Breathlessness that persists despite treatment for the underlying conditions is debilitating. Identifying this discrete entity as a clinical syndrome should raise awareness amongst patients, ...clinicians, service providers, researchers and research funders.Using the Delphi method, questions and statements were generated
expert group consultations and one-to-one interviews (n=17). These were subsequently circulated in three survey rounds (n=34, n=25, n=31) to an extended international group from various settings (clinical and laboratory; hospital, hospice and community) and working within the basic sciences and clinical specialties. The
target agreement for each question was 70%. Findings were discussed at a multinational workshop.The agreed term, chronic breathlessness syndrome, was defined as breathlessness that persists despite optimal treatment of the underlying pathophysiology and that results in disability. A stated duration was not needed for "chronic". Key terms for French and German translation were also discussed and the need for further consensus recognised, especially with regard to cultural and linguistic interpretation.We propose criteria for chronic breathlessness syndrome. Recognition is an important first step to address the therapeutic nihilism that has pervaded this neglected symptom and could empower patients and caregivers, improve clinical care, focus research, and encourage wider uptake of available and emerging evidence-based interventions.
The development of efficient catalytic systems for direct aromatic C–H bond functionalization is a long-desired goal of chemists, because these protocols provide environmental friendly and ...waste-reducing alternatives to classical methodologies for C–C and C–heteroatom bond formation. A key challenge for these transformations is the reoxidation of the in situ generated metal hydride or low-valent metal complexes of the primary catalytic bond forming cycle. To complete the catalytic cycle and to regenerate the C–H activation catalyst, (super)stoichiometric amounts of Cu(II) or Ag(I) salts have often been applied. Recently, “greener” approaches have been developed by applying molecular oxygen in combination with Cu(II) salts, internal oxidants that are cleaved during the reaction, or solvents or additives enabling the metal hydride reoxidation. All these approaches improved the environmental friendliness but have not overcome the obstacles associated with the overall limited functional group and substrate tolerance. Hence, catalytic processes that do not feature the unfavorable aspects described above and provide products in a streamlined as well as economically and ecologically advantageous manner would be desirable. In this context, we decided to examine visible light photoredox catalysis as a new alternative to conventionally applied regeneration/oxidation procedures. This Account summarizes our recent advances in this expanding area and will highlight the new concept of merging distinct redox catalytic processes for C–H functionalizations through the application of visible light photoredox catalysis. Photoredox catalysis can be considered as catalytic electron-donating or -accepting processes, making use of visible-light absorbing homogeneous and heterogeneous metal-based catalysts, as well as organic dye sensitizers or polymers. As a consequence, photoredox catalysis is, in principle, an ideal tool for the recycling of any given metal catalyst via a coupled electron transfer (ET) process. Here we describe our first successful endeavors to address the above challenges by combining visible light photoredox catalysis with different ruthenium, rhodium, or palladium catalyzed C–H activations. Since only small amounts of the oxidant are generated and are immediately consumed in these transformations, side reactions of substrates or products can be avoided. Thus, usually oxidant-sensible substrates can be used, which makes these methods highly suitable for complex molecular structure syntheses. Moreover, mechanistic studies shed light on new reaction pathways, intermediates, and in situ generated species. The successful development of our dual catalysis concept, consisting of combined visible light photoredox catalysis and metal catalyzed C–H functionalization, provides many new opportunities for further explorations in the field of C–H functionalization.
Dapagliflozin in Patients with Chronic Kidney Disease Heerspink, Hiddo J.L; Stefánsson, Bergur V; Correa-Rotter, Ricardo ...
The New England journal of medicine,
10/2020, Letnik:
383, Številka:
15
Journal Article
Recenzirano
Odprti dostop
In this trial, patients with CKD (with or without type 2 diabetes) were randomly assigned to receive dapagliflozin or placebo. The primary composite outcome — a sustained decline in the estimated GFR ...of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes — was less frequent with dapagliflozin.
Chronic breathlessness is a dominating symptom that restricts daily life for many people with cardiorespiratory disease 1. Different dimensions of the symptom, such as the intensity, sensory ...qualities and emotional responses, can be assessed using the instruments Dyspnea-12 (D-12) 2 and the Multidimensional Dyspnea Profile (MDP) 3, which share similarities in the underlying constructs of what is measured 4 and have emerged as widely used instruments for multi-dimensional measurement of breathlessness
Objective To evaluate the safety of benzodiazepines and opioids in patients with very severe chronic obstructive pulmonary disease (COPD).Design Population based longitudinal consecutive cohort ...study.Setting Centres prescribing long term oxygen therapy in Sweden.Patients 2249 patients starting long term oxygen therapy for COPD in Sweden between 2005 and 2009 in the national Swedevox Register.Main outcome measures Effects of benzodiazepines and opioids on rates of admission to hospital and mortality, adjusted for age, sex, arterial blood gases, body mass index (BMI), performance status, previous admissions, comorbidities, and concurrent drugs.Results 1681 (76%) patients were admitted to hospital, and 1129 (50%) died under observation. No patient was lost to follow-up. Benzodiazepines and opioids were not associated with increased admission: hazard ratio 0.98 (95% confidence interval, 0.87 to 1.10) and 0.98 (0.86 to 1.10), respectively. Benzodiazepines were associated with increased mortality (1.21, 1.05 to 1.39) with a dose response trend. Opioids also had a dose response relation with mortality: lower dose opioids (≤30 mg oral morphine equivalents a day) were not associated with increased mortality (1.03, 0.84 to 1.26) in contrast with higher dose opioids (1.21, 1.02 to 1.44). Concurrent benzodiazepines and opioids in lower doses were not associated with increased admissions (0.86, 0.53 to 1.42) or mortality (1.25, 0.78 to 1.99). Associations were not modified by being naive to the drugs or by hypercapnia.Conclusions Lower dose opioids are not associated with increased admissions or deaths in patients with COPD and might be safe for symptom reduction in severe respiratory disease.
Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from breathlessness, deconditioning, and reduced health-related quality of life (HRQL) despite best medical management. ...Opioids may relieve breathlessness at rest and on exertion in COPD.
We aimed to estimate the efficacy and safety of opioids on refractory breathlessness, exercise capacity, and HRQL in COPD.
This was a systematic review and metaanalysis using Cochrane methodology. We searched Cochrane Central Register of Controlled Trials, MEDLINE, and Embase up to 8 September, 2014 for randomized, double-blind, placebo-controlled trials of any opioid for breathlessness, exercise capacity, or HRQL that included at least one participant with COPD. Effects were analyzed as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random effect models.
A total of 16 studies (15 crossover trials and 1 parallel-group study, 271 participants, 95% with severe COPD) were included. There were no serious adverse effects. Breathlessness was reduced by opioids overall: SMD, -0.35 (95% CI, -0.53 to -0.17; I(2), 48.9%), by systemic opioids (eight studies, 118 participants): SMD, -0.34 (95% CI, -0.58 to -0.10; I(2), 0%), and less consistently by nebulized opioids (four studies, 82 participants): SMD, -0.39 (95% CI, -0.71 to -0.07; I(2), 78.9%). The quality of evidence was moderate for systemic opioids and low for nebulized opioids on breathlessness. Opioids did not affect exercise capacity (13 studies, 149 participants): SMD, 0.06 (95% CI, -0.15 to 0.28; I(2), 70.7%). HRQL could not be analyzed. Findings were robust in sensitivity analyses. Risk of study bias was low or unclear.
Opioids improved breathlessness but not exercise capacity in severe COPD.
The direct arylation of heteroaromatics with an easily accessible and recyclable, heterogeneous TiO2 catalyst and visible light was developed. Electron-rich as well as electron-poor heteroarenes ...could be applied in this transformation, and the corresponding products were isolated in very good yields. Azoethers were detected as reactive intermediates, and the unexpected role of TiO2 in their formation as well as reaction was established.
The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose co-transporter 2 (SGLT2) inhibitor ...dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials.
In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol).
Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR).
Participants with a wide range of underlying kidney diseases receiving renin-angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2-4 and increased albuminuria, with and without T2D.
Chronic breathlessness has devastating consequences. The minimal clinically important difference (MCID) for current intensity has been estimated as 9 mm on a 100-mm visual analogue scale (VAS). We ...aimed to determine MCIDs for commonly used dimensions and recall periods: the current unpleasantness and current, average, best and worst intensity of the past 24 h for chronic breathlessness.
This was a secondary analysis of a randomised controlled trial of morphine
placebo over 7 days in people with chronic breathlessness from severe disease. The breathlessness scores were self-reported using a diary each evening on 100-mm VAS. The MCID for improvement in each score was estimated using anchor-based and distribution-based methods.
283 participants (mean age 74.2 years; 63% male; 58% COPD; 87.0% modified Medical Research Council (mMRC) score 3-4) were included. Anchor-based MCIDs for breathlessness scores ranged from -13.9 mm to -9.5 mm. The MCIDs were similar when using different anchors and across all participants, and participants with more severe breathlessness (mMRC 3-4). Distribution-based effect sizes were classed as small (-4.7-6.3 mm), moderate (-9.4-12.5 mm) and large (-15.0-20.0 mm) effect. Sample sizes for trials using the different scores were proposed. MCIDs of absolute change were more stable than using relative change from baseline.
An improvement of ∼10 mm on a 100-mm VAS is likely to be clinically meaningful across commonly used measures of chronic breathlessness (current intensity, unpleasantness, and average, best and worst intensity over the past 24 h) to evaluate clinical benefit and effects in therapeutic trials.
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