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Background: The objective of the FAVOR study was to evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus tiotropium on peak forced expiratory volume in 1 s (FEV1) and also to investigate patient satisfaction and treatment preference.
Methods: Patients with moderate-to-severe airflow limitation (FEV1/forced vital capacity ratio of <0.70), those with a COPD assessment test score of ≥10, and those who were maintained on tiotropium HandiHaler® therapy prior to enrollment were recruited for the study, and randomized (1:1) to receive either 4 weeks open-label IND/GLY (110/50 µg) once daily followed by 4 weeks of tiotropium (18 µg) once daily or vice versa. The primary endpoint was FEV1 1 h post-inhalation after 4 weeks of treatment. Other endpoints included patient’s and physician’s preference for treatment, patient’s satisfaction evaluated using a study-specific questionnaire and the abbreviated Treatment Satisfaction Questionnaire for Medication, and safety and tolerability.
Results: Eighty-seven out of 88 randomized patients completed the study and showed significantly higher FEV1 1 h post-inhalation after 4 weeks of treatment with IND/GLY versus tiotropium (treatment difference =0.081 L; p=0.0017). IND/GLY was preferred over tiotropium among the patients (69.4% versus 30.6%, p=0.0004) and the physicians (81.6% versus 18.4%, p<0.0001). A higher proportion of the patients stated they were very satisfied or satisfied with IND/GLY versus tiotropium with regard to dyspnea reduction (79.3% versus 58.0%, respectively) and reduction of dyspnea on exertion (72.4% versus 43.2%, respectively). Patients treated with IND/GLY showed significant improvement in Treatment Satisfaction Questionnaire for Medication domain scores versus tiotropium. IND/GLY demonstrated a good safety and tolerability profile.
Conclusion: This study indicated that, beyond FEV1, important patient-reported outcomes improved with the open-label dual bronchodilator IND/GLY when compared with tiotropium. This study suggests that individual patients felt the lung function benefits with IND/GLY compared with tiotropium, which, in turn, may also have contributed to the preference for IND/GLY.
Purpose: DINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 µg once-daily add-on therapy.
Patients and methods: Patients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point.
Results: Of 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P<0.001]). Changes in CAT total score from baseline to Month 6 indicated that the average clinical impact of COPD was reduced from a severe (score: 21–30) to a moderate (score: 11–20) impairment. In DACOTA, mean change in post-bronchodilator FEV1 was 202 mL (P<0.001). Diarrhea, nausea, and weight decrease were the most frequently reported adverse drug reactions.
Conclusion: In real-life clinical practice, roflumilast treatment as an add-on therapy is associated with clinically relevant improvements in health status and quality of life.
Introduction: DACCORD is an observational, non-interventional study being conducted in German primary and secondary care centres. The study aims to describe the impact of disease (including exacerbations) and treatments over 2 years on ‘real-life’ patients with chronic obstructive pulmonary disease (COPD).
Materials and methods: Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years and, on recruitment, were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and randomised clinical trial participation. Exacerbations data were collected every 3 months. COPD medication, COPD Assessment Test (CAT) and forced expiratory volume in 1 s (FEV1) were recorded at baseline and after 1 and 2 years.
Results: A total of 6122 patients were recruited, 3137 (51.2%) of whom completed the 2-year visit. The mean age of these patients was 65.6 years, 59% were male, 69% had mild or moderate airflow limitation, and their mean COPD Assessment Test (CAT) total score was 20.3. Overall, there was a trend towards decreasing COPD exacerbation rates over the 2-year follow-up period, with rates of 0.390 during Year 1 and 0.347 during Year 2. Rates were lower in patients with no exacerbation during the 6 months prior to entry (0.263 and 0.251 during Years 1 and 2, respectively), with 51.6% of patients having no exacerbation during the 6 months prior to entry and over the 2-year follow-up. Approximately 50% of the overall population experienced a clinically relevant improvement from baseline in CAT total score at Year 1 and 2. When assessed by treatment class (or classes), persistence to medication was high (77.8% in Year 1 and 71.4% in Year 2).
Conclusions: Overall, the 2-year follow-up data from DACCORD suggest that for most patients with COPD exacerbations are a rare event. For the majority of patients, the focus should be on managing symptoms, and the impact that these symptoms have on their daily lives. Even for those patients who do exacerbate, although prevention of exacerbations is an important factor, management of symptoms should be a key consideration. DACCORD also suggests that COPD disease progression is not inevitable – providing patients are receiving pharmacological treatment.
This paper aims at reconstructing the development and role of German neurology between 1840 and 1940. Therefore a couple of original sources as well as selected material form the scattered secondary literature were assessed and reviewed. Since the middle of the nineteenth century, an intricate process of separation from internal medicine and psychiatry gradually led to forming a self-conscious community of German neurologists. While Moritz Heinrich Romberg had constructed a cognitive basis for neurology, scientific founders such as Wilhelm Erb, Carl Wernicke, Alois Alzheimer, Hermann Oppenheim, Max Nonne, and many others established the new discipline within modern medicine. In 1891, the first generation of “pure” neurologists succeeded in founding the German Journal for Neurology (Deutsche Zeitschrift für Nervenheilkunde) followed by an autonomous professional organisation, the Society of German Neurologists (Gesellschaft Deutscher Nervenärzte) in 1907. A variety of external factors, however, hampered the institutional evolution and thus the implementation of chairs and departments remained quite modest. In 1935, only 2 years after the National Socialists had seized power, the regulatory merger with the psychiatristsʼ society caused the cautious attempts of German neurologists for autonomy to end in complete failure. The imprisonment, murder and expulsion of neuroscientists declared as Jewish or non-Aryan caused profound changes in neurology, medicine, academic life, and health care in general. Further historical research is needed to reconstruct in detail the involvement of German neurologists in racial-hygienic and eugenic research as well as the institutional and scientific development of German neurology after World War II.
Simple Summary: Cancer immunotherapy mainly targets immune system components, such as immune-suppressive networks generated by cancer cells in the tumor microenvironment (TME). Programmed cell death ligand 1, which is a secretory immune-suppressive factor, is released by tumor-associated macrophages (TAMs). The TME also disrupts production of tumor-specific T cells and generates immunosuppressive leukocytes, regulatory T cells, and myeloid-derived suppressor cells. Immune checkpoint inhibitors are effective in various cancers but only in a subset of patients. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are dysregulated in cancer through transcriptional, post-transcriptional, and epigenetic changes and have significant roles in cancer initiation and progression, which depends on deregulation of lncRNA expression. TAM function can be influenced by lncRNAs in various ways. However, our understanding of lncRNA dysregulation and function in cancer remains in the early stage.
Abstract: Ever since RNA sequencing of whole genomes and transcriptomes became available, numerous RNA transcripts without having the classic function of encoding proteins have been discovered. Long non-coding RNAs (lncRNAs) with a length greater than 200 nucleotides were considered as “junk” in the beginning, but it has increasingly become clear that lncRNAs have crucial roles in regulating a variety of cellular mechanisms and are often deregulated in several diseases, such as cancer. Lung cancer is the leading cause of cancer-related deaths and has a survival rate of less than 10%. Immune cells infiltrating the tumor microenvironment (TME) have been shown to have a great effect on tumor development with macrophages being the major cell type within the TME. Macrophages can inherit an inflammatory M1 or an anti-inflammatory M2 phenotype. Tumor-associated macrophages, which are predominantly polarized to M2, favor tumor growth, angiogenesis, and metastasis. In this review, we aimed to describe the complex roles and functions of lncRNAs in macrophages and their influence on lung cancer development and progression through the TME.
Background Fermentation of lignocellulosic biomass is an attractive alternative for the production of bioethanol. Traditionally, the yeast Saccharomyces cerevisiae is used in industrial ethanol fermentations. However, S. cerevisiae is naturally not able to ferment the pentose sugars D-xylose and L-arabinose, which are present in high amounts in lignocellulosic raw materials. Results We describe the engineering of laboratory and industrial S. cerevisiae strains to co-ferment the pentose sugars D-xylose and L-arabinose. Introduction of a fungal xylose and a bacterial arabinose pathway resulted in strains able to grow on both pentose sugars. Introduction of a xylose pathway into an arabinose-fermenting laboratory strain resulted in nearly complete conversion of arabinose into arabitol due to the L-arabinose reductase activity of the xylose reductase. The industrial strain displayed lower arabitol yield and increased ethanol yield from xylose and arabinose. Conclusion Our work demonstrates simultaneous co-utilization of xylose and arabinose in recombinant strains of S. cerevisiae. In addition, the co-utilization of arabinose together with xylose significantly reduced formation of the by-product xylitol, which contributed to improved ethanol production.
Formation of pathological anti-FVIII antibodies, or “inhibitors,” is the most serious complication of therapeutic FVIII infusions, affecting up to 1/3 of severe Hemophilia A (HA) patients. Inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development vs. immune tolerance, achieved with or without Immune Tolerance Induction (ITI) therapy, are not well-understood. To address these questions, temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) was carried out for HA subjects with and without a current or historic inhibitor using RNA-Seq. PBMCs were isolated from 40 subjects in the following groups: HA with an inhibitor that resolved either following ITI or spontaneously; HA with a current inhibitor; HA with no inhibitor history and non-HA controls. PBMCs were stimulated with 5 nM FVIII and RNA was isolated 4, 16, 24, and 48 h following stimulation. Time-series differential expression analysis was performed and distinct transcriptional signatures were identified for each group, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. Subjects with a current inhibitor showed differential expression of 56 genes and a clustering analysis identified three major temporal profiles. Interestingly, gene ontology enrichments featured innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A, and COLEC12. NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1β and TNFα, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. RNA-Seq results were validated by RT-qPCR, ELISAs, multiplex cytokine analysis, and flow cytometry. The inflammatory status of HA patients suffering from an ongoing inhibitor includes up-regulated innate immune modulators, which may act as ongoing danger signals that influence the responses to, and eventual outcomes of, ITI therapy.
Obesity is associated with an increased risk of heart failure. Little is known about the impact of dietary changes on the cardiac sequelae in obese patients. Twenty-one obese subjects underwent a 12-week low calorie fasting phase of a formula diet. Transthoracic two-dimensional speckle-tracking echocardiography was performed to obtain systolic left ventricular strain before and after weight loss. Body mass index decreased significantly from 38.6 ± 6.2 to 31.5 ± 5.3 kg/m(2), and the total percentage fat loss was 19%. Weight reduction was associated with a reduction in blood pressure and heart rate. Left ventricular longitudinal global peak systolic strain was in the lower normal range (-18.7 ± 3.2%) before weight loss and was unchanged (-18.8 ± 2.4%) after 12 weeks on diet with substantial weight loss. Also, no significant change in global radial strain after weight loss was noted (41.1 ± 22.0 versus 43.9 ± 23.3, p = 0.09). Left atrial and ventricular dimensions were in normal range before fasting and remained unchanged after weight loss. In our study obesity was associated with normal systolic left ventricular function. A 12-week low calorie diet with successful weight loss can reduce blood pressure and heart rate. Systolic left ventricular function and morphology were not affected by rapid weight reduction.
Background/objectives: Obesity is independently associated with left ventricular (LV) diastolic dysfunction and altered cardiac morphology. Morbidity and mortality in patients with diastolic dysfunction are similar to values observed in patients with systolic heart failure. We hypothesized that dysfunctional cardiac responses in people with obesity are reversible after weight loss. Thus, we studied the effect of dietary weight reduction on LV diastolic function as well as on cardiac structure using transthoracic echocardiography and tissue Doppler imaging (TDI).
Subjects/methods: Thirty-two subjects with obesity underwent a 12-week low-calorie fasting phase of a formula diet. Echocardiographic tissue Doppler indices of diastolic function and measurements of cardiac size were obtained prior to and after the fasting phase.
Results: A 12-week diet significantly reduced body mass index from 40.3 ± 6.6 kg/m 2 to 33.2 ± 6.1 kg/m 2 ( p < 0.01). Weight loss was associated with a significant reduction in blood pressure and heart rate. Echocardiography revealed diastolic dysfunction in subjects with obesity, which was improved by dieting. After weight loss, trans-mitral Doppler echocardiography showed a significant reduction in A-wave velocity, from 65.8 ± 19.2 cm/s to 57.0 ± 16.8 cm/s, and an increase in E/A ratio from 1.2 ± 0.4 to 1.4 ± 0.5 ( p < 0.01). TDI displayed a significantly lower a'-wave velocity (10.3 ± 2.3 cm/s and 8.9 ± 1.7 cm/s; p < 0.01). Left atrial and LV dimensions were normal and remained unchanged after weight loss.
Conclusion: Obesity is associated with diastolic dysfunction. A 12-week low-calorie diet with successful weight loss can reduce blood pressure and heart rate and partially normalize diastolic dysfunction.