Skin diseases in displaced populations: a review of contributing factors,challenges, and approaches to care

There are 70.8 million persons displaced worldwide due to war, persecution, and violence. Eighty percent of displaced persons reside in low- and middle-income countries with limited healthcare resources. Cutaneous diseases are commonly reported among displaced persons owing to numerous interrelated factors such as inadequate housing, overcrowding, food insecurity, environmental exposures, violence including torture, and breakdown of healthcare infrastructure. Diagnosis and management of these conditions, as well as an understanding of the context in which they present, is crucial to providing dermatologic care for displaced populations worldwide. Herein, we define displaced populations and, within this context, review the epidemiology of skin diseases, discuss pertinent skin conditions, examine challenges to care provision, and present approaches for improving dermatologic care. Inflammatory and communicable infectious disorders are the most common skin diseases seen in displaced populations. Other relevant conditions include skin manifestations of heat injuries, cold injuries, immersion foot syndromes, macronutrient and micronutrient deficiencies, torture, and sexual and gender-based violence. Provision of dermatologic care to displaced populations is hampered by limited diagnostic and therapeutic resources and specialist expertise. Medical screening for cutaneous disorders, context-relevant dermatology training, and telemedicine are potential tools to improve diagnosis and management of skin diseases in displaced populations.     

Transient cortico-cortical disconnection during psychogenic nonepileptic seizures (PNES)

Psychogenic nonepileptic seizures (PNES) are paroxysmal clinical events that are often misdiagnosed as epileptic seizures, but which are not associated with electrographic discharge. Brain connectivity changes occurring during PNES are not known. We studied functional connectivity (Fc) in two patients with drug-resistant epilepsy, explored by stereotactic electroencephalography (EEG), in whom we recorded both epileptic seizures (ES) and PNES. Functional connectivity using pair-wise nonlinear correlation was computed between signals from seven brain areas: amygdala, hippocampus, lateral temporal cortex, anterior insula, orbitofrontal cortex, prefrontal cortex, and lateral parietal cortex. We assessed changes in global Fc during PNES in comparison with a background period. During PNES, a global decrease of Fc occurred between the different brain regions studied, compared with the interictal period. In both patients, decreased Fc was prominent in connections involving the anterior insula and parietal cortex. In conclusion, some PNES are associated with ictal functional disconnection between brain areas, particularly involving the parietal cortices and the anterior insula.     

Cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in Germany

Drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) significantly reduced mortality in severe sepsis in the PROWESS trial. We evaluate the cost-effectiveness of drotrecogin alfa (activated) as an adjunct to standard therapy from the German healthcare payer’s perspective with respect to patients with 1) severe sepsis and 2) severe sepsis and multiple organ failure the approved European indication. Hospital resource use based on PROWESS was valued using German unit costs. German life-tables and long-term survival assumptions determined life-years gained. European and German healthcare resource use data are examined in the sensitivity analysis. We assumed a unit price of €237.50 for drotrecogin alfa (activated). Per patient treated, drotrecogin alfa (activated) increased costs by €7,500, and hospital costs by €900 for all patients (€7,400 and €1,500 respectively for the approved indication) and survival by 0.59 life years (0.87 life years respectively for the approved indication). Thus drotrecogin alfa (activated) cost €14,100 (€17,700 discounting life years at 3%) per life year gained for all patients (€10,200 and €12,900, respectively, for the approved indication). Testing the unit cost of drotrecogin alfa (activated), pattern of resource use, and survival benefit, demonstrated that cost-effectiveness lies well within the range of other life saving interventions in Germany representing good economic value.     

PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity

Deregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway such as by PTEN loss or PIK3CA mutation occurs frequently in human cancer and contributes to resistance to antitumor therapies. Inhibition of key signaling proteins in the pathway therefore represents a valuable targeting strategy for diverse cancers. PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nmol/L and 3.8-20 nmol/L, respectively) and inhibited cell proliferation (IC(50) of 179-313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibited PI3K, whereas mTOR inhibition persisted for 24 to 48 hours. PF-04691502 induced cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity was observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. In summary, PF-04691502 is a potent dual PI3K/mTOR inhibitor with broad antitumor activity. PF-04691502 has entered phase I clinical trials.