Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases

Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed

Pair-Box (PAX8) protein-positive expression is associated with poor disease outcome in women with endometrial cancer

BACKGROUND: The Pax8 transcription factor genes have a role in cell differentiation and cell growth, and silencing of Pax8 in cell cultures results in cell death. The aims of this study were to determine the expression and correlation of Pax8 protein with several clinicopathological variables in patients with endometrial cancer. METHODS: The following clinical parameters from 229 patients were used for correlation with Pax8 expression; age, histological subtype, myometrial depth of invasion, lymphovascular invasion (LVI), the International Federation of Gynecology and Obstetrics grade, lymph nodes status, and disease status. RESULTS: A positive association of Pax8(+) expression was found with high tumour grade (P=0.002), LVI+(P=0.0186), and type II tumour subtype (P<0.0001) in univariate analysis. Survival analysis showed an association of Pax8 and 5-year overall survival probability (P=0.01486), 80.04% for patients with Pax8(−) and 55.59% for patients with Pax8(+). There was also an association of Pax8 and 5-year disease-free survival probability (P=0.02028), 72.12% for patients with Pax8(−) vs 49.88% for patients with Pax8(+). Finally, an association of Pax8(+) and shorter recurrence-free survival was also found (P=0.00203), with 74.36% for Pax8(−) and 52.11% for Pax8(+). CONCLUSION: Overexpression of Pax8 protein by endometrial cancer is associated with poor disease outcomes. Inhibition of Pax8 may be a very attractive targeted therapy for selective patients

A randomized controlled trial of an emollient with ceramide and filaggrin-associated amino acids for the primary prevention of atopic dermatitis in high-risk infants

Background: Skin barrier dysfunction may precede infantile development of clinical atopic dermatitis (AD). Early-life emollient therapy to enhance barrier function may prevent or modify AD development in high-risk infants. Objectives: (a) To determine whether daily full-body application of an emollient with ceramide and amino acids (study emollient) can reduce the cumulative AD incidence compared to standard skin care at 1 year of age. (b) To evaluate the study emollient's effect on skin barrier function, natural moisturizing factor and the microbiome using non-invasive biophysical and biochemical techniques. Methods: We performed a single-centre, investigator-blinded, randomized controlled trial enrolling infants at high risk for AD development determined by family history. The intervention was full-body once-daily application of the study emollient. The control arm was asked to not apply full-body emollient regularly and only use an emollient of their choice for dry skin. The primary outcome was the cumulative incidence of AD diagnosed at 12 months by a blinded investigator. Results: Less than half the target sample size was enrolled (n = 100, goal sample was 208) with 28% lost to follow-up. Across all clinical end points, a numerical trend was observed in favour of the intervention, although not statistically significant likely due to lack of power from under-enrolment. AD was diagnosed in 13.2% vs. 25.0% at 12 months (P = 0.204) and 19.4% vs. 31.0% at 2 years (P = 0.296) in intervention vs. control groups, respectively. There were no significant differences between groups in skin barrier or microbiome assessments. While there were no serious adverse events, there were more cases of reported contact dermatitis in the intervention vs. control arms, 9.3% vs. 4.3%, respectively; however, these events were not related to the study emollient and most mild in severity. Conclusion: The observed trends suggest a protective effect of daily study emollient therapy compared to control

Assessing the Difficulty and Long-Term Retention of Factual and Conceptual Knowledge Through Multiple-Choice Questions: A Longitudinal Study

Neil G Haycocks,1,2 Jessica Hernandez-Moreno,3 Johan C Bester,4 Robert Hernandez Jnr,3 Rosalie Kalili,3 Daman Samrao,3 Edward Simanton,3 Thomas A Vida3 1Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; 2Utah Office of the Medical Examiner, Taylorsville, UT, USA; 3Department of Medical Education, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV, USA; 4Office of Curricular Affairs and Department of Family and Community Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USACorrespondence: Thomas A Vida, Email [email protected]: Multiple choice questions (MCQs) are the mainstay in examinations for medical education, physician licensing, and board certification. Traditionally, MCQs tend to test rote recall of memorized facts. Their utility in assessing higher cognitive functions has been more problematic to determine. This work evaluates and compares the difficulty and long-term retention of factual versus conceptual knowledge using multiple-choice questions in a longitudinal study.Patients and Methods: We classified a series of MCQs into two groups to test recall/verbatim and conceptual/inferential thinking, respectively. We used the MCQs to test a two-part hypothesis: 1) scores for recall/verbatim questions would be significantly higher than for concept/inference questions, and 2) memory loss over time would be more significant for factual knowledge than conceptual understanding compared with a loss in the ability to reason about concepts critically. We first used the MCQs with pre-clinical medical students on a summative exam in 2020, which served as a retrospective benchmark of their performance characteristics. After two years, the same questions were re-administered to volunteers from the same cohort of students in 2020.Results: Retrospective analysis revealed that recall/verbatim questions were answered correctly more frequently (82.0% vs 60.9%, P = 0.002). Performance on concept/inference questions showed a significant decline, but a larger decline was observed for recall/verbatim questions after two years. Performance on concept/inference questions showed a slight decline across quartiles, while two years later, recall/verbatim questions experienced substantial performance loss. Subgroup analysis indicated convergence in performance on both question types, suggesting that the clinical relevance of the MCQ content may have influenced a regression toward a baseline mean.Conclusion: These findings suggest conceptual/inferential thinking is more complex than rote memorization. However, the knowledge acquired is more durable in a longitudinal fashion, especially if it is reinforced in clinical settings.Keywords: medical education assessment, multiple choice questions (MCQs), long-term knowledge retention, conceptual learning, cognitive function testin