Factors linked to disease severity and time to remission in patients with chronic spontaneous urticaria

Biomarkers useful for the evaluation and management of patients with chronic spontaneous urticaria (CSU) are not currently available. A review of various clinical and laboratory markers that have been studied to assess their value for determining the severity or predicting the evolution of disease in adult patients with CSU was carried out. A search of the medical literature on PubMed and MEDLINE including the terms urticaria, chronic urticaria, chronic idiopathic urticaria, CSU, severity, prognosis and treatment was performed. Based on our review of the literature, among the clinical markers studied, higher age at onset, being female, long disease duration and aspirin/NSAID hypersensitivity may be linked to both severe CSU and a long time to spontaneous remission. In addition, a positive autologous serum skin test (ASST) may be associated with severe CSU, and comorbidity of inducible urticaria and concomitant recurrent angio‐oedema may be linked to longer CSU duration. Potential biomarkers of CSU severity and/or duration include basophil numbers and susceptibility to activation, inflammatory markers, markers of activation of the extrinsic coagulation pathway, immunoglobulin E and vitamin D. Although the described markers are promising, further studies on representative and well‐characterized patient populations are needed to determine the value of these clinical and biological markers for predicting the severity and course of disease in patients with CSU.     

Late-onset epilepsy and occult cerebrovascular disease

The interface between cerebrovascular disease (CVD) and epilepsy is complex and multifaceted. Late-onset epilepsy (LOE) is increasingly common and is often attributed to CVD, and is indeed associated with an increased risk of stroke. This relationship is easily recognizable where there is a history of stroke, particularly involving the cerebral cortex. However, the relationship with otherwise occult, subcortical CVD is currently less well established yet causality is often invoked. In this review, we consider the diagnosis of LOE in clinical practice—including its behaviour as a potential mimic of acute ischemic stroke and transient ischemic attack; evidence for an association between occult CVD and LOE; and potential mechanisms of epileptogenesis in occult CVD, including potential interrelationships between disordered cerebral metabolism and perfusion, disrupted neurovascular unit integrity, blood–brain barrier dysfunction, and inflammation. We also discuss recently recognized issues concerning antiepileptic drug treatment and vascular risk and consider a variety of less common CVD entities associated with seizures.     

Theoretical and Experimental Evaluation of Flow Pattern of Pharmaceutical Powder Blends Discharged From Intermediate Bulk Containers (IBCs)

The purpose of this study is to assess the prevalence of funnel flow pattern for common pharmaceutical powder blends, upon discharging from modern intermediate bulk containers (IBCs) in drug product manufacturing. The estimation was built upon Jenike’s original radial stress field theory. It was modified to account for the stress-dependence of wall friction angle commonly observed in pharmaceutical powders. A total of 260 flow pattern estimations, based on 20 real-life IBCs and 13 investigational powder blends, were made. The estimated results showed that the mass flow pattern is present in less than 5% of all cases. Funnel flow pattern is clearly prevalent among pharmaceutical powder blends. The prevalence of funnel flow stems from several factors: 1) relatively shallow hopper section shared by all IBCs, 2) the common transition-type geometry, leading to even shallower hopper inclination at the edge of the hopper section, and 3) relatively high wall friction angles resulting from low wall normal stresses. This conclusion was verified through at-scale experiments, by discharging multiple pharmaceutical powder blends from a representative IBC. In general, our study suggests that, unless the powder wall friction can be substantially reduced, pharmaceutical powders are likely to discharge under funnel flow from modern IBCs.     

GeneYenta: A Phenotype­Based Rare Disease Case Matching Tool Based on Online Dating Algorithms for the Acceleration of Exome Interpretation

Advances in next‐generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology­based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching.     

H1‐antihistamines and urticaria: how can we predict the best drug for our patient?

Urticaria, and especially chronic spontaneous urticaria (CSU), is a difficult condition to treat. Consequently, clinicians need to use the best H₁‐antihistamines currently available and the pharmaceutical industries need to keep developing H₁‐antihistamines that are more effective than the ones we have today. To do this we need to be able to compare the clinical efficacy of both established and new drugs. Obviously, the ideal way to do this is to use head‐to‐head studies in CSU. However, such studies are extremely expensive and, in the case of novel molecules, have ethical and logistical problems. Consequently, we need to have predictive models. Although determination of Ki, an indicator of the in vitro potency of an H₁‐antihistamine, may help in the initial selection of candidate molecules, the large differences in volume of distribution and tissue accumulation in humans, precludes this from being a good predictor of clinical efficacy in CSU. From the data reviewed in this article, especially the direct comparative data of desloratadine and levocetirizine in weal and flare studies and CSU, weal and flare response would appear to be the best indicator we have of effectiveness of H₁‐antihistamines in clinical practice. However, it must be pointed out that the conclusion is, essentially, based on detailed comparisons of two drugs in studies sponsored by pharmaceutical companies. Consequently, to confirm the conclusions of this review, a multicentre study independent from the influence of pharmaceutical companies should be commissioned to compare the speed of onset and effectiveness of desloratadine, fexofenadine and levocetirizine in chronic spontaneous urticaria and against histamine‐induced weal and flare responses in the same patients so that we have a clear understanding of the predictive value of our models.