Inefficiencies in Digital Advertising Markets

Digital advertising markets are growing and attracting increased scrutiny. This article explores four market inefficiencies that remain poorly understood: ad effect measurement, frictions between and within advertising channel members, ad blocking, and ad fraud. Although these topics are not unique to digital advertising, each manifests in unique ways in markets for digital ads. The authors identify relevant findings in the academic literature, recent developments in practice, and promising topics for future research

Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment

Tranexamic acid (TXA), an effective anti-fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter-patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re-examined with a two-compartment model using the ADAPT5® and NONMEMVII® to identify covariates that explain inter-patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two-compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg·L(-1) ). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB

De-novo Onset of Eosinophilic Esophagitis After Large Volume Allergen Exposures

Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition believed to have an allergic component, but the timing of the initial allergen triggers that cause the disease is poorly understood. While the clinical presentation of EoE is often of longstanding symptoms, in animal models, acute exposure to an allergen challenge successfully produces EoE. In this report, we present three cases of individuals who developed esophageal eosinophilia and EoE shortly after a clearly identified exposure to aeroallergens. These cases highlight the allergic etiology of EoE, and provide a link from humans to the previously described experimental mechanisms

A 6-month, multicenter, open-label study of fixed dose naproxen/esomeprazole in adolescent patients with juvenile idiopathic arthritis

© 2018 The Author(s). Background: Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of unknown etiology, which lasts for greater than 6 weeks with onset before 16 years of age. JIA is the most common chronic rheumatic disease in children. NSAIDs have been the mainstay of initial management with naproxen (NAP) being commonly used, but they may cause serious side effects such as gastric ulcers which can be reduced by concomitant administration of proton pump inhibitors, such as esomeprazole (ESO). Methods: Primary objective was to evaluate the safety and tolerability of 3 fixed doses of NAP/ESO in JIA patients aged 12 to 16 years. Forty-six children and adolescents with JIA by International League of Associations for Rheumatology criteria, mean age of 13.6 years, from 18 US sites were prospectively enrolled over 2 years and followed for up to 6 months. Doses of the NAP/ESO fixed combination were based on baseline weight. The exploratory efficacy outcome was assessed with the ACR Pediatric-30, - 50, - 70, - 90 Response and the Childhood Health Assessment Questionnaire (CHAQ) discomfort and functional scores at months 1, 3, and 6 as change from baseline. Occurrence and causality were assessed for treatment emergent AEs (TEAEs) and discontinuations were monitored monthly. Results: Forty-six patients received at least 1 dose of naproxen/esomeprazole and 36 completed the trial. Thirty-seven (80.4%) had at least 1 treatment emergent adverse event (TEAE) and, with the exception of 2 events in one patient, all of the TEAEs were mild or moderate. Frequent TEAEs (≥5% of patients) were upper respiratory tract and gastrointestinal related. Eleven (23.9%) had at least 1 TEAE considered to be related to study drug. Four patients (8.7%) discontinued due to a TEAE with one of these being the only serious AE reported, acute hepatitis. Mean number of active joints at baseline was 3.1. Improvement in JIA signs and symptoms occurred at most assessments and by month 6, the percentage of patients with an ACR Pediatric-30, - 50, - 70, and - 90 Response was 47.1, 38.2, 32.4, and 17.6%, respectively. The percent of patients achieving ACR Pediatric response increased over time. CHAQ discomfort improved at each assessment and functional scores improved at all assessments for \u27Arising, Walking, and Activities\u27 with several improved for \u27Dressing and Grooming, Eating, Hygiene, and Grip\u27. There was no indication of a dose-related efficacy effect. Conclusion: NAP/ESO was well tolerated in JIA patients aged 12 to 16 years with high levels of response to ACR criteria. No new safety signals were identified for the well-characterized components of this fixed dosed JIA treatment, which was developed to reduce the risk of gastric ulcers

Healthy, affordable and climate-friendly diets in India

India has among the highest lost years of life from micronutrient deficiencies. We investigate what dietary shifts would eliminate protein, iron, zinc and Vitamin A deficiencies within households’ food budgets and whether these shifts would be compatible with mitigating climate change. This analysis uses the National Sample Survey (2011–12) of consumption expenditure to calculate calorie, protein and the above micronutrient intake deficiencies and relate them to diets, income and location. We show that more than two-thirds of Indians consume insufficient micronutrients, particularly iron and Vitamin A, and to a lesser extent zinc. A greater proportion of urban households than rural households are deficient at all income levels and for all nutrients, with few exceptions. Deficiencies reduce with increasing income. Using constrained optimization, we find that households could overcome these nutrient deficiencies within their food budgets by diversifying their diets, particularly towards coarse cereals, pulses, and leafy vegetables, and away from rice. These dietary changes could reduce India’s agricultural greenhouse gas (GHG) emissions by up to 25%. Current agricultural and food pricing policies may disincentivize these dietary shifts, particularly among the poor

Dietary Elimination Therapy Is an Effective Option for Adults With Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is an immune-mediated disorder. Food elimination is an established treatment for children, but data in adults are limited. We aimed to determine the response of adults with EoE to dietary therapy

Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation

<p>Abstract</p> <p>Objectives</p> <p>The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation.</p> <p>Methods</p> <p>The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs.</p> <p>Results</p> <p>MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009).</p> <p>Conclusion</p> <p>In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.</p

Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease

OBJECTIVES: To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). METHODS: Combined analysis of newly identified patients with NEFL-related CMT and all previously reported cases from the literature. RESULTS: Five new unrelated patients with CMT carrying the NEFL mutations P8R and N98S and the novel variant L311P were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively. Eight patients had de novo mutations. Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and 'onion bulb' formations and/or thin myelin sheaths were observed in 14 (67%) of them. The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases. Pyramidal tract signs were described in 13 patients and 7 patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia and/or cerebellar atrophy on brain MRI. CONCLUSIONS: NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT

Assessing the sustainability of post-Green Revolution cereals in India

Sustainable food systems aim to provide sufficient and nutritious food, while maximizing climate resilience and minimizing resource demands as well as negative environmental impacts. Historical practices, notably the Green Revolution, prioritized the single objective to maximize production over other nutritional and environmental dimensions. We quantitatively assess outcomes of alternative production decisions across multiple objectives using India’s ricedominated monsoon cereal production as an example. We perform a series of optimizations to maximize nutrient production (i.e., protein and iron), minimize greenhouse gas (GHG) emissions and resource use (i.e., water and energy), ormaximize resilience to climate extremes.We find that increasing the area under coarse cereals (i.e., millets, sorghum) improves nutritional supply (on average, +1% to +5% protein and +5% to +49% iron), increases climate resilience (1% to 13% fewer calories lost during an extreme dry year), and reduces GHGs (−2% to −13%) and demand for irrigation water (−3% to −21%) and energy (−2% to −12%) while maintaining calorie production and cropped area. The extent of these benefits partly depends on the feasibility of switching cropped area from rice to coarse cereals. Based on current production practices in 2 states, supporting these cobenefits could require greater manure and draft power but similar or less labor, fertilizer, and machinery. Nationaland state-level strategies considering multiple objectives in decisions about cereal production can move beyond many shortcomings of the Green Revolution while reinforcing the benefits. This ability to realistically incorporate multiple dimensions into intervention planning and implementation is the crux of sustainable food production systems worldwide