The GLAS editing procedures for the FGGE level II-B data collected during SOP-1 and 2

The modifications made to the FGGE Level II-b data are discussed and the FORTRAN program developed to perform the modifications is described. It is suggested that the edited database is the most accurate one available for FGGE SOP-1 and 2

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC—Real World Efficacy

SIMPLE SUMMARY: The expected change in overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) after the clinical implementation of immune checkpoint inhibitor therapy (ICI) has not been substantially investigated in large real-world cohorts outside randomized controlled trials (RCTs). In this nationwide study, we compared OS before and after the implementation of ICI and found that 3-year OS tripled from 6% to 18%. Patients receiving ICI had a lower OS than demonstrated in RCTs, except for patients with performance status (PS) 0. More than a fifth of the patients progressed early within the first six ICI cycles. Adverse prognostic factors were PS ≥ 1 and metastases to the bone and liver. ABSTRACT: Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6–20.0) and 6% (95% CI 5.1–7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis

Psychology as a natural science in the eighteenth century

Psychology considered as a natural science began as Aristotelian "physics" or "natural philosophy" of the soul. C. Wolff placed psychology under metaphysics, coordinate with cosmology. Scottish thinkers placed it within moral philosophy, but distinguished its "physical" laws from properly moral laws (for guiding conduct). Several Germans sought to establish an autonomous empirical psychology as a branch of natural science. British and French visual theorists developed mathematically precise theories of size and distance perception; they created instruments to test these theories and to measure visual phenomena such as the duration of visual impressions. These investigators typically were dualists who included mental phenomena within nature

The placebo effect and its determinants in fibromyalgia: meta-analysis of randomized controlled trials

The aims of this study were to determine whether placebo treatment in randomised controlled trials (RCTs) is effective for fibromyalgia and to identify possible determinants of the magnitude of any such placebo effect. A systematic literature search was undertaken for RCTs in people with fibromyalgia that included a placebo and/or a no-treatment (observation only or waiting list) control group. Placebo effect size (ES) for pain and other outcomes was measured as the improvement of each outcome from baseline divided by the standard deviation of the change from baseline. This effect was compared with changes in the no-treatment control groups. Meta-analysis was undertaken to combine data from different studies. Subgroup analysis was conducted to identify possible determinants of the placebo ES. A total of 3912 studies were identified from the literature search. After scrutiny, 229 trials met the inclusion criteria. Participants who received placebo in the RCTs experienced significantly better improvements in pain, fatigue, sleep quality, physical function, and other main outcomes than those receiving no treatment. The ES of placebo for pain relief was clinically moderate (0.53, 95%CI 0.48 to 0.57). The ES increased with increasing strength of the active treatment, increasing participant age and higher baseline pain severity, but decreased in RCTS with more women and with longer duration of fibromyalgia. In addition, placebo treatment in RCTs is effective in fibromyalgia. A number of factors (expected strength of treatment, age, gender, disease duration) appear to influence the magnitude of the placebo effect in this condition

Fitness efficacy of vibratory exercise compared to walking in postmenopausal women

In this study, we compared the efficacy of 8 months of low-frequency vibration and a walk-based program in health-related fitness. Twenty-seven postmenopausal women were randomly assigned into two groups: whole-body vibration (WBV) group (n = 18) performed three times/week a static exercise on a vibration platform (6 sets of 1-min with 1 min of rest, with a 12.6 Hz of frequency and an amplitude of 3 mm); walk-based program (WP) group (n = 18) performed three times/week a 60-min of walk activity at 70-75% of maximal heart rate. A health-related battery of tests was applied. Maximal unilateral concentric and eccentric isokinetic torque of the knee extensors was recorded by an isokinetic dynamometer. Physical fitness was measured using the following tests: vertical jump test, chair rise test and maximal walking speed test over 4 m. Maximal unilateral isokinetic strength was measured in the knee extensors in concentric actions at 60 and 300 degrees /s, and eccentric action at 60 degrees /s. After 8 months, the WP improved the time spent to walk 4 m (20%) and to perform the chair rise test (12%) compared to the WBV group (P = 0.006, 0.002, respectively). In contrast, the comparison of the changes in vertical jump showed the higher effectiveness of the vibratory exercise in 7% (P = 0.025). None of exercise programs showed change on isokinetic measurements. These results indicate that both programs differed in the main achievements and could be complementary to prevent lower limbs muscle strength decrease as we age [ISRCTN76235671]

Interleukin 15 Levels in Serum May Predict a Severe Disease Course in Patients with Early Arthritis

Background: Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA). Methodology and Results: Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient [95% confidence interval]: 0.12 [0.06-0.18]; p&0.001) or ACPA (0.34 [0.01-0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007). Conclusions: Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatmentThe work of Belen Díaz-Sánchez was supported by the RETICS Programme (Programa de Redes Temáticas de Investigación Colaborativa [Colaborative Research Thematic Network Programme]; RD08/0075 - RIER [Red de Inflamación y Enfermedades Reumáticas; Inflammation and Rheumatic Diseases Network]) from the Instituto de Salud Carlos III, Spain (URL: www.isciii.es) within the VI National Plan for I+D+I 2008–2011 (FEDER). The work of Isidoro González-Álvaro was in part supported by a grant for the Intensification of the Research Tasks in the National Health Care System from Instituto de Salud Carlos III, Spain. The consumables for measurements and data analysis were supported by a Fondo de Investigación Sanitaria grant (08/0754) from the Instituto de Salud Carlos II

Carnap’s Aufbau in the Weimar Context

Quine’s classical classic interpretation succinctly characterized characterizes Carnap’s Aufbau as an attempt “to account for the external world as a logical construct of sense-data....” Consequently, “Russell” was characterized as the most important influence on the Aufbau. Those times have passed. Formulating a comprehensive and balanced interpretation of the Aufbau has turned out to be a difficult task and one that must take into account several disjointed sources. My thesis is that the core of the Aufbau rested on a problem that had haunted German philosophy since the end of the 19th century. In terms fashionable at the time, this problem may be expressed as the polarity between Leben and Geist that characterized German philosophy during the years of the Weimar Republic. At that time, many philosophers, including Cassirer, Rickert and Vaihinger, were engaged in overcoming this polarity. As I will show, Carnap’s Aufbau joined the ranks of these projects. This suggests that Lebensphilosophie and Rickert’s System der Philosophie exerted a strong influence on Carnap’s projects, an influence that is particularly conspicuous in his unpublished manuscript Vom Chaos zur Wirklichkeit. Carnap himself asserted that this manuscript could be considered “the germ of the constitution theory” of the Aufbau. Reading Chaos also reveals another strong but neglected influence on the Aufbau, namely a specific version of neutral monism put forward by the philosopher and psychologist Theodor Ziehen before World War I. Ziehen’s work contributed much to the invention of the constitutional method of quasi-analysis. -/