Evaluation of a measles vaccine campaign by oral-fluid surveys in a rural Kenyan district: interpretation of antibody prevalence data using mixture models

We evaluated the effectiveness of a measles vaccine campaign in rural Kenya, based on oral-fluid surveys and mixture-modelling analysis. Specimens were collected from 886 children aged 9 months to 14 years pre-campaign and from a comparison sample of 598 children aged 6 months post-campaign. Quantitative measles-specific antibody data were obtained by commercial kit. The estimated proportions of measles-specific antibody negative in children aged 0–4, 5–9 and 10–14 years were 51%, 42% and 27%, respectively, pre- campaign and 18%, 14% and 6%, respectively, post-campaign. We estimate a reduction in the proportion susceptible of 65–78%, with ~85% of the population recorded to have received vaccine. The proportion of ‘weak’ positive individuals rose from 35% pre-campaign to 54% post-campaign. Our results confirm the effectiveness of the campaign in reducing susceptibility to measles and demonstrate the potential of oral-fluid studies to monitor the impact of measles vaccination campaigns

Improving sensitivity of oral fluid testing in IgG prevalence studies: application of mixture models to a rubella antibody survey

A method for the analysis of age-stratified antibody prevalence surveys is applied to a previously reported survey of antibody to rubella virus using oral fluid samples in which the sensitivity of the assay used was shown to be compromised. The age-specific distribution of the quantitative results of antibody tests using oral fluids is modelled as a mixture of strong positive, weak positive and negative components. This yields maximum likelihood estimates of the prevalence at each age and demonstrates that, when used in conjunction with mixture modelling techniques, the results of antibody prevalence studies using oral fluids accurately reflect those obtained using sera

Avoiding Misdiagnosis in Patients with Neurological Emergencies

Approximately 5% of patients presenting to emergency departments have neurological symptoms. The most common symptoms or diagnoses include headache, dizziness, back pain, weakness, and seizure disorder. Little is known about the actual misdiagnosis of these patients, which can have disastrous consequences for both the patients and the physicians. This paper reviews the existing literature about the misdiagnosis of neurological emergencies and analyzes the reason behind the misdiagnosis by specific presenting complaint. Our goal is to help emergency physicians and other providers reduce diagnostic error, understand how these errors are made, and improve patient care

Intermittent consequences and problem solving: the experimental control of “superstitious” beliefs

Three groups of college students were asked to determine how points were earned in a task that allowed the assessment of response variability. All students received points for sequences of eight presses distributed across two keys (four presses on each key). One group received a point for each correct sequence, one group received points on a fixed-ratio 2 schedule, and one group received points on a random-ratio 2 schedule. There were no significant differences in nonverbal response variability across the three groups, and the fixed-ratio 2 and random-ratio 2 groups obtained equivalent point totals. However, participants in the random-ratio group were significantly more likely to write verbal descriptions of the task that made reference to performance-consequence relations that were not in effect. The results demonstrate that superstitious rule generation is more probable when consequences are random and not merely intermittent

Exploiting Synthetic Lethality and Network Biology to Overcome EGFR Inhibitor Resistance in Lung Cancer.

Despite the recent approval of third-generation therapies, overcoming resistance to epidermal growth factor receptor (EGFR) inhibitors remains a major challenge in non-small cell lung cancer. Conceptually, synthetic lethality holds the promise of identifying non-intuitive targets for tackling both acquired and intrinsic resistance in this setting. However, translating these laboratory findings into effective clinical strategies continues to be elusive. Here, we provide an overview of the synthetic lethal approaches that have been employed to study EGFR inhibitor resistance and review the oncogene and non-oncogene signalling mechanisms that have thus far been unveiled by synthetic lethality screens. We highlight the potential challenges associated with progressing these discoveries into the clinic including context dependency, signalling plasticity, and tumour heterogeneity, and we offer a perspective on emerging network biology and computational solutions to exploit these phenomena for cancer therapy and biomarker discovery. We conclude by presenting a number of tangible steps to bolster our understanding of fundamental synthetic lethality mechanisms and advance these findings beyond the confines of the laboratory

Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis.

BACKGROUND: Autoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA. METHODS: Using a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients), and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D) and rs2104286 with multiple sclerosis (MS) and T1D. RESULTS: We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV. CONCLUSION: We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease

Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib.

Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.Significance Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy