Reliability and validity of a Dutch version of the Leicester Cough Questionnaire

BACKGROUND: Chronic cough is a common condition with a significant impact on quality of life. Currently, no health status measure specific for chronic cough exists in the Netherlands. Thus we developed a Dutch version of the Leicester Cough Questionnaire (LCQ) and tested its scaling and clinical properties. METHODS: The LCQ was adapted for Dutch conditions following a forward-backward translation procedure. All patients referred to our cough clinic between May 2004 and February 2005 completed five questionnaires, the LCQ, the modified Borg score for cough, the Short-Form 36 (SF-36), the Hospital Anxiety and Depression Scale (HADS) and the Global Rating of Change (GRC) upon presentation, after two weeks and after 6 months. Concurrent validation, internal consistency, repeatability and responsiveness were determined. RESULTS: For the concurrent validation the correlation coefficients (n = 152 patients) between the LCQ and the other outcome measures varied between 0.22 and 0.61. The internal consistency of the LCQ (n = 58) was high for each of the domains with a Crohnbach's alpha coefficient between 0.77 and 0.91. The two week repeatability of the LCQ in patients with no change in cough (n = 48) was high with intraclass correlation coefficients varying between 0.86 and 0.93. Patients who reported an improvement in cough (n = 140) after 6 months demonstrated significant improvement on each of the domains of the LCQ. CONCLUSION: The Dutch version of the LCQ is a valid and reliable questionnaire to measure (changes of) health status in patients with chronic cough

Diagnostic yield of CT thorax angiography in patients suspected of pulmonary embolism: independent predictors and protocol adherence

OBJECTIVES: To determine the diagnostic yield of computed tomography scanning of the pulmonary arteries (CTPA) in our centre and factors associated with it. Differences between specialties as well as adherence to protocol were investigated. METHODS: All patients receiving a first CTPA for pulmonary embolism (PE) in 2010 were included. Data about relevant clinical information and the requesting specialty were retrospectively obtained. Differences in diagnostic yield were tested using a chi-squared test. Independent predictors were identified with multivariate logistic regression. RESULTS: PE on CTPA was found in 224 of the 974 patients (23 %). Between specialties, diagnostic yield varied from 19.5 to 23.9 % (p = 0.20). Independent predictors of diagnostic yield were: age, sex, D-dimer, cough, dyspnea, cardiac history, chronic obstructive pulmonary disease (COPD), atelectasis/consolidation, intrapulmonary mass and/or interstitial pulmonary disease on CT. Wells scores were poorly documented (n = 127, 13.0 %). Poor adherence to protocol was also shown by a high amount of unnecessary D-dimer values with a high Wells-score (35 of 58; 58.6 %). CONCLUSIONS: The diagnostic yield of CTPA in this study was relatively high in comparison with other studies (6.7–31 %). Better adherence to protocol might improve the diagnostic yield further. A prospective study could confirm the independent predictors found in this study. TEACHING POINTS: • Pulmonary embolism is potentially life-threatening and requires quick and reliable diagnosis. • Computed tomography of the pulmonary arteries (CTPA) provides this reliable diagnosis. • Several independent predictors of diagnostic yield of CTPA for pulmonary embolism were identified. • Diagnostic yield of CTPA did not differ between requesting specialties in our Hospital. • Better protocol adherence could improve the diagnostic yield of CTPA for pulmonary embolism

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial

BACKGROUND: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. METHODS: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. RESULTS: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. CONCLUSIONS: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168

Opioids in patients with COPD and refractory dyspnea:literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD)

BACKGROUND: Refractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine.METHODS: We describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV1 &lt; 50%, mMRC ≥ 3, on optimal standard therapy) will be included.DISCUSSION: Evidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD. Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363 .</p

Opioids in patients with COPD and refractory dyspnea:literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD)

Abstract Background Refractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine. Methods We describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV1 < 50%, mMRC ≥ 3, on optimal standard therapy) will be included. Discussion Evidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD. Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363

Direct measurements of meltwater runoff on the Greenland ice sheet surface

Meltwater runoff from the Greenland ice sheet surface influences surface mass balance (SMB), ice dynamics, and global sea level rise, but is estimated with climate models and thus difficult to validate. We present a way to measure ice surface runoff directly, from hourly in situ supraglacial river discharge measurements and simultaneous high-resolution satellite/drone remote sensing of upstream fluvial catchment area. A first 72-h trial for a 63.1-km2 moulin-terminating internally drained catchment (IDC) on Greenland?s midelevation (1,207?1,381 m above sea level) ablation zone is compared with melt and runoff simulations from HIRHAM5, MAR3.6, RACMO2.3, MERRA-2, and SEB climate/SMB models. Current models cannot reproduce peak discharges or timing of runoff entering moulins but are improved using synthetic unit hydrograph (SUH) theory. Retroactive SUH applications to two older field studies reproduce their findings, signifying that remotely sensed IDC area, shape, and supraglacial river length are useful for predicting delays in peak runoff delivery to moulins. Applying SUH to HIRHAM5, MAR3.6, and RACMO2.3 gridded melt products for 799 surrounding IDCs suggests their terminal moulins receive lower peak discharges, less diurnal variability, and asynchronous runoff timing relative to climate/SMB model output alone. Conversely, large IDCs produce high moulin discharges, even at high elevations where melt rates are low. During this particular field experiment, models overestimated runoff by +21 to +58%, linked to overestimated surface ablation and possible meltwater retention in bare, porous, low-density ice. Direct measurements of ice surface runoff will improve climate/SMB models, and incorporating remotely sensed IDCs will aid coupling of SMB with ice dynamics and subglacial systemspublishersversionPeer reviewe

Assessment of the growth in social groups for sustainable agriculture and land management

Non-technical summary Until the past half-century, all agriculture and land management was framed by local institutions strong in social capital. But neoliberal forms of development came to undermine existing structures, thus reducing sustainability and equity. The past 20 years, though, have seen the deliberate establishment of more than 8 million new social groups across the world. This restructuring and growth of rural social capital within specific territories is leading to increased productivity of agricultural and land management systems, with particular benefits for those previously excluded. Further growth would occur with more national and regional policy support. Technical summary For agriculture and land management to improve natural capital over whole landscapes, social cooperation has long been required. The political economy of the later twentieth and early twenty-first centuries prioritized unfettered individual action over the collective, and many rural institutions were harmed or destroyed. Since then, a wide range of social movements, networks and federations have emerged to support transitions towards sustainability and equity. Here, we focus on social capital manifested as intentionally formed collaborative groups within specific geographic territories. These groups focus on: (1) integrated pest management; (2) forests; (3) land; (4) water; (5) pastures; (6) support services; (7) innovation platforms; and (8) small-scale systems. We show across 122 initiatives in 55 countries that the number of groups has grown from 0.50 million (in 2000) to 8.54 million (in 2020). The area of land transformed by the 170–255 million group members is 300 Mha, mostly in less-developed countries (98% groups; 94% area). Farmers and land managers working with scientists and extensionists in these groups have improved both environmental outcomes and agricultural productivity. In some cases, changes to national or regional policy supported this growth in groups. Together with other movements, these social groups could now support further transitions towards policies and behaviours for global sustainability. Social media summary Millions of geographically based new social groups are leading to more sustainable agriculture and forestry worldwide. © The Author(s), 2020

PORTEC-4a: International randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer

Background Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with highintermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients’ risk of recurrence based on molecular tumor characteristics. Primary objectives To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecularintegrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy Study hypothesis Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant t

A high resolution record of Greenland mass balance

We map recent Greenland Ice Sheet elevation change at high spatial (5-km) and temporal (monthly) resolution using CryoSat-2 altimetry. After correcting for the impact of changing snowpack properties associated with unprecedented surface melting in 2012, we find good agreement (3 cm/yr bias) with airborne measurements. With the aid of regional climate and firn modelling, we compute high spatial and temporal resolution records of Greenland mass evolution, which correlate (R=0.96) with monthly satellite gravimetry, and reveal glacier dynamic imbalance. During 2011-2014, Greenland mass loss averaged 269±51 Gt/yr. Atmospherically-driven losses were widespread, with surface melt variability driving large fluctuations in the annual mass deficit. Terminus regions of five dynamically-thinning glaciers, which constitute less than 1% of Greenland's area, contributed more than 12% of the net ice loss. This high-resolution record demonstrates that mass deficits extending over small spatial and temporal scales have made a relatively large contribution to recent ice sheet imbalance

Mass balance of the Greenland Ice Sheet from 1992 to 2018

In recent decades, the Greenland Ice Sheet has been a major contributor to global sea-level rise1,2, and it is expected to be so in the future3. Although increases in glacier flow4–6 and surface melting7–9 have been driven by oceanic10–12 and atmospheric13,14 warming, the degree and trajectory of today’s imbalance remain uncertain. Here we compare and combine 26 individual satellite measurements of changes in the ice sheet’s volume, flow and gravitational potential to produce a reconciled estimate of its mass balance. Although the ice sheet was close to a state of balance in the 1990s, annual losses have risen since then, peaking at 335 ± 62 billion tonnes per year in 2011. In all, Greenland lost 3,800 ± 339 billion tonnes of ice between 1992 and 2018, causing the mean sea level to rise by 10.6 ± 0.9 millimetres. Using three regional climate models, we show that reduced surface mass balance has driven 1,971 ± 555 billion tonnes (52%) of the ice loss owing to increased meltwater runoff. The remaining 1,827 ± 538 billion tonnes (48%) of ice loss was due to increased glacier discharge, which rose from 41 ± 37 billion tonnes per year in the 1990s to 87 ± 25 billion tonnes per year since then. Between 2013 and 2017, the total rate of ice loss slowed to 217 ± 32 billion tonnes per year, on average, as atmospheric circulation favoured cooler conditions15 and as ocean temperatures fell at the terminus of Jakobshavn Isbræ16. Cumulative ice losses from Greenland as a whole have been close to the IPCC’s predicted rates for their high-end climate warming scenario17, which forecast an additional 50 to 120 millimetres of global sea-level rise by 2100 when compared to their central estimate