Latent analysis of unmodified biomolecules and their complexes in solution with attomole detection sensitivity

The study of biomolecular interactions is central to an understanding of function, malfunction and therapeutic modulation of biological systems, yet often involves a compromise between sensitivity and accuracy. Many conventional analytical steps and the procedures required to facilitate sensitive detection, such as the incorporation of chemical labels, are prone to perturb the complexes under observation. Here we present a 'latent' analysis approach that uses chemical and microfluidic tools to reveal, through highly sensitive detection of a labelled system, the behaviour of the physiologically relevant unlabelled system. We implement this strategy in a native microfluidic diffusional sizing platform, allowing us to achieve detection sensitivity at the attomole level, determine the hydrodynamic radii of biomolecules that vary by over three orders of magnitude in molecular weight, and study heterogeneous mixtures. We illustrate these key advantages by characterizing a complex of an antibody domain in the solution phase and under physiologically relevant conditions.We would like to thank the ERC, BBSRC, Wellcome Trust, Newman Foundation, Winston Churchill Foundation, and Elan Pharmaceuticals for financial support. E.D.G was supported by the MRC (G1002272)

Hospitalizations for vaccine preventable pneumonias in patients with inflammatory bowel disease: a 6-year analysis of the Nationwide Inpatient Sample

Derrick J Stobaugh,1,2 Parakkal Deepak,1,2 Eli D Ehrenpreis1,21Center for the Study of Complex Diseases, Research Institute, NorthShore University HealthSystem, Evanston, IL, USA; 2Gastroenterology Department, NorthShore University HealthSystem, Highland Park, IL, USABackground: Pneumonias are among the most common causes of hospitalization among inflammatory bowel disease (IBD) patients. Guidelines published in 2004 advocate vaccination against Streptococcus pneumoniae and influenza virus. We sought to examine trends in hospitalizations for vaccine preventable pneumonias among IBD patients since the availability of published guidelines, and to identify whether Haemophilus influenzae is a causative organism for pneumonia hospitalizations among IBD patients.Methods: This cross-sectional study on the Nationwide Inpatient Sample was used to identify admissions for pneumonias in patients with IBD between 2004 and 2009. A multivariate logistic regression analysis was performed comparing IBD patients to controls, accounting for potential confounders.Results: There were more admissions for S. pneumoniae pneumonia than influenza virus or H. influenzae (787, 393, and 183 respectively). Crohn’s disease (CD) as well as ulcerative colitis (UC) patients did not demonstrate increased adjusted odds of hospitalization for S. pneumoniae pneumonia (1.08; confidence interval [CI] 0.99–1.17 compared to 0.93; CI 0.82–1.06 respectively). Increased adjusted odds for hospitalization for pneumonias due to influenza virus were seen among UC patients in the bottom quartile of income (1.86; CI 1.46–2.37). Adjusted odds for H. influenzae pneumonia admission in patients with UC and CD patients were increased compared to controls (1.42; CI 1.13–1.79 and 1.28; CI 1.06–1.54, respectively).Conclusion: The study identified lowest income UC patients as having higher adjusted odds, and these patients should be targeted for influenza virus vaccination. Additionally, H. influenzae may be another vaccine preventable cause for pneumonia among IBD patients.Keywords: infection, Crohn’s disease, colitis, ulcerative, vaccination, pneumoni

Reporting of drug induced depression and fatal and non-fatal suicidal behaviour in the UK from 1998 to 2011

BACKGROUND: Psychiatric adverse drug reactions (ADRs) are distressing for patients and have important public health implications. We identified the drugs with the most frequent spontaneous reports of depression, and fatal and non-fatal suicidal behaviour to the UK’s Yellow Card Scheme from 1998 to 2011. METHODS: We obtained Yellow Card data from the Medicines and Healthcare products Regulatory Agency for the drugs with the most frequent spontaneous reports of depression and suicidal behaviour from 1964 onwards. Prescribing data were obtained from the NHS Information Centre and the Department of Health. We examined the frequency of reports for drugs and estimated rates of reporting of psychiatric ADRs using prescribing data as proxy denominators from 1998 to 2011, as prescribing data were not available prior to 1998. RESULTS: There were 110 different drugs with ≥ 20 reports of depression, 58 with ≥10 reports of non-fatal suicidal behaviour and 33 with ≥5 reports of fatal suicidal behaviour in the time period. The top five drugs with the most frequent reports of depression were the smoking cessation medicines varenicline and bupropion, followed by paroxetine (a selective serotonin reuptake inhibitor), isotretinoin (used in acne treatment) and rimonabant (a weight loss drug). Selective serotonin reuptake inhibitors, varenicline and the antipsychotic medicine clozapine were included in the top five medicines with the most frequent reports of fatal and non-fatal suicidal behaviour. Medicines with the highest reliably measured reporting rates of psychiatric ADRs per million prescriptions dispensed in the community included rimonabant, isotretinoin, mefloquine (an antimalarial), varenicline and bupropion. Robust denominators for community prescribing were not available for two drugs with five or more suicide reports, efavirenz (an antiretroviral medicine) and clozapine. CONCLUSIONS: Depression and suicide-related ADRs are reported for many nervous system and non-nervous system drugs. As spontaneous reports cannot be used to determine causality between the drug and the ADR, psychiatric ADRs which can cause significant public alarm should be specifically assessed and reported in all randomised controlled trials