastography score proposed and previously published by Izumo, in particular its capacity to perfectly identify benign lymph node, and to discriminate malignant ones. METHODS: This study included patients undergoing EBUS-TBNA for mediastinal lymph nodes (LN). Before LN needle aspiration, an elastography was performed which allowed a color elastogram to be superimposed on the ultrasound image. Three blinded assessors classified these elastograms into 3 types using the score published by Izumo: type 1 (predominantly not blue), type 2 (partially blue, partially not blue), or type 3 (predominantly blue). These types were then compared with pathology results. RESULTS: A total of 217 LN (114 patients) were analyzed: histologic findings identified 97 benign LN (44.7% of the lymph nodes) and 120 malignant LN (55.3%). There were 44 elastographies (20.2%) that were classified as type 1, 90 elastographies (41.5%) classified as type 2, and 83 elastographies (38.3%) classified as type 3. Considering type 1 as benign and type 3 as malignant, sensitivity, specificity, positive predictive value, and negative predictive value were respectively 87.0%, 68.0% , 80.0% , and 77.0%. Ten (23%) of the 44 lymph nodes with a type 1 elastogram were malignant. CONCLUSION: Elastography does not preclude performing TBNA of the lymph nodes. It does not preclude EBUS-TBNA when a type 1 elastogram pattern is found. All lymph nodes visualized should be sampled by EBUS-TBNA, regardless of elastography pattern.

Photocontrol in Complex Polymeric Materials: Fact or Illusion?

Photoswitches: Exciting recent progress realized in the field of light-controlled polymeric materials is highlighted. It is discussed how the rational choice of azobenzene molecules and their incorporation into complex materials by making use of physical interactions can lead to genuine photocontrollable polymeric systems.

Simultaneous two and three photon resonant enhancement of third-order NLO susceptibility in an azo-dye functionalized polymer film.

We report the observation of simultaneous two and three photon resonances, enhancing the third-order NLO susceptibility in a thin film of an azo-dye polymer. The possibility of 2-3 orders of magnitude increase in χ((3)) susceptibility is sustained by quantum mechanical calculations. This improves the applications of azo-polymers in all optical signal processing as well as in nonlinear optical imaging.