Obesity and Breast Cancer: Interaction or Interference with the Response to Therapy?

Background: Aromatase inhibitors (AI) are widely used for treating hormone-sensitive breast cancer (BC). Obesity, however, due to aromatase-mediated androgen conversion into estradiol in the peripheral adipose tissue, might impair AI inhibitory capacity. We aimed at identifying a cut-off of body mass index (BMI) with significant prognostic impact, in a cohort of stage I-II BC patients on systemic adjuvant therapy with AI. Methods: we retrospectively evaluated routinely collected baseline parameters. The optimal BMI cut-off affecting disease-free survival (DFS) in AI-treated BC patients was identified through maximally selected rank statistics; non-linear association between BMI and DFS in the AI cohort was assessed by hazard-ratio-smoothed curve analysis using BMI as continuous variable. The impact of the BMI cut-off on survival outcomes was estimated through Kaplan-Meier plots, with log-rank test and hazard ratio estimation comparing patient subgroups. Results: A total of 319 BC patients under adjuvant endocrine therapy and/or adjuvant chemotherapy were included. Curve-fitting analysis showed that for a BMI cut-off >29 in AI-treated BC patients (n = 172), DFS was increasingly deteriorating and that the impact of BMI on 2-year DFS identified a cut-off specific only for the cohort of postmenopausal BC patients under adjuvant therapy with AI. Conclusion: in radically resected hormone-sensitive BC patients undergoing neoadjuvant or adjuvant chemotherapy and treated with AI, obesity represents a risk factor for recurrence, with a significantly reduced 2-year DFS

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 x 10(-5)) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 x 10(-8)). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 x 10(-9)). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression

Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease

BACKGROUND: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. METHODS: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. RESULTS: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.013 and 0.015 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p=0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p=0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. CONCLUSIONS: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function

Comparison Wage in Trade Union Decision Making

The starting point of this paper is the idea that trade unions and individual workers pay attention to wage settlements in similar sectors of the economy. The foundations of this concept can be found in other social sciences and also in the literature of psychological economics. However, it has not received much attention in connection to union decision making. This comparison or reference wage enters the decision making of the union (i.e. the union utility function). In this paper, we employ a union utility function which incorporates this concept. The analysis is conducted in a bargaining framework and the results show the effects on the optimal wage of important variables like comparison wage, unemployment benefit, union power and of the weight that the union places on the comparison wag

Effects of opiates on blood rheology

To evaluate the possible effect of opiates on blood rheology, the plasma fibrinogen, prothrombin time and leukocyte aggregation were measured in 75 heroin addicts categorized by the time of abstention from heroin and the administration of naltrexone (25 active heroin abusers, 25 abstaining for 1 week, 11 abstaining for at least 5 months and 14 abstaining for 1 month and taking naltrexone during this period). No difference was detected in prothrombin time, but the leukocyte aggregation and fibrinogen were significantly different among the four groups (p = 0.028 and p = 0.0001, respectively). In particular, fibrinogen was 318 +/- 10.9 mg/dL in heroin abusers, significantly higher than that of the remaining three groups; the percentage of aggregated leukocytes was 5.01 +/- 0.77 in heroin users, significantly higher than that of subjects abstaining for at least 5 months. The fibrinogen levels declined sharply with abstention and an additive effect was noted with the administration of naltrexone, but leukocyte aggregation changed more slowly, and the effect of naltrexone (if any) was weaker. These data indicate an adverse effect of opiates on blood rheology and suggest that further studies should be performed to evaluate whether naltrexone may be useful in the prevention of major ischemic syndromes in patients with hyperfibrinogenemia and, perhaps, in those with high levels of leukocyte aggregation

Praticare l’islam ai tempi del Covid-19 La giurisprudenza del Consiglio Europeo per le Fatāwā e le Ricerche

Many countries have been forced to implement measures aimed at limiting the spread of Covid-19. These measures have also affected worshipping, especially with reference to those practices whose execution is linked to the community dimension (collective prayers, pilgrimage, feast for the end of fasting and that of sacrifice, funeral rites, etc.). In order to identify possible solutions to the problems deriving from the limits that the spread of Covid-19 has imposed on worshipping, Muslims have turned to their jurists (fuqahā᾿), who issued dozens of responses (fatāwā) to respond to the many and different requests. This contribution intends to analyse those that have been issued by the European Council for Fatwa and Research. Indeed, it held an extra session, in March and April 2020, and produced two collections of fatāwā and recommendations entitled, respectively, Juridical Developments Related to the Virus Corona Covid-19 and The Rules of Fasting and their Developments in Light of the Corona Covid-19. In addition to the presentation of the content of such responses, particularly those concerning collective prayers, the contribution is also aimed at discussing whether the solutions issued by the Council are compatible with the provisions adopted by the European governments to cope with the pandemic

Effects of opiates on blood rheology

To evaluate the possible effect of opiates on blood rheology, the plasma fibrinogen, prothrombin time and leukocyte aggregation were measured in 75 heroin addicts categorized by the time of abstention from heroin and the administration of naltrexone (25 active heroin abusers, 25 abstaining for 1 week, 11 abstaining for at least 5 months and 14 abstaining for 1 month and taking naltrexone during this period). No difference was detected in prothrombin time, but the leukocyte aggregation and fibrinogen were significantly different among the four groups (p = 0.028 and p = 0.0001, respectively). In particular, fibrinogen was 318 +/- 10.9 mg/dL in heroin abusers, significantly higher than that of the remaining three groups; the percentage of aggregated leukocytes was 5.01 +/- 0.77 in heroin users, significantly higher than that of subjects abstaining for at least 5 months. The fibrinogen levels declined sharply with abstention and an additive effect was noted with the administration of naltrexone, but leukocyte aggregation changed more slowly, and the effect of naltrexone (if any) was weaker. These data indicate an adverse effect of opiates on blood rheology and suggest that further studies should be performed to evaluate whether naltrexone may be useful in the prevention of major ischemic syndromes in patients with hyperfibrinogenemia and, perhaps, in those with high levels of leukocyte aggregation