Resource use and direct medical costs of acute respiratory illness in the UK based on linked primary and secondary care records from 2001 to 2009

BackgroundPrevious studies have shown that influenza is associated with a substantial healthcare burden in the United Kingdom (UK), but more studies are needed to evaluate the resource use and direct medical costs of influenza in primary care and secondary care.MethodsA retrospective observational database study in the UK to describe the primary care and directly-associated secondary care resource use, and direct medical costs of acute respiratory illness (ARI), according to age, and risk status (NCT Number: 01521416). Patients with influenza, ARI or influenza-related respiratory infections during 9 consecutive pre-pandemic influenza peak seasons were identified by READ codes in the linked Clinical Practice Research Datalink (CPRD) and Hospital Episodes Statistics (HES) dataset. The study period was from 21st January 2001 to 31st March 2009.ResultsA total of 156,193 patients had ≥1 general practitioner (GP) episode of ARI, and a total of 82,204 patients received ≥1 GP prescription, at a mean of 2.5 (standard deviation [SD]: 3.0) prescriptions per patient. The total cost of GP consultations and prescriptions equated to £462,827 per year per 100,000 patients. The yearly cost of prescribed medication for ARI was £319,732, at an estimated cost of £11,596,350 per year extrapolated to the UK, with 40% attributable to antibiotics. The mean cost of hospital admissions equated to a yearly cost of £981,808 per 100,000 patients. The total mean direct medical cost of ARI over 9 influenza seasons was £21,343,445 (SD: £10,441,364), at £136.65 (SD: £66.85) per case.ConclusionsExtrapolating to the UK population, for pre-pandemic influenza seasons from 2001 to 2009, the direct medical cost of ARI equated to £86 million each year. More studies are needed to assess the costs of influenza disease to help guide public health decision-making for seasonal influenza in the UK

Portrait of a Pathogen: The Mycobacterium tuberculosis Proteome In Vivo

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a facultative intracellular pathogen that can persist within the host. The bacteria are thought to be in a state of reduced replication and metabolism as part of the chronic lung infection. Many in vitro studies have dissected the hypothesized environment within the infected lung, defining the bacterial response to pH, starvation and hypoxia. While these experiments have afforded great insight, the picture remains incomplete. The only way to study the combined effects of these environmental factors and the mycobacterial response is to study the bacterial response in vivo.We used the guinea pig model of tuberculosis to examine the bacterial proteome during the early and chronic stages of disease. Lungs were harvested thirty and ninety days after aerosol challenge with Mtb, and analyzed by liquid chromatography-mass spectrometry. To date, in vivo proteomics of the tubercle bacillus has not been described and this work has generated the first large-scale shotgun proteomic data set, comprising over 500 unique protein identifications. Cell wall and cell wall processes, and intermediary metabolism and respiration were the two major functional classes of proteins represented in the infected lung. These classes of proteins displayed the greatest heterogeneity indicating important biological processes for establishment of a productive bacterial infection and its persistence. Proteins necessary for adaptation throughout infection, such as nitrate/nitrite reduction were found at both time points. The PE-PPE protein class, while not well characterized, represented the third most abundant category and showed the most consistent expression during the infection.Cumulatively, the results of this work may provide the basis for rational drug design - identifying numerous Mtb proteins, from essential kinases to products involved in metal regulation and cell wall remodeling, all present throughout the course of infection

Why so serious? Theorising playful model-driven group decision support with situated affectivity

This is the author accepted manuscript. The final version is available from Springer via the DOI in this record.An integrative approach to theorising behavioural, affective and cognitive processes in modeldriven group decision support (GDS) interventions is needed to gain insight into the (micro-)processes by which outcomes are accomplished. This paper proposes that the theoretical lens of situated affectivity, grounded in recent extensions of scaffolded mind models, is suitable to understand the performativity of affective micro-processes in model-driven GDS interventions. An illustrative vignette of a humorous micro-moment in a group decision workshop is presented to reveal the performativity of extended affective scaffolding processes for group decision development. The lens of situated affectivity constitutes a novel approach for the study of interventionist practice in the context of group decision making (and negotiation). An outlook with opportunities for future research is offered to facilitate an integrated approach to the study of cognitive-affective and behavioural micro-processes in model-driven GDS interventions.This work was supported in part by the EU FP7-ENERGY- SMARTCITIES-2012 (314277) project STEEP (Systems Thinking for Comprehensive City Efficient Energy Planning

Structural insights into the catalysis and regulation of E3 ubiquitin ligases

Covalent attachment (conjugation) of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes, including apoptosis, cell division and immune responses. Ubiquitylation was originally associated with protein degradation, but it is now clear that ubiquitylation also mediates processes such as protein–protein interactions and cell signalling depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyse the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, more than 600 E3s contribute to determining the fates of thousands of substrates; hence, E3s need to be tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s function on a structural level and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin. Insights regarding the mechanisms of E3 regulation, including structural aspects of their autoinhibition and activation are also emerging

IgE binds asymmetrically to its B cell receptor CD23.

The antibody IgE plays a central role in allergic disease mechanisms. Its effector functions are controlled through interactions between the Fc region and two principal cell surface receptors FcεRI and CD23. The interaction with FcεRI is primarily responsible for allergic sensitization and the inflammatory response, while IgE binding to CD23 is involved in the regulation of IgE synthesis and allergen transcytosis. Here we present the crystal structure of a CD23/IgE-Fc complex and conduct isothermal titration calorimetric binding studies. Two lectin-like "head" domains of CD23 bind to IgE-Fc with affinities that differ by more than an order of magnitude, but the crystal structure reveals only one head bound to one of the two identical heavy-chains in the asymmetrically bent IgE-Fc. These results highlight the subtle interplay between receptor binding sites in IgE-Fc and their affinities, the understanding of which may be exploited for therapeutic intervention in allergic disease

Validity and Internal Consistency of the New Knee Society Knee Scoring System

BackgroundIn 2012, a new Knee Society Knee Scoring System (KSS) was developed and validated to address the needs for a scoring system that better encompasses the expectations, satisfaction, and physical involvement of a younger, more active population of patients undergoing TKA. Revalidating this tool in a separate population by individuals other than the developers of the scoring system seems important, because such replication would tend to confirm the generalizability of this tool.Questions/purposesThe purposes of this study were (1) to validate the KSS using a separate sample of patients undergoing primary TKA; and (2) to evaluate the internal consistency of the KSS.MethodsIntervention and control groups from a randomized controlled trial with no between-group differences were pooled. Preoperative and postoperative (6 weeks and 1 year) data were used. Patients with osteoarthritis undergoing primary TKA completed the patient-reported component of the KSS, Knee Injury and Osteoarthritis Outcome Score (KOOS), SF-12, two independent questions about expectations of surgery, and the Patient Acceptable Symptom State (PASS) single-question outcome. This study included 345 patients with 221 (64%) women, an average (SD) age of 64 (8.6) years, a mean (SD) body mass index of 32.9 (7.5) kg/m(2), and 225 (68%) having their first primary TKA. Loss to followup in the control group was 18% and loss to followup in the intervention group was 13%. We quantified cross-sectional (preoperative scores) and longitudinal validity (pre- to postoperative change scores) by evaluating associations between the KSS and KOOS subscales using Spearman\u27s correlation coefficient. Preoperative known-group validity of the KSS symptoms and functional activity score was evaluated with a one-way analysis of variance across three levels of physical health status using the SF-12 Physical Component Score. Known-group validity of the KSS expectation score was evaluated with an unpaired t-test by comparing means across known expectation groups. Known-group validity of the KSS satisfaction score was evaluated with an unpaired t-test by comparing means across yes/no response groupings of the PASS single-question outcome. Internal consistency for each KSS subscale was evaluated with Cronbach\u27s .ResultsCross-sectional validity (ie, associations at a single point in time) was supported because correlation coefficients between KSS symptoms, functional activities, and satisfaction scores and scores on the KOOS pain subscale ranged from 0.60 to 0.73 (all correlations p \u3c 0.01). Values were similar for associations with the KOOS function in the activities of daily living (ADL) subscale (0.66-0.69) and less (0.41-0.58) for correlations with the other three KOOS subscales. Longitudinal validity (ie, associations of change scores between two time points) was also supported because correlation coefficients between KSS symptoms, functional activities, and satisfaction change scores and the KOOS pain and ADL change scores varied from 0.63 to 0.73. Correlation coefficients were lower for the other three KOOS subscale change scores, suggesting a weaker relationship with KOOS symptoms (0.48-0.53), sports (0.47-0.51), and quality of life (0.60-0.65) (all correlations p \u3c 0.01). Known-group validity (ie, differences between groups that are known to differ on a given characteristic) was confirmed by between-group differences for the symptoms and functional activities score comparisons as well as the comparisons with the expectations and satisfaction scores of the KSS (all p \u3c 0.01). Cronbach\u27s (ie, association among subscale items) varied from 0.68 (discretionary activities) to 0.94 (postoperative expectations) across four KSS subscales.ConclusionsModerate-sized correlation coefficients and consistent differences between known groups support the validity of the KSS. Internal consistency values were also acceptable. The patient-reported subscales of the KSS are a valid and internally consistent outcome assessment for TKA