The Federal Sentencing Guidelines for Corporations: Their Development, Theoretical Underpinnings, and Some Thoughts About Their Future

This Article traces the Sentencing Commission\u27s path in completing that task32 and considers what work lies ahead. The Article addresses four specific questions: (1) Given that the Commission\u27s primary mandate is to facilitate greater certainty, uniformity, effectiveness and rationality in the sentencing of individuals, why did the Commission tackle the area of corporate sentencing at all? (2) How did the Commission arrive at the philosophical bases that underlie the fine provisions of the corporate sentencing guidelines? (3) How did the principles of deterrence and just punishment for the offense shape the Commission\u27s decisionmaking with respect to the key structural issues involved in creating the corporate fine guidelines, and what other factors played a role in the construction of these guidelines? and (4) Are the corporate Sentencing Guidelines cast in stone, or can organizations and attorneys expect changes in the future

The Federal Sentencing Guidelines for Corporations: Their Development, Theoretical Underpinnings, and Some Thoughts About Their Future

This Article traces the Sentencing Commission\u27s path in completing that task32 and considers what work lies ahead. The Article addresses four specific questions: (1) Given that the Commission\u27s primary mandate is to facilitate greater certainty, uniformity, effectiveness and rationality in the sentencing of individuals, why did the Commission tackle the area of corporate sentencing at all? (2) How did the Commission arrive at the philosophical bases that underlie the fine provisions of the corporate sentencing guidelines? (3) How did the principles of deterrence and just punishment for the offense shape the Commission\u27s decisionmaking with respect to the key structural issues involved in creating the corporate fine guidelines, and what other factors played a role in the construction of these guidelines? and (4) Are the corporate Sentencing Guidelines cast in stone, or can organizations and attorneys expect changes in the future

Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA)

Background: Patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.<p></p> Objectives: To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide.<p></p> Methods Study design: international, cross-sectional. Patients: consecutive RA patients. Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).<p></p> Results: Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)–erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.<p></p> Conclusions: Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.<p></p&gt

Application of a stochastic modeling to evaluate tuberculosis onset in patients treated with tumor necrosis factor inhibitors

In this manuscript we apply stochastic modeling to investigate the risk of reactivation of latent mycobacterial infections in patients undergoing treatment with tumor necrosis factor inhibitors. First, we review the perspective proposed by one of the authors in a previous work and which consists in predicting the occurrence of reactivation of latent tuberculosis infection or newly acquired tuberculosis during treatment; this is based on variational procedures on a simple set of parameters (e.g. rate of reactivation of a latent infection). Then, we develop a full analytical study of this approach through a Markov chain analysis and we find an exact solution for the temporal evolution of the number of cases of tuberculosis infection (re)activation. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excellent agreement. The generality of this theoretical framework allows to investigate also the case of non-tuberculous mycobacteria infections; in particular, we show that reactivation in that context plays a minor role. This may suggest that, while the screening for tuberculous is necessary prior to initiating biologics, when considering non-tuberculous mycobacteria only a watchful monitoring during the treatment is recommended. The framework outlined in this paper is quite general and could be extremely promising in further researches on drug-related adverse events.Comment: 26 pages, 7 figure

Inhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases

Treatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFN gamma were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS