| 1. |
- Currow, David, et al.
(författare)
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A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-Arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness : Breathlessness, Exertion and Morphine Sulfate (BEAMS) study protocol
- 2017
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended-release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-Arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. Methods and analysis The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics and dissemination Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. Trial registration number NCT02720822; Pre-results.
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| 2. |
- Currow, David C., et al.
(författare)
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Chronic breathlessness and sleep problems : A population-based survey
- 2021
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study aimed to explore the relationship (presence and severity) between chronic breathlessness and sleep problems, independently of diagnoses and health service contact by surveying a large, representative sample of the general population. Setting Analysis of the 2017 South Australian Health Omnibus Survey, an annual, cross-sectional, face-to-face, multistage, clustered area systematic sampling survey carried out in Spring 2017. Chronic breathlessness was self-reported using the ordinal modified Medical Research Council (mMRC; scores 0 (none) to 4 (housebound)) where breathlessness has been present for more than 3 of the previous 6 months. a € Sleep problems - ever' and a € sleep problem - current' were assessed dichotomously. Regression models were adjusted for age; sex and body mass index (BMI). Results 2900 responses were available (mean age 48.2 years (SD=18.6); 51% were female; mean BMI 27. 1 (SD=5.9)). Prevalence was: 2.7% (n=78) sleep problems - past; 6.8% (n=198) sleep problems - current and breathlessness (mMRC 1-4) was 8.8% (n=254). Respondents with sleep problemspast were more likely to be breathless, older with a higher BMI and sleep problems - present also included a higher likelihood of being female. After adjusting for age, sex and BMI, respondents with chronic breathlessness had 1.9 (95% CI=1.0 to 3.5) times the odds of sleep problems - past and sleep problems - current (adjusted OR=2.3; 95% CI=1.6 to 3.3). Conclusions There is a strong association between the two prevalent conditions. Future work will seek to understand if there is a causal relationship using validated sleep assessment tools and whether better managing one condition improves the other.
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| 3. |
- Eckert, Diana, et al.
(författare)
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CO2 refixation is higher in leaves of woody species with high mesophyll and stomatal resistances to CO2 diffusion
- 2021
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Ingår i: Tree Physiology. - : Oxford University Press. - 0829-318X .- 1758-4469. ; 41:8, s. 1450-1461
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Tidskriftsartikel (refereegranskat)abstract
- The percentage of respiratory and photorespiratory CO2 refixed in leaves (P-r) represents part of the CO2 used in photosynthesis. The importance of P-r as well as differences between species and functional types are still not well investigated. In this study, we examine how P-r differs between six temperate and boreal woody species: Betula pendula, Quercus robur, Larix decidua, Pinus sylvestris, Picea abies and Vaccinium vitis-idaea. The study covers early and late successional species, deciduous broadleaves, deciduous conifers, evergreen conifers and evergreen broadleaves. We investigated whether some species or functional types had higher refixation percentages than others, whether leaf traits could predict higher P-r and whether these traits and their impact on P-r changed during growing seasons. Photosynthesis CO2 response (A/C-i)-curves, measured early, mid and late season, were used to estimate and compare P-r, mesophyll resistance (r(m)) and stomatal resistance (r(s)) to CO2 diffusion. Additionally, light images and transmission electron microscope images were used to approximate the fraction of intercellular airspace and cell wall thickness. We found that evergreens, especially late successional species, refixed a significantly higher amount of CO2 than the other species throughout the entire growing season. In addition, r(m), r(s) and leaf mass per area, traits that typically are higher in evergreen species, were also significantly, positively correlated with P-r. We suggest that this is due to higher r(m) decreasing diffusion of (photo) respiratory CO2 out of the leaf. Cell wall thickness had a positive effect on P-r and r(m), while the fraction of intercellular airspace had no effect. Both were significantly different between evergreen conifers and other types. Our findings suggest that species with a higher r(m) use a greater fraction of mitochondria-derived CO2, especially when stomatal conductance is low. This should be taken into account when modeling the overall CO2 fertilization effect for terrestrial ecosystems dominated by high r(m) species.
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| 4. |
- Eckert, Diana
(författare)
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Refixation of respiratory CO2 in leaves
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Photosynthesis is a vital process for trees, one in which CO2 plays a major role. At the same time, the tree’s own metabolism produces CO2. For this PhD thesis, I investigated the fate of respiratory CO2 – is it all released back into the atmosphere or is it re-used in photosynthesis? The new LeafWeb-model uses gas exchange measurements of leaves to estimate the percentage of respiratory CO2 that is being refixed in photosynthesis (Pr). This thesis examined the effectson Pr of physiological, anatomical, and morphological traits; those of light availability and temperature; and Pr variations between species, functional groups or biomes. In addition, an experimental study explored the effect of drought on carbon allocation, which implied potential advantages of high Pr.I found that Pr is increased with high mesophyll resistance to CO2 diffusion (rm), high maximum carboxylation rate of Rubisco (Vcmax), and low stomatal conductance to CO2 diffusion (gs). This suggests that these physiological states slow CO2 diffusion out of the leaf (high rm and low gs) while increasing the draw on CO2 at the photosynthetic sites (high Vcmax). Thus, all three increase refixation probability. High leaf mass per area (LMA) and thick cell walls, traits known to correlate positively with rm, also increased refixation. The fact that both morphological and anatomical traits that are known to correlate with high rm also correlated with high Pr in my findings supports the assumption of the model regarding the relationship between Pr and rm. Furthermore, Pr increasing with rm is likely the reason Pr was highest in evergreen needle species and in the boreal biomes where this trait is prevalent. Species with high Pr might be less dependent on uptake of atmospheric CO2 and can close more of their stomata to conserve water. Models calculating terrestrial CO2-uptake should therefore consider including Pr, and assume that plants with high rm and high Vcmax refixate most of their (photo)respiratory-derived CO2.The thesis also includes a study that found that drought during early development of P.mariana shoots affected carbon partitioning and shoot morphology. The shoots allocated carbon away from structural components andtowards respiratory or osmoregulation processes. This might result in mature shoots with lower rm, which could reduce their Pr permanently. High Pr couldbe an advantage in conditions where stomata are closed; efficiently reusing(photo)respiratory CO2 during winter or mild drought could make it possible to maintain some photosynthesis even with very low gs. If this is true, new shoots with less efficient refixation might make the tree as a whole less resilient during future droughts. A possible implication is that while the higher Pr of boreal biomes and evergreen conifers may make them better able to tolerate future dry-periods, such periods may weaken this effect if they happen during shoot development.
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| 5. |
- Eckert, Diana, et al.
(författare)
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The maximum carboxylation rate of Rubisco affects CO2 refixation in temperate broadleaved forest trees
- 2020
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Ingår i: Plant physiology and biochemistry (Paris). - : Elsevier. - 0981-9428 .- 1873-2690. ; 155, s. 330-337
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Tidskriftsartikel (refereegranskat)abstract
- Mesophyll resistance to CO2 diffusion (rm) and the maximum carboxylation rate of Rubisco (Vcmax) affect photosynthetic rates, and can potentially also influence the percentage of respiratory and photorespiratory CO2 being refixated (Pr) by mesophyll cells. Here we investigated how various leaf anatomical traits (e.g. leaf mass per area [LMA] and leaf dry matter content [LDMC]) influenced rm in leaves of mature forest trees. We further explored how rm and Vcmax in turn affected Pr, and if these traits varied among species and leaves along a light gradient. Photosynthetic CO2 response of leaves grown in high-, medium-, and low-light environments was measured, from Pinus sylvestris [Scots pine], Picea abies [Norway spruce], Quercus robur [English oak], and Betula pendula [Silver birch] in southern Sweden. A modified version of the Farquhar-von Caemmerer-Berry model was fitted to the leaf gas exchange data to estimate Vcmax, rm and Pr. We found that of all leaf traits measured, only LMA for Q. robur was significantly higher in leaves from high-light environments. When comparing species, both rm and LMA were significantly higher in the conifers, and rm had a negative correlation with Vcmax. We found that Pr was similar between different species and functional groups, with an average of 73.2% (and SD of ±10.4) across all species. There was a strong, positive correlation between Pr and Vcmax in broadleaves, and we hypothesise that this effect might derive from a higher CO2 drawdown near Rubisco in leaves with high Vcmax.
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| 6. |
- Ekström, Magnus, et al.
(författare)
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Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease : The BEAMS Randomized Clinical Trial
- 2022
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Ingår i: JAMA. - : American Medical Association (AMA). - 0098-7484. ; 328:20, s. 2022-2032
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed.OBJECTIVE: To determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment.DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019.INTERVENTIONS: People were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week's dose, or placebo.MAIN OUTCOMES AND MEASURES: The primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 [none] to 10 [being worst or most intense]) using the mean score at baseline (from days -3 to -1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day -1) to the mean step count from week 3 (from days 19 to 21).RESULTS: Among the 160 people randomized, 156 were included in the primary analyses (median age, 72 years [IQR, 67 to 78 years]; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -0.3 [95% CI, -0.9 to 0.4]) or between the 16 mg/d of morphine group and the placebo group (mean difference, -0.3 [95%, CI, -1.0 to 0.4]). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -1453 [95% CI, -3310 to 405]), between the 16 mg/d of morphine group and the placebo group (mean difference, -1312 [95% CI, -3220 to 596]), between the 24 mg/d of morphine group and the placebo group (mean difference, -692 [95% CI, -2553 to 1170]), or between the 32 mg/d of morphine group and the placebo group (mean difference, -1924 [95% CI, -47 699 to 921]).CONCLUSIONS AND RELEVANCE: Among people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02720822.
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| 7. |
- Ferreira, Diana H., et al.
(författare)
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Extended-Release Morphine for Chronic Breathlessness in Pulmonary Arterial Hypertension—A Randomized, Double-Blind, Placebo-Controlled, Crossover Study
- 2018
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Ingår i: Journal of Pain and Symptom Management. - : Elsevier BV. - 0885-3924. ; 56:4, s. 483-492
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Tidskriftsartikel (refereegranskat)abstract
- Context: Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH. Objectives: This randomized, placebo-controlled, double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness. Methods: Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness “right now”—morning and evening—measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291). Results: Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness “right now” was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = −0.22 (−0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = −0.33 (−0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation. Conclusion: This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.
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| 8. |
- Jensen, Anna M., 1978-, et al.
(författare)
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Springtime Drought Shifts Carbon Partitioning of Recent Photosynthates in 10-Year Old Picea mariana Trees, Causing Restricted Canopy Development
- 2021
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Ingår i: Frontiers in Forests and Global Change. - : Frontiers Media S.A.. - 2624-893X. ; 3, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Springtime bud-break and shoot development induces substantial carbon (C) costs in trees. Drought stress during shoot development can impede C uptake and translocation. This is therefore a channel through which water shortage can lead to restricted shoot expansion and physiological capacity, which in turn may impact annual canopy C uptake. We studied effects of drought and re-hydration on early season shoot development, C uptake and partitioning in five individual 10-year old Picea mariana [black spruce] trees to identify and quantify dynamics of key morphological/physiological processes. Trees were subjected to one of two treatments: (i) well-watered control or (ii) drought and rehydration. We monitored changes in morphological [shoot volume, leaf mass area (LMA)], biochemical [osmolality, non-structural carbohydrates (NSC)] and physiological [rates of respiration (Rd) and light-saturated photosynthesis (Asat)] processes during shoot development. Further, to study functional compartmentalization and use of new assimilates, we 13C-pulse labeled shoots at multiple development stages, and measured isotopic signatures of leaf respiration, NSC pools and structural biomass. Shoot water potential dropped to a minimum of −2.5 MPa in shoots on the droughted trees. Development of the photosynthetic apparatus was delayed, as shoots on well-watered trees broke-even 14 days prior to shoots from trees exposed to water deficit. Rd decreased with shoot maturation as growth respiration declined, and was lower in shoots exposed to drought. We found that shoot development was delayed by drought, and while rehydration resulted in recovery of Asat to similar levels as shoots on the well-watered trees, shoot volume remained lower. Water deficit during shoot expansion resulted in longer, yet more compact (i.e., with greater LMA) shoots with greater needle osmolality. The 12C:13C isotopic patterns indicated that internal C partitioning and use was dependent on foliar developmental and hydration status. Shoots on drought-stressed trees prioritized allocating newly fixed C to respiration over structural components. In conclusion, temporary water deficit delayed new shoot development and resulted in greater LMA in black spruce. Since evergreen species such as black spruce retain active foliage for multiple years, impacts of early season drought on net primary productivity could be carried forward into subsequent years.
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| 9. |
- Kochovska, Slavica, et al.
(författare)
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Prevalence, severity and impacts of breathlessness in Indian adults : An exploratory, nationally representative, cross-sectional online survey
- 2024
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Ingår i: PLOS global public health. - 2767-3375. ; 4:5 May
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Tidskriftsartikel (refereegranskat)abstract
- There are no known estimates of the prevalence, severity and impacts from breathlessness in low- and middle-income countries. This study aimed to explore the prevalence, severity, self-attributed underlying conditions and impacts of breathlessness limiting exertion in community-dwelling adults in India. This exploratory, population-based online survey recruited a pre-planned sample of 3,000 adult respondents stratified by age, sex and rurality (quotas as per the 2011 Indian National Census). Measures included: demographics; breathlessness limiting exertion (modified Medical Research [mMRC] scale); health-related quality of life (EQ-5D-5L); and disability (World Health Organisation’s Disability Assessment Schedule 2.0 12-item questionnaire [WHODAS-12]). Respondents (n = 3,046) had a mean age of 38 years (SD 15); 57% were male, 59% lived in rural areas and 33% had completed 12th grade. Breathlessness limiting exertion (mMRC ≥1) was reported by 44%, mostly attributed to poor nutrition (28%), lung conditions excluding tuberculosis (17%) or anaemia (13%). Compared to those without breathlessness, a higher proportion of people with breathlessness (mMRC ≥1) reported problems across all EQ-5D-5L dimensions. Most people reporting breathlessness (81%) indicated the symptom had adversely affected their normal activities. Disability scores (WHODAS-12 total and individual domains) increased as breathlessness worsened. To conclude, in India, conservative estimates indicate 626 million people live with breathlessness of whom 52 million people live with severe breathlessness. The symptom is associated with poorer health-related quality of life and marked disability, including reduced ability to perform daily activities.
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