Platelets are critical to arterial thrombosis, which underlies myocardial infarction and stroke. Activated platelets, regardless of the nature of their stimulus, initiate energy-intensive processes that sustain thrombus, while adapting to potential adversities of hypoxia and nutrient deprivation within the densely packed thrombotic milieu. We report here that stimulated platelets switch their energy metabolism to aerobic glycolysis by modulating enzymes at key checkpoints in glucose metabolism. We found that aerobic glycolysis, in turn, accelerates flux through the pentose phosphate pathway and supports platelet activation. Hence, reversing metabolic adaptations of platelets could be an effective alternative to conventional anti-platelet approaches, which are crippled by remarkable redundancy in platelet agonists and ensuing signaling pathways. In support of this hypothesis, small-molecule modulators of pyruvate dehydrogenase, pyruvate kinase M2 and glucose-6-phosphate dehydrogenase, all of which impede aerobic glycolysis and/or the pentose phosphate pathway, restrained the agonist-induced platelet responses ex vivo . These drugs, which include the anti-neoplastic candidate, dichloroacetate, and the Food and Drug Administration-approved dehydroepiandrosterone, profoundly impaired thrombosis in mice, thereby exhibiting potential as anti-thrombotic agents.
Quality of life (QOL) of patients affected by various diseases is now recognized as an important outcome variable. Consenting patients with rheumatoid arthritis (American College of Rheumatology criteria) were included in the study. Quality of life was assessed using the World Health Organization Quality of Life assessment, short form (WHOQOL-BREF). Disease activity was assessed by the Disease Activity Score (DAS28) for 3 variables and functional disability by the Health Assessment Questionnaire (HAQ). Extra-articular manifestations (ExRA) were diagnosed clinically. Seventy-five age-matched normal controls and 136 patients (19 males) were included. The mean duration of rheumatoid arthritis (RA) was 9 +/- 5.8 years. The mean DAS28 and HAQ were 4.43 +/- 1.4 and 0.97 +/- 1.6, respectively. At least one ExRA was present in 30 (22.1%) patients. The WHOQOL scores were significantly lower in patients with RA compared to normal controls. Patients and normal controls scored highest in the social relationship domain. There was significant inverse correlation of HAQ with all four domains of WHOQOL. There was significant inverse correlation of DAS28 with the physical health and psychological domains. Patients with ExRA scored significantly lower in the physical health domain of WHOQOL. Multiple regression analysis showed only HAQ to independently affect QOL. Quality of life is compromised in patients with RA. Patients and normal controls scored higher in the social relationship domain. Functional disability is the most important factor affecting QOL in RA.
Background COVID‐19‐associated pulmonary aspergillosis (CAPA) has been widely reported but homogenous large cohort studies are needed to gain real‐world insights about the disease. Methods We collected clinical and laboratory data of 1161 patients hospitalised at our Institute from March 2020 to August 2021, defined their CAPA pathology, and analysed the data of CAPA/non‐CAPA and deceased/survived CAPA patients using univariable and multivariable models. Results The overall prevalence and mortality of CAPA in our homogenous cohort of 1161 patients were 6.4% and 47.3%, respectively. The mortality of CAPA was higher than that of non‐CAPA patients (hazard ratio: 1.8 [95% confidence interval: 1.1–2.8]). Diabetes (odds ratio [OR] 1.92 [1.15–3.21]); persistent fever (2.54 [1.17–5.53]); hemoptysis (7.91 [4.45–14.06]); and lung lesions of cavitation (8.78 [2.27–34.03]), consolidation (9.06 [2.03–40.39]), and nodules (8.26 [2.39–28.58]) were associated with development of CAPA by multivariable analysis. Acute respiratory distress syndrome (ARDS) (2.68 [1.09–6.55]), a high computed tomography score index (OR 1.18 [1.08–1.29]; p < .001), and pulse glucocorticoid treatment (HR 4.0 [1.3–9.2]) were associated with mortality of the disease. Whereas neutrophilic leukocytosis (development: 1.09 [1.03–1.15] and mortality: 1.17 [1.08–1.28]) and lymphopenia (development: 0.68 [0.51–0.91] and mortality: 0.40 [0.20–0.83]) were associated with the development as well as mortality of CAPA. Conclusion We observed a low but likely underestimated prevalence of CAPA in our study. CAPA is a disease with high mortality and diabetes is a significant factor for its development while ARDS and pulse glucocorticoid treatment are significant factors for its mortality. Cellular immune dysregulation may have a central role in CAPA from its development to mortality.
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