Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials

Background

Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT – Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.

Methods

This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset.

Results

In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman’s rho; p < 0.01, all comparisons listed here): FEV₁% predicted (−0.19, −0.14, −0.15); St. George’s Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (−0.30, −0.14) and incremental shuttle walk (ISWT) (−0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.

Conclusions

Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.

Trial registration

MPEX: {"type":"clinical-trial","attrs":{"text":"NCT00739648","term_id":"NCT00739648"}}NCT00739648; AZ1: {"type":"clinical-trial","attrs":{"text":"NCT00949975","term_id":"NCT00949975"}}NCT00949975; AZ 2: {"type":"clinical-trial","attrs":{"text":"NCT01023516","term_id":"NCT01023516"}}NCT01023516

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0124-z) contains supplementary material, which is available to authorized users.     

Microorganisms for degrading simmondsin and related cyanogenic toxins in jojoba

Summary Four microorganisms that metabolize simmondsin (S) and related cyanogenic toxins from jojoba (Simmondsia chinensis) were isolated by enrichment: Pseudallescheria boydii, a fungus which specifically degrades simmondsin ferulate but not S; Fusarium moniliforme; Flavobacterium aurantiacum; and Pseudomonas maltophilia. The latter three organisms grow on S as a sole carbon and nitrogen source in culture media, but only F. moniliforme attacks S in the complete jojoba meal. Combinations of the four microorganisms at two temperatures, and with free air or limited air exchange for up to 20 days, were tested on jojoba meal to determine an optimum detoxification method. Degradation of toxins was most rapid and complete when Pseudallescheria boydii and Fusarium moniliforme together were incubated on jojoba meal at 25°C with free air exchange for 20 days. Mice were fed fermented meals at 0, 5, 10 and 20% substitution levels to determine detoxification and nutritional quality. Average daily gains during rapid growth of weanling (1–3 weeks) and mature (4–8 weeks) mice did not differ significantly from controls for mice on all diets containing fermented meal. Diets containing fungally detoxified jojoba meal were more efficient for maintaenance of mature weight than jojoba meal detoxified with enzymes naturally present in the meal. Meal can be detoxified by ensilage for 20 days at 80% water content. Detoxification is attributed to as yet unidentified enzymes inherent in the jojoba seed.The mention of firm names or trade products does not imply that they are endorsed or recommended by the U. S. Department of Agriculture over other firms or similar products not mentionedOffprint requests to: Thomas P. Abbott     

How the mirror-image pattern specified by a janus mutation of Tetrahymena thermophila comes to expression

The initial changes of cell-surface organization that occurred as the recessive janAl (janus) mutation of Tetrahymena thermophila first became expressed were elucidated in a special mating scheme in which old macronuclei homozygous for janA⁺ were synchronously replaced by new macronuclei homozygous for janAl. During this period of onset of expression, the number, regularity, and asymmetry of the ciliary rows remained unchanged. New normal (primary) oral apparatuses (OAs) continued to be formed posterior to old OAs, as in normal cells. At about four fissions after conjugation, abnormal (secondary) OAs with a partial reversal of asymmetry began to appear nearly opposite to the primary OAs, close to but not at the eventual circumferential position of janAl secondary OAs. The array of contractile vacuole pores (CVPs), normally located adjacent to two ciliary rows centered near 22% of the cell circumference to the righ of the primary oral meridian, underwent a two-step transformation: first, the number of adjacent ciliary rows bearing CVPs increased to 3, 4, and sometimes 5, then “skipped” rows appeared within this broadened CVP-arc to split the single set of CVPs into two separated subsets. The CVP transformations occurred gradually and progressively. They began prior to the expression of secondary OAs but accelerated as secondary OAs appeared. As the CVP are became broader, its midpoint shifted somewhat to the right, away from the primary oral meridian, but ended up close to halfway between the primary and secondary oral meridians. The data provide a better fit to an intercalation model than to an alternative double gradient model, suggesting that the janAl mutation alters the large-scale organization of positional values by preventing the expression of a subset of these values and thus provoking reverse-intercalation of the remainder.     

Non-genic inheritance of cellular handedness

Ciliates exhibit an asymmetry in arrangement of surface structures around the cell which could be termed handedness. If the usual order of placement of structures defines a 'right-handed' (RH) cell, then a cell with this order reversed would be 'left-handed' (LH). Such LH forms appear to be produced in Tetrahymena thermophila through aberrant reorganization of homopolar doublets back to the singlet condition. Four clones of LH forms were selected and subjected to genetic analysis to test whether this drastic phenotypic alteration resulted from a nuclear genetic change. The results of this analysis indicate that the change in handedness is not due to a genetic change in either the micronucleus or macronucleus. The LH form can, under certain circumstances, revert to the RH form, but typically it propagates itself across both vegetative and sexual generations with similar fidelity. While this analysis does not formally rule out certain possibilities of nuclear genic control involving regulatory elements transmitted through the cytoplasm, when the circumstances of origin and propagation of the LH condition are taken into account direct cortical perpetuation seems far more likely. Here we outline a conceptual framework centred on the idea of longitudinally propagated positional information; the positive evidence supporting this idea as well as further application of the idea itself are presented in the accompanying paper.     

Oral assembly in left-handed Tetrahymena thermophila

We have investigated oral development in a non-genetically derived left-handed (LH) form of Tetrahymena thermophila, in which the large-scale asymmetry of arrangement of cortical structures is reversed whereas the local asymmetry of ciliary architecture remains normal. Approximately 1/2 of the oral apparatuses (OAs) of LH cells develop in the form of superficial mirror-images of OAs of RH cells. In most of these OAs, membranelles are assembled from the cells' anterior to posterior. Nonetheless, the posterior ends of these membranelles undergo the basal body displacements that lead to a "sculptured" appearance, so that the membranelles of LH OAs become organized as rotational permutations of membranelles of normal RH OAs. Many of these membranelles re-orient to a normal orientation near the end of oral development. Membranelles and undulating membranes (UMs) may develop independently of each other, and formation of postciliary microtubules of UMs is separate from that of ribbed wall microtubules. In some cases, the entire OA develops and remains as a 180 degrees rotational permutation of the normal, resembling the inverted OAs of mirror-image doublets and LH cells of Glaucoma scintillans described by Suhama. We present a model for these complex developmental outcomes. These developmental patterns resemble those described previously and less completely for "secondary" OAs of cells with mirror-image global patterns, including janus cells. The present study demonstrates that such alterations in oral development are not a direct outcome of genotypic changes.     

REGULATION OF MICROTUBULES IN TETRAHYMENA : II. Relation Between Turnover of Microtubule Proteins and Microtubule Dissociation and Assembly during Oral Replacement

Experiments are reported which were designed to test for induced synthesis of microtubule proteins associated with the rapid proliferation of basal bodies and associated intracytoplasmic microtubules which occurs during oral replacement in Tetrahymena. None was found. Instead, it is shown that these structures can be formed with de novo synthesis of as little as 6% of their microtubule proteins. It is suggested that basal body proliferation may be controlled by synthesis of morphogenetic regulator proteins.     

Wachstum und Organentwicklung bei Lachm?wennestlingen (Larus ridibundus)

Zusammenfassung Aus den Daten von acht handaufgezogenen Lachmöwennestlingen wurde eine Wachstumskurve ermittelt und die Wachstumsrate berechnet. 26 Küken wurden nach dem Töten vermessen (Extremitäten), gewogen (Organe) und die Allometriekoeffizienten ermittelt, sowie der Wasser- und der Lipidgehalt bestimmt. Lachmöwen gehören zu den schnell wachsenden Vogelarten (K_L=0.19). Organe der Nahrungsaufnahme und -verwertung wie Schnabel, Magen und Darm sind bereits beim Schlüpfen gut entwickelt. Der Wassergehalt der Organe, der Aufschluß über ihren Funktionszustand gibt, sinkt im Körper entsprechend dem steigenden Fettgehalt. Der Wassergehalt der Leber zeigt keine Veränderung im Laufe der Entwicklung; die Leber ist schon von Anfang an voll funktionstüchtig. Es wird die Hypothese aufgestellt, daß Räuber den evolutionsbiologischen Grund für das schnelle Heranwachsen der Nestlinge darstellen, wobei kannibalische Koloniemitglieder der eigenen Art einen ähnlichen Effekt haben.

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Growth and body composition in nestlings of the Black-headed Gull (Larus ridibundus)

Summary From eight hand-raised Black-headed Gull nestlings a growth curve and the growth rate were calculated. 26 chicks were killed and afterwards measured. From these data we computed allometric relationships with body weight and determined the water and lipid content. Blackheaded Gulls are fast growing birds (K_L=0.19). The digestive organs (bill, gizzard and alimentary tract) and the legs are well developed after hatching. The percentage of water decreases as the fat content increases. The liver water content does not change with age, suggesting that the liver is biological mature soon after hatching. It is hypothesized that predators and intraspecific predation are the ultimate factors in the evolution of the rapid growth in gulls.

     

Escape of Steinernema feltiae from Alginate Capsules Containing Tomato Seeds

The entomogenous nematode Steinernema feltiae was encapsulated in an alginate matrix containing a tomato seed. When these capsules were placed on 0.8% agar for 7 days, the seed germinated and ca. 20% of the nematodes escaped from the capsules, whereas only 0.1% escaped from capsules without seeds. When capsules containing nematodes and a seed were planted into sterilized or nonsterilized soil, nematodes escaped to infect Galleria mellonella larvae. When seed in capsules containing ca. 274 nematodes per capsule were planted in nonsterilized soil, Galleria mortality was 90% 1 week later. Galleria mortality declined to 27%, 23%, and 0% in weeks 2, 4, and 8 postplant, respectively. In sterilized soil, Galleria mortality was 96% and did not differ significantly from the nonsterilized soil in week 1, but was significantly higher in sterilized soil over nonsterilized soil for week 2 (81%) and week 4 (51%). When capsules containing nematodes only were used, Galleria mortality was 71% in sterilized soil 1 week after planting and 58%, 33%, and 12% in weeks 2, 4, and 8 postplant, respectively. In nonsterilized soil, Galleria mortality was 8%, 30%, 21%, and 28% after 1, 2, 4, and 8 weeks, respectively, using only encapsulated nematodes. When the number of nematodes per capsule was increased to ca. 817, Galleria mortality was 92 % or higher in sterilized soil from week 1 to week 4.     

A Simulation Model of Heterodera schachtii Infecting Beta vulgaris

A simulation model of a single sugarbeet, Beta vulgaris L., plant infected by the sugarbeet cyst nematode, Heterodera schachtii Schmidt, was developed using published information. The model is an interactive computer simulation programmed in FORTRAN. Given initial population densities of the nematode at planting, the model simulates nematode population dynamics and the growth of plant tap and fibrous roots. The driving variable for nematode development and plant growth is temperature.     

Development of the ciliature of Tetrahymena thermophila: I. Temporal coordination with oral development

The number of basal bodies and cilia along pole-to-pole ciliary rows was enumerated in Tetrahymena thermophila cells sampled during the rapid-exponential phase of culture growth in three different media that supported generation times ranging from 2 to 4 hr. The time required for oral development was nearly constant in the three media, and thus most of the differences in generation time were accounted for by differences in the interval prior to the onset of oral development (stage 0), which ranged from 50% of the generation time in the “poorest” medium to 20% in the “richest.” There was very little increase in number of basal bodies and of cilia along ciliary rows during stage 0, irrespective of the duration of this stage. The bulk of the increase took place during oral development, following a time course suggestive of coordination wth oral development. The same temporal pattern of increase was found in several ciliary rows, although the proportion of basal bodies that were ciliated differed among rows. There is no simple relationship between the number of basal bodies along ciliary rows and cell length, surface area, or volume. However, a large and constant proportion of the total division-to-division cell growth took place during the interval prior to the onset of oral development, suggesting that an ensemble of developmental events, including oral development and an associated activation of the remainder of the cell surface, may be triggered by attainment of a threshold cell size.