Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents. © 2009 Elsevier Ltd. All rights reserved

Iatrogenic Burden of Atopic Dermatitis

The management required for atopic dermatitis (AD) may worsen patient burden, thereby resulting in iatrogenic burden, that is, morbidity caused by medical treatment. We sought to describe the iatrogenic burden of AD and conducted a narrative review of key areas that clinicians can address to minimize it. Clinicians should think strategically about itch trigger avoidance, encourage slow incorporation of lifestyle changes, and emphasize step-up therapy when avoidance becomes too burdensome. Out-of-pocket treatment costs should be incorporated into shared decision making to balance affordability, preference, efficacy, and safety. Polypharmacy should be minimized by eliminating ineffective, nonevidence-based, and redundant therapies while appropriately stepping up to advanced therapy. Clinicians should take adequate time to communicate, the impact of AD on quality of life, and incorporate evidence-based guidelines. The multidimensional nature of AD requires a dynamic approach. Future guidelines should incorporate step-up, step-down, and maintenance approaches to reduce treatment burden and improve quality of life

Association of pemphigus and pemphigoid with osteoporosis and pathological fractures

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Patients with pemphigus and bullous pemphigoid (BP) have potential risk factors for osteoporosis and/or fractures. To determine whether pemphigus and BP are associated with osteoporosis and fractures in the US, a cross-sectional study of 198,102,435 adults was performed, including 4506 with pemphigus and 8864 with BP from the 2006–2012 National Emergency Department Sample, a 20% sample of emergency care visits throughout the US. Pemphigus was associated with higher odds (multivariate logistic regression; adjusted odds ratio [95% confidence intervals]) of osteopenia (2.20 [1.59–3.05]), osteoporosis (2.54 [2.16–2.98]), osteomalacia (29.70 [4.05–217.83]), and pathological fractures (2.04 [1.42–2.91]). BP was associated with osteoporosis (1.55 [1.39–1.73]) and pathological fractures (1.52 [1.22–1.88]). When compared to BP, pemphigus was associated with higher odds of osteopenia (1.59 [1.06–2.41]), osteoporosis (1.38 [1.18–1.63]), and fractures (1.26 [1.04–1.53]), particularly of the ulna and radius (3.17 [1.23–8.17]). Patients with pemphigus or BP as well as long-term systemic corticosteroid use had highest odds of osteoporosis and fractures. No data were available on treatments for pemphigus or BP. Pemphigus and BP were associated with osteopenia, osteoporosis, and pathologic fractures. Patients with PEM and BP may benefit from increased screening for osteoporosis and interventions to prevent fractures

Inpatient morbidity and mortality of measles in the United States.

BACKGROUND:Measles is an extremely contagious, vaccine-preventable infection that was officially declared eradicated in the US in 2000. However, measles outbreaks are increasingly occurring in the US. Measles cases have considerable morbidity requiring hospitalization, yet little is known about hospitalization and complications from measles in recent years. OBJECTIVES:To analyze the frequency, predictors, costs and other outcomes of hospitalization for measles in the US. METHODS:The 2002-2016 Nationwide Inpatient Sample, containing a 20% sample of US hospitalizations (n = 96,568,625), was analyzed. Measles and comorbidities were defined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) or ICD-10-CM codes. Multivariable survey logistic regression and linear regression models controlling for sociodemographic demographic factors were constructed to understand associations with organ-specific complications, and cost of care and length of stay, respectively. RESULTS:Overall, 1,018 measles hospitalizations occurred in 2002-2016, and hospitalizations increased over time. In multivariable logistic regression models, measles was associated with higher odds of gastrointestinal, hematologic, infectious, neurologic, ophthalmologic, pulmonary, and renal complications, with the strongest association observed with encephalitis (39.84 [16.51-96.12], P0.05). There were 34 deaths in hospitalized measles patients; inpatient mortality was numerically higher in those with vs. without measles (proportion ± SEM: 3.3±1.2% vs. 2.3±0.01%, P = 0.333). LIMITATIONS:Lack of outpatient or prescription data. CONCLUSIONS:Measles continues to pose a substantial and preventable health care burden, with serious complications, hospitalization and inpatient mortality. Further studies are needed to improve the prevention and management of measles

Association of pemphigus and pemphigoid with osteoporosis and pathological fractures

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Patients with pemphigus and bullous pemphigoid (BP) have potential risk factors for osteoporosis and/or fractures. To determine whether pemphigus and BP are associated with osteoporosis and fractures in the US, a cross-sectional study of 198,102,435 adults was performed, including 4506 with pemphigus and 8864 with BP from the 2006–2012 National Emergency Department Sample, a 20% sample of emergency care visits throughout the US. Pemphigus was associated with higher odds (multivariate logistic regression; adjusted odds ratio [95% confidence intervals]) of osteopenia (2.20 [1.59–3.05]), osteoporosis (2.54 [2.16–2.98]), osteomalacia (29.70 [4.05–217.83]), and pathological fractures (2.04 [1.42–2.91]). BP was associated with osteoporosis (1.55 [1.39–1.73]) and pathological fractures (1.52 [1.22–1.88]). When compared to BP, pemphigus was associated with higher odds of osteopenia (1.59 [1.06–2.41]), osteoporosis (1.38 [1.18–1.63]), and fractures (1.26 [1.04–1.53]), particularly of the ulna and radius (3.17 [1.23–8.17]). Patients with pemphigus or BP as well as long-term systemic corticosteroid use had highest odds of osteoporosis and fractures. No data were available on treatments for pemphigus or BP. Pemphigus and BP were associated with osteopenia, osteoporosis, and pathologic fractures. Patients with PEM and BP may benefit from increased screening for osteoporosis and interventions to prevent fractures

DESCRIBE-AD: A novel classification framework for atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory skin disease associated with heterogeneous morphology, distribution, symptoms, severity, extent, longitudinal courses, quality of life burden, comorbidities, and treatment responses. This heterogeneity contributes to challenges in diagnosis, the characterization of disease activity, and therapeutic stratification. OBJECTIVE: To develop a framework to standardize AD assessment. METHODS: We propose a novel framework to assess AD based on a literature review and clinical experience. RESULTS: DESCRIBE-AD is a framework that can effectively capture the clinical domains contributing to AD heterogeneity and includes both patient- and clinician-reported perspectives. DESCRIBE-AD includes assessments of Dermatitis morphology and phenotype, Evolution of disease, Symptom severity, Comorbid health disorders, Response to therapy, Intensity of lesions, Burden of disease, and Extent of lesions. Rather than placing the focus on any single, specific aspect of AD, DESCRIBE-AD allows for a comprehensive approach to the assessment and clinical management of AD. CONCLUSIONS: DESCRIBE-AD is a novel framework that can be used to better describe the heterogeneity of AD and guide treatment decisions

Evaluating the Longitudinal Course of Atopic Dermatitis: Implications for Clinical Practice

Atopic dermatitis (AD) is characterized by a heterogenous longitudinal course with varying severity, flares, and persistence. However, AD course is not routinely assessed in clinical practice or controlled trials. Our objective was to review the longitudinal course of AD in children and adults and discuss implications for routine practice and clinical trials. We conducted a focused review of the published literature, including retrospective, prospective, and interventional studies, clinical trials, and consensus guidelines. Estimates of AD persistence varied widely across studies but suggested that AD can indeed persist through childhood and into adulthood. Predictors of persistence are broad and include both disease-intrinsic and disease-extrinsic (i.e., environmental) factors. In real-world practice, most individuals with AD experience fluctuations in the signs and symptoms over time and do not experience persistent clearance of skin lesions. Clinical trials use mainly static measurements that do not take into account fluctuations in course, which may confound treatment effects. The heterogenous temporal pattern of AD can be incorporated into routine practice to better set expectations and offer a realistic prognosis. AD course should be routinely incorporated into clinical decision making. Future studies are needed to develop a standardized approach to AD assessment and treatment that includes longitudinal course

Pathophysiology of Atopic Dermatitis and Psoriasis: Implications for Management in Children.

Atopic dermatitis (AD) and psoriasis are chronic inflammatory skin diseases associated with a significant cutaneous and systemic burden of disease as well as a poor health-related quality of life. Here, we review the complex pathophysiology of both AD and psoriasis and discuss the implications for treatment with current state-of-the-art and emerging topical and systemic therapies. Both AD and psoriasis are caused by a complex combination of immune dysregulation, skin-barrier disruption, genetic factors, and environmental influences. Previous treatments for both diseases were limited to anti-inflammatory agents that broadly suppress inflammation. Emerging insights into relevant pathways, including recognition of the role of T-helper type 2 driven inflammation in AD and T-helper 1 and 17 driven inflammation in psoriasis, have led to a therapeutic revolution. There are a number of novel treatment options available for AD and psoriasis with many more currently under investigation