Benoit Wallaert
email: pr.b.wallaert@gmail.com

Justine Briand

Hélène Behal

Thierry Perez

Lidwine Wemeau

Cécile Chenivesse

The 1-Minute Sit-to-Stand Test to Evaluate Quadriceps Muscle Strength in Patients with Interstitial Lung Disease

Keywords: interstitial lung disease, sarcoidosis, pulmonary fibrosis, muscle strength, sit-tostand test

Skeletal muscle dysfunction is prevalent in patients with chronic respiratory diseases.

In patients with interstitial lung diseases (ILDs), such dysfunction has been associated with lower exercise capacity and reduced quality of life [START_REF] Spruit | Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status[END_REF][START_REF] Nishiyama | Quadriceps weakness is related to exercise capacity in idiopathic pulmonary fibrosis[END_REF][START_REF] Watanabe | Quadriceps weakness contributes to exercise capacity in nonspecific interstitial pneumonia[END_REF][START_REF] Marcellis | Exercise capacity, muscle strength and fatigue in sarcoidosis[END_REF]. Although evaluation of quadriceps strength is useful for monitoring progress during pulmonary rehabilitation (PR), it is not easily performed outside of specialized units. Exercise training is the most effective method for improving quadriceps strength [START_REF] Maltais | An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease[END_REF]. Therefore, we investigated whether an exercise test could act as a surrogate measure of quadriceps strength in ILD patients.

We recently found that the number of repetitions performed during the 1-minute sitto-stand test (1STST) correlated strongly with exercise performance in the 6-minute walk test (6MWT) in patients with ILDs [START_REF] Briand | The 1-minute sitto-stand test to detect exercise-induced oxygen desaturation in patients with interstitial lung disease[END_REF]. The 1STST requires a chair but no specialized equipment and it is easy to perform, making it an ideal exercise test for use in the physician's office. The aim of the present study was to determine whether performance in the 1STST correlates with quadriceps muscle strength in patients with ILDs.

We enrolled all patients with ILDs (n = 107) who were admitted for assessment at the Rare Lung Disease Reference Center in Lille between May and December 2015, regardless of disease etiology or severity. Exclusion criteria were an inability to perform the 1STST, unstable respiratory status, or recent respiratory infection. Approval for the use of these retrospectively collected data was provided by the Institutional Review Board of the French Learned Society for Pulmonology (CEPRO 2011-039), and informed consent was obtained from all patients.

As routinely performed, clinical characteristics and pulmonary function tests were recorded. Patients performed muscle strength tests followed by the 1STST, or vice versa, on the same day in a random order. A rest period of at least 30 minutes was allowed between the tests to ensure complete recovery. One technician supervised the 1STST for all patients, and another technician supervised the muscle strength test for all patients. Both technicians were blind to the results of the other test. The 1STST was performed as previously described [START_REF] Briand | The 1-minute sitto-stand test to detect exercise-induced oxygen desaturation in patients with interstitial lung disease[END_REF]. Briefly, the patient was seated upright on a chair of standard height (46 cm) without arm rests positioned against a wall. The patient sat with knees and hips flexed at 90°, feet placed flat on the floor hip-width apart, and arms held stationary by placing hands on the hips.

Subjects were asked to perform repetitions of standing upright and then sitting down in the same position, as many times as possible at a self-paced speed (safe and comfortable) for 1 minute, without using their arms for support while rising or sitting. Subjects were permitted to rest within the 1-minute period. The maximum isometric voluntary force of the quadriceps muscle was measured by an isometric method using a hand-held dynamometer (MicroFet2; Hoggan Health Industries, Salt Lake City, UT, USA) held by a strap at a fixed point. A total of five measurements per leg, each for 5 s, were taken and the maximum value was used for analysis [START_REF] Prévotat | Improvement in body composition following a supervised exercise-training program of adult patients with cystic fibrosis[END_REF].

Continuous variables are presented as the mean ± standard deviation. Normality of distribution was checked graphically and using the Shapiro-Wilk test. The relationship between quadriceps muscle strength and 1STST repetitions in the overall population was evaluated by Pearson's correlation coefficient. Data were analyzed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA) and all tests were performed with a two-tailed alpha error of 0.05. A total of 107 patients were included in this retrospective analysis (62 men, 45 women, age 57 ± 14 years, BMI 28 ± 5 kg/m², FVC 83 ± 19 % predicted, FEV1 75 ± 22 % predicted, and DLCO 75 ± 22 % predicted). Of the 107, 31 patients had sarcoidosis, 21 had idiopathic pulmonary fibrosis, 25 had fibrotic non-specific interstitial pneumonia, 5 had chronic hypersensitivity pneumonitis and 25 had miscellaneous other ILDs. The average number of 1STST repetitions for all patients was 21 ± 6, and the average strengths of the right and left quadriceps were 354 ± 135 N and 332 ± 124 N, respectively. As shown in Figure 1, the number of 1STST repetitions for all patients correlated with the right quadriceps strength, left quadriceps strength, and age, but not with weight, body mass index, or FVC.

Interestingly, Lord et al. [START_REF] Lord | Sit-to-stand performance depends on sensation, speed, balance, and psychological status in addition to strength in older people[END_REF], in their study of 669 subjects aged 75-93 years, indicated that STS performance was influenced not only by multiple physiological and psychological processes such as sensorimotor, balance, and psychological factors, but also by quadriceps strength; indeed, the latter was the most important variable in explaining the number of repetitions during a STST. Four previous studies have identified reduced quadriceps endurance and strength in patients with sarcoidosis [START_REF] Spruit | Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status[END_REF][4] or f-IIP [START_REF] Nishiyama | Quadriceps weakness is related to exercise capacity in idiopathic pulmonary fibrosis[END_REF][3] [START_REF] Mendoza | Quadriceps strength and endurance in fibrotic idiopathic interstitial pneumonia[END_REF]. Skeletal muscle weakness is associated with exercise intolerance (maximum oxygen uptake or 6-minute walking distance) and is a predictor of exercise capacity. In a study of 25 patients with sarcoidosis, Spruit et al. reported that skeletal weakness might be related to corticosteroid treatment [START_REF] Spruit | Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status[END_REF], and in their study of 98 patients with various ILDs, Hanada et al. found that corticosteroid treatment contributed to muscle weakness [START_REF] Hanada | Effect of long-term treatment with corticosteroids on skeletal muscle strength, functional exercise capacity and health status in patients with interstitial lung disease[END_REF]. Evaluation of the influence of steroids was beyond the scope of the present study. Nishiyama et al. studied 25 patients with sarcoidosis and showed that exercise limitation was observed even in patients with mildly impaired lung function, and that maximum oxygen uptake and muscle weakness were correlated [START_REF] Nishiyama | Quadriceps weakness is related to exercise capacity in idiopathic pulmonary fibrosis[END_REF]. It is also interesting to note that the reduction in skeletal muscle endurance in idiopathic pulmonary fibrosis patients identified here was not related to hypoxia or disease duration. Taken together, these results imply that peripheral muscle training during PR could increase the exercise capacity of patients with ILDs.

In conclusion, we found that quadriceps strength correlated with performance in the 1STST in patients with ILDs, suggesting that this simple exercise may be a valuable tool for assessing skeletal muscle dysfunction in a clinical setting. However, this should be further evaluated in prospective studies.

Conflicts of interest

The authors disclose no financial or personal relationships with people or organizations that could inappropriately influence this work.

Ethical statement

Approval for the use of these data was provided by the Institutional Review Board of the French Learned Society for Pulmonology (CEPRO 2011-039) and informed consent was obtained from all patients.


Venkata Swaroopa

Datta Devulapalli

Mélissandre Richard

Tian-Yi Luo

Mattheus L De Souza

Nathaniel L Rosi

Eric Borguet

Tuning the Lewis acidity of metal-organic frameworks for enhanced catalysis

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Tuning the Lewis acidity of metal-organic frameworks for enhanced catalysis †

In situ conversion of zirconium chloride to zirconium oxy-hydroxide was identified as the key step.

We propose a precursor-MOF activity relationship.

The development of materials which can detect, adsorb and readily degrade toxic chemicals such as chemical warfare agents (CWAs) is essential to mitigate their harmful effects on military and civilians.

CWAs include a wide range of chemicals with a variety of functional groups. They are broadly classified as nerve agents (organophosphorus molecules), vesicants (mustards and arsenicals), blood agents (cyanide containing molecules) and choking agents (phosgene and derivatives).1 Out of these, organophosphorus nerve agents are lethal considering their immediate and severe impact on the nervous system, thereby affecting simple life processes, leading to death in a short time.2 Small amounts of these nerve agents used in the form of aerosol, gas, liquid or adsorbed on solids cause serious long-term effects.

It is clear that a better understanding of the mechanisms of action of materials that can readily adsorb and efficiently degrade these toxic chemicals is crucial to find the best formulation. Early studies of nerve agent detoxification utilized oxides of transition metals such as zirconium oxides,3 hydroxides4 or titanium oxides.5 Oxides dispersed in polymers were also studied for the oxidation of sulfur mustards.6 One major disadvantage of these materials was the low surface areas, low porosity and active site poisoning after nerve agent sorption resulting in low efficiency of the catalyst.7 Other studies report the sorption of dimethyl methyl phosphonate (DMMP) and its photocatalytic degradation by TiO2 using UV light5 which may be challenging for in-operando applications. Thus, different techniques and new materials have been explored for efficient and targeted CWA degradation. Metal-organic frameworks (MOFs) are crystalline organic porous materials with high surface areas and porosities.8 MOFs consist of inorganic metal/metal oxide (and/or hydroxide) clusters linked together in 3 dimensions by organic molecules (linkers) via coordination bonding. The high degree of property tunability using simple chemistry such as modification of the linkers is one of the attractive features of MOFs. The freedom of choosing the metal/metal cluster, and also the organic linker, facilitates the generation of MOFs with a myriad of topologies, suitable for separations and catalysis.9,10 Moreover, the facile functionalization of MOFs makes them appropriate for targeted applications in the fields of gas sorption and bio-medical applications.11-14 Zirconium MOFs have been explored for their ability to catalyze several reactions. Different techniques such as UV-vis,15 in situ FTIR,16 in situ X-ray,17 TPD,16,18 DRIFTS,17 NMR19 and also theoretical modelling17,20 have been utilized to study the interactions between the molecules and MOFs.

Particularly, for the hydrolysis of organophosphorus nerve agents such as Sarin (GB), Soman (GD) and nerve agent simulants, zirconium MOFs have proven to be efficient catalysts. Reports suggest that zirconium MOFs were chosen not only due to the similarities in chemistry with their hydroxides which degrade CWA simulants, but also because they mimic the structure of phosphotriesterase enzyme,21 As for all catalytic reactions, a clearer understanding of the role of the catalyst and the nature of active species responsible is necessary for an optimal catalyst selection and better reaction kinetics. However, the effect of MOF precursors on CWA hydrolysis (e.g. DMNP hydrolysis) is seldom discussed. We believe that the fundamental properties of MOFs, especially chemical, are best represented and governed by their precursors. Hence, we expect that, a critical understanding of the reactivity of a MOF, in a particular reaction, can be achieved via an analysis of the MOF's constituents. Moreover, predicting their properties by testing the precursors could motivate the effort of MOF synthesis and provide a direct way of comparing different MOFs for a particular reaction, in a short time, without actually synthesizing them.

As CWAs are lethal and working with them requires great caution and specialized personal protective equipment, our study was carried out using simulants, i.e., molecules that are structurally and/or chemically similar to nerve agents but relatively less toxic. We investigated the roles of the UiO-67 MOF precursors, zirconium chloride (ZrCl4), nanoparticulate zirconium hydroxide (Zr(OH)4) and the biphenyl dicarboxylic acid (BPDC) linker, in dimethyl nitrophenyl phosphate (DMNP) hydrolysis under basic conditions as shown in Fig. 1. DMNP was chosen as a simulant of the nerve agent Soman (GD) for its similarities in structure and heat of adsorption, based on the study performed by Agrawal et al.28 Under basic conditions (pH = 10), DMNP hydrolysis leads to the formation of 4-nitrophenolate and dimethyl hydrogen phosphate as products (Fig. 1). The dark yellow 4-nitrophenolate has an absorption band that peaks at ∼400 nm whose intensity is monitored with time to follow the reaction progress. The addition of DMNP to the buffer solution containing UiO-67 MOFs leads to the catalytic degradation of DMNP with a half-life of ∼10 min (Fig. 2). In the absence of the MOF little change in absorbance after 90 min is observed showing that the reaction does not proceed if it is not catalyzed. In addition, substitution of the MOF linker with NH2 group on the meta position of the benzene ring does not impact the initial rate of the reaction significantly, (Fig. 2) and ∼90% overall DMNP conversion for UiO-67-NH2 vs. ∼100% conversion for UiO-67 is observed.

Interestingly, we noticed that the precursor of the UiO-67 MOF nodes, ZrCl4, was able to hydrolyze DMNP but with a slower rate (∼65% conversion after 60 min) compared to that of MOFs. However, similar experiments using the linker (BPDC) showed no hydrolysis activity towards DMNP. Based on the obtained results, other precursors of MOFs were tested. Our observations highlight that nanoparticulate Zr(OH)4 was also active for the degradation of DMNP. However, Zr(OH)4 shows slower kinetics (∼40% conversion after 60 min) than ZrCl4 and seems to reach a maximum DMNP conversion at an absorbance of 0.4 after 60 min of reaction.

Previous studies performed by Mondloch et al. concluded that bulk Zr(OH)4 cannot catalyze DMNP

hydrolysis. 15 Our study reveals that nanoparticulate Zr(OH)4 can degrade DMNP, in agreement with studies revealing the activity of Zr(OH)4 to degrade the nerve agent GD itself. 29 The enhanced catalytic activity of the nanoparticles may be attributed to their higher active surface area, and increased number of defects, as well as differences in morphology and electronic structure compared to that of bulk. This result suggests that zirconium metal precursors would be the origin for the activity of zirconium MOFs and attests that at least one of the precursors of the MOF should catalyze the degradation in order for the MOF itself to do the same. As seen in Fig. 2, linker substitution on the meta position does not have a significant impact on the rate of DMNP hydrolysis, contrary to previous reports where enhancement in rate of hydrolysis of DMNP was observed using ortho and meta-amine substituted zirconium MOFs.30 A plausible explanation for the differences in rates of hydrolysis could be the concentration of defects in the MOF resulting from differences in the synthesis procedures.

Hydrolysis of organophosphorus molecules by MOFs is reported to occur via nucleophilic attack on P-X bond on live agents (P-O in DMNP) by the available free hydroxyl groups on the node of the UiO MOFs.20 In addition to the accessibility, the nucleophilicity of free hydroxyl groups is directly proportional to the Lewis acidity of the metal they are bound to. When the same reaction is performed with ZrCl4 the rate of hydrolysis is reduced with t1/2 being approximately 50 min (Table SI1). Astle et al. reported in situ conversion of ZrCl4 to an active zirconium oxy-hydroxide, which resembles the node of the MOF containing oxy, hydroxyl and aquo groups. 31 We believe that this oxy-hydroxide can serve as a catalyst for the decomposition of the nerve agent and its simulants. The experiments reported here, in agreement with a previous study,29 suggest that the active site of the MOF, responsible for DMNP hydrolysis, is the inorganic zirconium node.

Compared to Zr(OH)4, ZrCl4 has higher activity for the degradation of DMNP, which can be attributed to higher solubility observed in water of ZrCl4 compared to Zr(OH)4. The labile chlorine ions are reported to favor the hydrolysis of ZrCl4, forming ZrOCl2, which is further hydrolyzed to form zirconium oxy-hydroxide.32

The zirconium oxy-hydroxide formed in the solution exhibits a high degree of similarity to the MOF node, as depicted in Fig. 3, thus displaying activities comparable to MOFs. This hydrolysis is less likely in the case of Zr(OH)4 thereby resulting in lower activity of Zr(OH)4.31 In fact, the non-zero background of Zr(OH)4 (corrected in Fig. 2) suggests scattering by undissolved Zr(OH)4 particles. However, no background absorbance was observed for UiO-67 MOF or ZrCl4 suggesting smaller crystallites compared to Zr(OH)4 (Fig. SI1-3).

Interestingly, a study performed on UiO-66, by Bůžek et al., reports that the widely employed reaction conditions (pH = 10) to test nerve agent degradation/simulant degradation destabilizes the MOF via breakage of Zr-OC bond between the metal node and the linker, thereby allowing the active node material to leach into the solution and catalyze the reaction.33 Based on this study, it is reasonable to expect that mechanistically, ZrCl4 also behaves in similar fashion to MOFs in the hydrolysis of DMNP (dissolution followed by generation of catalytic species).

Utilizing the insights from theoretical studies on nerve agent degradation by MOFs,20,34 a base catalyzed hydrolysis mechanism of DMNP degradation by in situ formed zirconium oxy-hydroxide is presented in Fig. 4. Step i represents association of DMNP and H2O to the Zr in the node. Subsequently in step ii, nucleophilic attack by oxygen on the electrophilic PvO results in the release of 4nitrophenolate and dimethyl hydrogen phosphate as products (steps iii and iv).

Previous literature reports, and the results obtained from our studies, have motivated us to formulate a relationship between the activity of MOFs and the activity of their precursors. Hence, we hypothesize that at least one of the MOF precursors should be active in hydrolyzing DMNP, under basic conditions, and that Lewis acidity of the metal node plays a determinant role in this activity. To validate our hypothesis, the effect of a different metal MOF, i.e. UiO-67(Hf) and its precursor hafnium chloride (HfCl4) were tested to evaluate their efficiency towards the hydrolysis of DMNP.

The choice of hafnium was motivated by the fact that this element belongs to the same group as zirconium. The interesting difference is that hafnium is relatively less Lewis acidic than zirconium. 35 As expected HfCl4 displayed lower activity towards DMNP hydrolysis in basic medium compared to ZrCl4 (Fig. 2), confirming the crucial role of Lewis acidity in this reaction. According to our proposed hypothesis, one would expect a lower activity of UiO-67(Hf) towards DMNP hydrolysis and indeed, UiO-67 (Hf) displayed lower activity compared to UiO-67 (Zr). This observation clearly validates our precursor-MOF hypothesis -the higher the activity of the MOF precursor for DMNP degradation, higher will be the activity of the MOF itself. In a computational study performed by Mendonca et al., the effects of the metal node, its topology and connectivity on the hydrolysis of 6 nerve agents were systematically studied and zirconium MOFs performed better than hafnium MOFs irrespective of the nerve agent/MOF identity,36 which is in line with our verified hypothesis and predictions. In summary, the efficiency of zirconium MOFs and their precursors for the hydrolysis of DMNP, in a basic buffer medium, was investigated. Our results support the fact that the active site in UiO-67 MOFs responsible for the hydrolysis of DMNP is the metal node and is dependent on the Lewisacidic strength of the metal. Due to a higher solubility of ZrCl4 (which favors formation of zirconium oxy-hydroxide) compared to Zr(OH)4, the rate of hydrolysis of DMNP by ZrCl4 was higher compared to Zr(OH)4. No DMNP hydrolysis was observed due to the BPDC linker. This suggests that at least one of the precursors has to be active in order for the MOF to hydrolyze DMNP. Based on our results we hypothesized that MOFs made with precursors showing high activity for a reaction will in turn exhibit higher activity for the same reaction. Tests performed using UiO-67(Hf) and HfCl4 revealed a slower rate of DMNP hydrolysis compared to UiO-67(Zr) and ZrCl4 respectively, in line with the lower Lewis acidities of the Hf based materials, thus validating our hypothesis. We expect that our precursor-MOF activity hypothesis will guide in choosing the right metal, based on its Lewis acidity, for synthesizing MOFs that can actively destroy DMNP and relevant organophosphorus nerve agents/their simulants, as well as for catalyzing other organic reactions.

Conflicts of interest

There are no conflicts to declare.

  Swaroopa Datta Devulapalli, a Mélissandre Richard, a Tian-Yi Luo, b Mattheus L. De Souza,b Nathaniel L. Rosi b and Eric Borguet *a The kinetics of hydrolysis of dimethyl nitrophenyl phosphate (DMNP), a simulant of the nerve agent Soman, was studied and revealed transition metal salts as catalysts. The relative rates of DMNP hydrolysis by zirconium and hafnium chlorides are in accordance with their Lewis acidity.

  present in nature, that can catalytically hydrolyze the P-O bond of phosphate/phosphonate containing molecules. Hence many zirconium MOFs such as UiO MOFs,22 NU-1000,15 MOF-808 23 were tested for organophosphorus nerve agent detoxification under basic conditions (buffer pH = 8-10) where the nucleophilic cleavage of P-O is favored, and Zr4+ shows a strong Lewis acidity character. Additionally, recent studies have focused on CWA degradation by MOFs in neutral pH,24 under the effects of ambient gases25 and using polymers such as polyethyleneimine (PEI), which are crucial for practical applications.26 Moreover, defects in MOFs play a decisive role in catalysis and destruction of CWAs.For instance, theoretical and experimental studies performed under UHV, showed that the initial binding and the degradation of live agent/simulant on MOFs surface requires a Lewis-acidic under-coordinated (defect) zirconium site.18,27 It was observed that UiO-67 zirconium MOFs were able to degrade DMMP,18 whereas similar studies performed by Ruffley et al. using nearly pristine, defect free UiO-67 MOFs revealed simple physisorption without any degradation.16

  In a recent study byLionetti et al., the qualitative rate of oxygen atom transfer (OAT) in heterometallic cubanes was observed to increase with increasing Lewis acidity of the redox inactive metal, thus providing a handle to tune the OAT reactivity of the cubane clusters.37 Another study performed by Johnson et al. on cobalt assisted Fischer-Tropsch synthesis reports a positive correlation between the Lewis acidity of the metal oxide promoter, product selectivity and the rate coefficient, thereby establishing a guideline for a rational selection of promoter materials.38 Therefore, the paradigm proposed in this paper of using the MOF precursors as models to predict the activity of the MOF itself should guide researchers in clearly and rapidly choosing the optimum metals for synthesizing suitable MOFs for DMNP hydrolysis or any other specific reaction.

Acknowledgements

This project received support from the Defense Threat Reduction Agency (DTRA) (grant no. HDTRA1-16-1-0044). M. L. D. acknowledges support from the University of Pittsburgh through a Dietrich School of Arts and Sciences graduate research fellowship. This work was performed, in part, at the Nanoscale Fabrication and Characterization Facility, a laboratory of the Gertrude E. and John M. Petersen Institute of NanoScience and Engineering, housed at the University of Pittsburgh. VSDD and EB thank Dr Ramanathan Vaidhyanathan from the Indian Institute of Science Education and Research, Pune, India for useful discussions.