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1.  Structure of the RNA-directed RNA Polymerase from the Cystovirus φ12 
Proteins  2013;81(8):1479-1484.
We have determined the structure of P2, the self-priming RdRp from cystovirus φ12 in two crystal forms (A, B) at resolutions of 1.7 Å and 2.1 Å. Form A contains Mg2+ bound at a site that deviates from the canonical non-catalytic position seen in form B. These structures provide insight into the temperature sensitivity of a ts-mutant. However, the tunnel through which template ssRNA accesses the active site is partially occluded by a flexible loop; this feature, along with sub-optimal positioning of other structural elements that prevent the formation of a stable initiation complex, indicate an inactive conformation in crystallo.
PMCID: PMC4090683  PMID: 23568335
bacteriophage; cystovirus; RNA-directed RNA polymerase; de novo initiation; transcription; replication
2.  Health status of UK care home residents: a cohort study 
Age and Ageing  2013;43(1):97-103.
Background: UK care home residents are often poorly served by existing healthcare arrangements. Published descriptions of residents’ health status have been limited by lack of detail and use of data derived from surveys drawn from social, rather than health, care records.
Aim: to describe in detail the health status and healthcare resource use of UK care home residents
Design and setting: a 180-day longitudinal cohort study of 227 residents across 11 UK care homes, 5 nursing and 6 residential, selected to be representative for nursing/residential status and dementia registration.
Method: Barthel index (BI), Mini-mental state examination (MMSE), Neuropsychiatric index (NPI), Mini-nutritional index (MNA), EuroQoL-5D (EQ-5D), 12-item General Health Questionnaire (GHQ-12), diagnoses and medications were recorded at baseline and BI, NPI, GHQ-12 and EQ-5D at follow-up after 180 days. National Health Service (NHS) resource use data were collected from databases of local healthcare providers.
Results: out of a total of 323, 227 residents were recruited. The median BI was 9 (IQR: 2.5–15.5), MMSE 13 (4–22) and number of medications 8 (5.5–10.5). The mean number of diagnoses per resident was 6.2 (SD: 4). Thirty per cent were malnourished, 66% had evidence of behavioural disturbance. Residents had contact with the NHS on average once per month.
Conclusion: residents from both residential and nursing settings are dependent, cognitively impaired, have mild frequent behavioural symptoms, multimorbidity, polypharmacy and frequently use NHS resources. Effective care for such a cohort requires broad expertise from multiple disciplines delivered in a co-ordinated and managed way.
PMCID: PMC3861334  PMID: 23864424
homes for the aged; nursing homes; cohort studies; health status; health resources; older people
3.  Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction 
PLoS ONE  2013;8(5):e63369.
In the future, we may be faced with the need to provide treatment for an emergent biological threat against which existing vaccines and drugs have limited efficacy or availability. To prepare for this eventuality, our objective was to use a metabolic network-based approach to rapidly identify potential drug targets and prospectively screen and validate novel small-molecule antimicrobials. Our target organism was the fully virulent Francisella tularensis subspecies tularensis Schu S4 strain, a highly infectious intracellular pathogen that is the causative agent of tularemia and is classified as a category A biological agent by the Centers for Disease Control and Prevention. We proceeded with a staggered computational and experimental workflow that used a strain-specific metabolic network model, homology modeling and X-ray crystallography of protein targets, and ligand- and structure-based drug design. Selected compounds were subsequently filtered based on physiological-based pharmacokinetic modeling, and we selected a final set of 40 compounds for experimental validation of antimicrobial activity. We began screening these compounds in whole bacterial cell-based assays in biosafety level 3 facilities in the 20th week of the study and completed the screens within 12 weeks. Six compounds showed significant growth inhibition of F. tularensis, and we determined their respective minimum inhibitory concentrations and mammalian cell cytotoxicities. The most promising compound had a low molecular weight, was non-toxic, and abolished bacterial growth at 13 µM, with putative activity against pantetheine-phosphate adenylyltransferase, an enzyme involved in the biosynthesis of coenzyme A, encoded by gene coaD. The novel antimicrobial compounds identified in this study serve as starting points for lead optimization, animal testing, and drug development against tularemia. Our integrated in silico/in vitro approach had an overall 15% success rate in terms of active versus tested compounds over an elapsed time period of 32 weeks, from pathogen strain identification to selection and validation of novel antimicrobial compounds.
PMCID: PMC3660459  PMID: 23704901
4.  The Identification of Seniors at Risk (ISAR) score to predict clinical outcomes and health service costs in older people discharged from UK acute medical units 
Age and Ageing  2013;42(6):747-753.
Background: tools are required to identify high-risk older people in acute emergency settings so that appropriate services can be directed towards them.
Objective: to evaluate whether the Identification of Seniors At Risk (ISAR) predicts the clinical outcomes and health and social services costs of older people discharged from acute medical units.
Design: an observational cohort study using receiver–operator curve analysis to compare baseline ISAR to an adverse clinical outcome at 90 days (where an adverse outcome was any of death, institutionalisation, hospital readmission, increased dependency in activities of daily living (decrease of 2 or more points on the Barthel ADL Index), reduced mental well-being (increase of 2 or more points on the 12-point General Health Questionnaire) or reduced quality of life (reduction in the EuroQol-5D) and high health and social services costs over 90 days estimated from routine electronic service records.
Setting: two acute medical units in the East Midlands, UK.
Participants: a total of 667 patients aged ≥70 discharged from acute medical units.
Results: an adverse outcome at 90 days was observed in 76% of participants. The ISAR was poor at predicting adverse outcomes (AUC: 0.60, 95% CI: 0.54–0.65) and fair for health and social care costs (AUC: 0.70, 95% CI: 0.59–0.81).
Conclusions: adverse outcomes are common in older people discharged from acute medical units in the UK; the poor predictive ability of the ISAR in older people discharged from acute medical units makes it unsuitable as a sole tool in clinical decision-making.
PMCID: PMC3809718  PMID: 23666405
older people; acute care; screening
5.  The predictive properties of frailty-rating scales in the acute medical unit 
Age and Ageing  2013;42(6):776-781.
Background: older people are at an increased risk of adverse outcomes following attendance at acute hospitals. Screening tools may help identify those most at risk. The objective of this study was to compare the predictive properties of five frailty-rating scales.
Method: this was a secondary analysis of a cohort study involving participants aged 70 years and above attending two acute medical units in the East Midlands, UK. Participants were classified at baseline as frail or non-frail using five different frailty-rating scales. The ability of each scale to predict outcomes at 90 days (mortality, readmissions, institutionalisation, functional decline and a composite adverse outcome) was assessed using area under a receiver-operating characteristic curve (AUC).
Results: six hundred and sixty-seven participants were studied. Frail participants according to all scales were associated with a significant increased risk of mortality [relative risk (RR) range 1.6–3.1], readmission (RR range 1.1–1.6), functional decline (RR range 1.2–2.1) and the composite adverse outcome (RR range 1.2–1.6). However, the predictive properties of the frailty-rating scales were poor, at best, for all outcomes assessed (AUC ranging from 0.44 to 0.69).
Conclusion: frailty-rating scales alone are of limited use in risk stratifying older people being discharged from acute medical units.
PMCID: PMC3809719  PMID: 23666406
frailty; risk stratification; acute hospital care; older people
6.  Persistent frequent attenders in primary care: costs, reasons for attendance, organisation of care and potential for cognitive behavioural therapeutic intervention 
BMC Family Practice  2012;13:39.
The top 3% of frequent attendance in primary care is associated with 15% of all appointments in primary care, a fivefold increase in hospital expenditure, and more mental disorder and functional somatic symptoms compared to normal attendance. Although often temporary if these rates of attendance last more than two years, they may become persistent (persistent frequent or regular attendance). However, there is no long-term study of the economic impact or clinical characteristics of regular attendance in primary care. Cognitive behaviour formulation and treatment (CBT) for regular attendance as a motivated behaviour may offer an understanding of the development, maintenance and treatment of regular attendance in the context of their health problems, cognitive processes and social context.
A case control design will compare the clinical characteristics, patterns of health care use and economic costs over the last 10 years of 100 regular attenders (≥30 appointments with general practitioner [GP] over 2 years) with 100 normal attenders (6–22 appointments with GP over 2 years), from purposefully selected primary care practices with differing organisation of care and patient demographics. Qualitative interviews with regular attending patients and practice staff will explore patient barriers, drivers and experiences of consultation, and organisation of care by practices with its challenges. Cognitive behaviour formulation analysed thematically will explore the development, maintenance and therapeutic opportunities for management in regular attenders. The feasibility, acceptability and utility of CBT for regular attendance will be examined.
The health care costs, clinical needs, patient motivation for consultation and organisation of care for persistent frequent or regular attendance in primary care will be explored to develop training and policies for service providers. CBT for regular attendance will be piloted with a view to developing this approach as part of a multifaceted intervention.
PMCID: PMC3390898  PMID: 22607525
High utilisers of care; Primary care; Cognitive behavior therapy; Hypochondriasis; Somatoform disorders; Health care economics and organizations
7.  A pharmacist-led information technology intervention for medication errors (PINCER): a multicentre, cluster randomised, controlled trial and cost-effectiveness analysis 
Lancet  2012;379(9823):136-142.
Medication errors are common in primary care and are associated with considerable risk of patient harm. We tested whether a pharmacist-led, information technology-based intervention was more effective than simple feedback in reducing the number of patients at risk of measures related to hazardous prescribing and inadequate blood-test monitoring of medicines 6 months after the intervention.
In this pragmatic, cluster randomised trial general practices in the UK were stratified by research site and list size, and randomly assigned by a web-based randomisation service in block sizes of two or four to one of two groups. The practices were allocated to either computer-generated simple feedback for at-risk patients (control) or a pharmacist-led information technology intervention (PINCER), composed of feedback, educational outreach, and dedicated support. The allocation was masked to general practices, patients, pharmacists, researchers, and statisticians. Primary outcomes were the proportions of patients at 6 months after the intervention who had had any of three clinically important errors: non-selective non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to those with a history of peptic ulcer without co-prescription of a proton-pump inhibitor; β blockers prescribed to those with a history of asthma; long-term prescription of angiotensin converting enzyme (ACE) inhibitor or loop diuretics to those 75 years or older without assessment of urea and electrolytes in the preceding 15 months. The cost per error avoided was estimated by incremental cost-effectiveness analysis. This study is registered with, number ISRCTN21785299.
72 general practices with a combined list size of 480 942 patients were randomised. At 6 months' follow-up, patients in the PINCER group were significantly less likely to have been prescribed a non-selective NSAID if they had a history of peptic ulcer without gastroprotection (OR 0·58, 95% CI 0·38–0·89); a β blocker if they had asthma (0·73, 0·58–0·91); or an ACE inhibitor or loop diuretic without appropriate monitoring (0·51, 0·34–0·78). PINCER has a 95% probability of being cost effective if the decision-maker's ceiling willingness to pay reaches £75 per error avoided at 6 months.
The PINCER intervention is an effective method for reducing a range of medication errors in general practices with computerised clinical records.
Patient Safety Research Portfolio, Department of Health, England.
PMCID: PMC3328846
8.  Acute medical unit comprehensive geriatric assessment intervention study (AMIGOS) 
Trials  2011;12:200.
Many older people presenting to Acute Medical Units (AMU) are discharged after only a short stay (< 72 hours), yet many re-present to hospital or die within 1 year. Comprehensive Geriatric Assessment may improve patient outcomes for this group.
Patients aged > 70 years and scoring positive on a risk screening tool ('Identification of Seniors At Risk') who are discharged within 72 hours of attending an AMU with a medical crisis, recruited prior to discharge. Sample size is 400. Carers of participants will also be recruited.
Assessment on the AMU and further out-patient management by a specialist physician in geriatric medicine. Assessment and further management will follow the principles of Comprehensive Geriatric Assessment, providing advice and support to primary care services.
Multi-centre, individual patient randomised controlled trial comparing intervention with usual care.
Outcome measurement
Follow up is by postal questionnaire 90 days after randomisation, and data will be entered into the study database by a researcher blind to allocation. The primary outcome is the number of days spent at home (for those admitted from home), or days spent in the same care home (if admitted from a care home). Secondary outcomes include mortality, institutionalisation, health and social care resource use, and scaled outcome measures, including quality of life, disability, mental well-being. Carer strain and well being will also be measured at 90 days.
Comparisons of outcomes and costs, and a cost utility analysis between the intervention and control groups will be carried out.
Trial Registration
PMCID: PMC3184060  PMID: 21864399
9.  Specialist geriatric medical assessment for patients discharged from hospital acute assessment units: randomised controlled trial 
Objective To evaluate the effect of specialist geriatric medical management on the outcomes of at risk older people discharged from acute medical assessment units.
Design Individual patient randomised controlled trial comparing intervention with usual care.
Setting Two hospitals in Nottingham and Leicester, UK.
Participants 433 patients aged 70 or over who were discharged within 72 hours of attending an acute medical assessment unit and at risk of decline as indicated by a score of at least 2 on the Identification of Seniors At Risk tool.
Intervention Assessment made on the acute medical assessment unit and further outpatient management by specialist physicians in geriatric medicine, including advice and support to primary care services.
Main outcome measures The primary outcome was the number of days spent at home (for those admitted from home) or days spent in the same care home (if admitted from a care home) in the 90 days after randomisation. Secondary outcomes were determined at 90 days and included mortality, institutionalisation, dependency, mental wellbeing, quality of life, and health and social care resource use.
Results The two groups were well matched for baseline characteristics, and withdrawal rates were similar in both groups (5%). Mean days at home over 90 days’ follow-up were 80.2 days in the control group and 79.7 in the intervention group. The 95% confidence interval for the difference in means was −4.6 to 3.6 days (P=0.31). No significant differences were found for any of the secondary outcomes.
Conclusions This specialist geriatric medical intervention applied to an at risk population of older people attending and being discharged from acute medical units had no effect on patients’ outcomes or subsequent use of secondary care or long term care.
PMCID: PMC3793323  PMID: 24103444

Results 1-9 (9)