Acceptability and accuracy of patient-reported outcome measures (PROMs) for surveillance of breathlessness in routine lung cancer care: A mixed-method study.

BACKGROUND: Breathlessness in lung cancer negatively impacts on quality of life but often goes undetected and undertreated in clinical practice. There is a need for routine surveillance for early identification and proactive management of breathlessness using patient reported outcome measures (PROMs) in clinical care but it is unclear what PROMs should be used or are accurate for use in routine care. METHODS: We used mixed-methods (quantitative surveys and qualitative interviews) to examine the predictors of breathlessness in 339 lung cancer participants and acceptability of PROMs. In addition to multivariate analysis to examine predictors of dyspnea, participants completed an acceptability survey and themes were derived for the qualitative data (n = 26) to explore patient experience of PROMs. We also tested the accuracy of PROMs using a Receiver Operating Characteristic and Area Under the Curve analysis. RESULTS: A total of 339 patients completed the breathlessness PROMs and acceptability survey and 26 patients participated in an in-depth interview to investigate their experiences of breathlessness and its PROMs. Prevalence of breathlessness was 51.9 % (n = 176) and 70.5 % of patients preferred the Medical Research Council (MRC) scale followed by the Breathlessness Intensity (BI) scale (63.7 %) among the five measures for breathlessness- Modified Borg Scale (MBS), Cancer Dyspnea Scale (CDS), MRC, BI, and Breathlessness Distress (BD). The finding showed wide variation in the MRC grades across the BI rating even among patients with the same BI score. AUC scores for the Borg scale was 0.71 (using MRC cut-off score of < 2), for CDS, 0.72, for BD, 0.70, and for BI 0.79. For an MRC score of 2, the Borg score cut-off was 0.8 (optimal sensitivity, 50 %; specificity, 93.3 %); the cut-off score of CDS, BD, BI score was 1.4 (optimal sensitivity, 67.1 %; specificity, 70 %), 1.5 (optimal sensitivity, 57.5 %; specificity, 73.3 %), and 1.5 (optimal sensitivity, 72.6 %; specificity, 83.3 %) respectively. AUC by ROC analysis for breathlessness and modest concordance among five PROMs showed important gaps between the individuals' experience and PROMs data. Three main themes from qualitative data included 1) Making sense of symptom reporting, 2) Valuing the reported data, 3) Managing the symptom of breathlessness. CONCLUSION: This study examined measurement of breathlessness using PROMs for routine clinical care and showed that severity measures alone do not accurately detect this symptomnor the experiential dimensions of breathlessness that are critical to guide appropriate intervention.

Ablating the Rab-GTPase activating protein TBC1D1 predisposes rats to high-fat diet-induced cardiomyopathy.

KEY POINTS: Although the role of TBC1D1 within the heart remains unknown, expression of TBC1D1 increases in the left ventricle following an acute infarction, suggesting a biological importance within this tissue. We investigated the mechanistic role of TBC1D1 within the heart, aiming to establish the consequences of attenuating TBC1D1 signalling in the development of diabetic cardiomyopathy, as well as to determine potential sex differences. TBC1D1 ablation increased plasma membrane fatty acid binding protein content and myocardial palmitate oxidation. Following high-fat feeding, TBC1D1 ablation dramatically increased fibrosis and induced end-diastolic dysfunction in both male and female rats in the absence of changes in mitochondrial bioenergetics. Altogether, independent of sex, ablating TBC1D1 predisposes the left ventricle to pathological remodelling following high-fat feeding, and suggests TBC1D1 protects against diabetic cardiomyopathy. ABSTRACT: TBC1D1, a Rab-GTPase activating protein, is involved in the regulation of glucose handling and substrate metabolism within skeletal muscle, and is essential for maintaining pancreatic ß-cell mass and insulin secretion. However, the function of TBC1D1 within the heart is largely unknown. Therefore, we examined the role of TBC1D1 in the left ventricle and the functional consequence of ablating TBC1D1 on the susceptibility to high-fat diet-induced abnormalities. Since mutations within TBC1D1 (R125W) display stronger associations with clinical parameters in women, we further examined possible sex differences in the predisposition to diabetic cardiomyopathy. In control-fed animals, TBC1D1 ablation did not alter insulin-stimulated glucose uptake, or echocardiogram parameters, but increased accumulation of a plasma membrane fatty acid transporter and the capacity for palmitate oxidation. When challenged with an 8 week high-fat diet, TBC1D1 knockout rats displayed a four-fold increase in fibrosis compared to wild-type animals, and this was associated with diastolic dysfunction, suggesting a predisposition to diet-induced cardiomyopathy. Interestingly, high-fat feeding only induced cardiac hypertrophy in male TBC1D1 knockout animals, implicating a possible sex difference. Mitochondrial respiratory capacity and substrate sensitivity to pyruvate and ADP were not altered by diet or TBC1D1 ablation, nor were markers of oxidative stress, or indices of overt heart failure. Altogether, independent of sex, ablation of TBC1D1 not only increased the susceptibility to high-fat diet-induced diastolic dysfunction and left ventricular fibrosis, independent of sex, but also predisposed male animals to the development of cardiac hypertrophy. These data suggest that TBC1D1 may exert cardioprotective effects in the development of diabetic cardiomyopathy.