Considering Usual Medical Care in Clinical Trial Design

Liza Dawson and colleagues discuss the scientific and ethical issues associated with choosing clinical trial designs when there is no consensus on what constitutes usual care

Predicting infectious complications in neutropenic children and young people with cancer (IPD protocol)

<p>Abstract</p> <p>Background</p> <p>A common and potentially life-threatening complication of the treatment of childhood cancer is infection, which frequently presents as fever with neutropenia. The standard management of such episodes is the extensive use of intravenous antibiotics, and though it produces excellent survival rates of over 95%, it greatly inconveniences the three-fourths of patients who do not require such aggressive treatment. There have been a number of studies which have aimed to develop risk prediction models to stratify treatment. Individual participant data (IPD) meta-analysis in therapeutic studies has been developed to improve the precision and reliability of answers to questions of treatment effect and recently have been suggested to be used to answer questions regarding prognosis and diagnosis to gain greater power from the frequently small individual studies.</p> <p>Design</p> <p>In the IPD protocol, we will collect and synthesise IPD from multiple studies and examine the outcomes of episodes of febrile neutropenia as a consequence of their treatment for malignant disease. We will develop and evaluate a risk stratification model using hierarchical regression models to stratify patients by their risk of experiencing adverse outcomes during an episode. We will also explore specific practical and methodological issues regarding adaptation of established techniques of IPD meta-analysis of interventions for use in synthesising evidence derived from IPD from multiple studies for use in predictive modelling contexts.</p> <p>Discussion</p> <p>Our aim in using this model is to define a group of individuals at low risk for febrile neutropenia who might be treated with reduced intensity or duration of antibiotic therapy and so reduce the inconvenience and cost of these episodes, as well as to define a group of patients at very high risk of complications who could be subject to more intensive therapies. The project will also help develop methods of IPD predictive modelling for use in future studies of risk prediction.</p

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Guidelines for management of ischaemic stroke and transient ischaemic attack 2008

This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation

Impact of contextual factors on the effect of interventions to improve health worker performance in sub-Saharan Africa: review of randomised clinical trials

Africa bears 24% of the global burden of disease but has only 3% of the world's health workers. Substantial variation in health worker performance adds to the negative impact of this significant shortfall. We therefore sought to identify interventions implemented in sub-Saharan African aiming to improve health worker performance and the contextual factors likely to influence local effectiveness.A systematic search for randomised controlled trials of interventions to improve health worker performance undertaken in sub-Saharan Africa identified 41 eligible trials. Data were extracted to define the interventions' components, calculate the absolute improvement in performance achieved, and document the likelihood of bias. Within-study variability in effect was extracted where reported. Statements about contextual factors likely to have modified effect were subjected to thematic analysis. Interventions to improve health worker performance can be very effective. Two of the three trials assessing mortality impact showed significant reductions in death rates (age&lt;5 case fatality 5% versus 10%, p&lt;0.01; maternal in-hospital mortality 6.8/1000 versus 10.3/1000; p&lt;0.05). Eight of twelve trials focusing on prescribing had a statistically significant positive effect, achieving an absolute improvement varying from 9% to 48%. However, reported range of improvement between centres within trials varied substantially, in many cases exceeding the mean effect. Nine contextual themes were identified as modifiers of intervention effect across studies; most frequently cited were supply-line failures, inadequate supervision or management, and failure to follow-up training interventions with ongoing support, in addition to staff turnover.Interventions to improve performance of existing staff and service quality have the potential to improve patient care in underserved settings. But in order to implement interventions effectively, policy makers need to understand and address the contextual factors which can contribute to differences in local effect. Researchers therefore must recognise the importance of reporting how context may modify effect size

Which early 'red flag' symptoms identify children with meningococcal disease in primary care?

BACKGROUND: Symptoms are part of the initial evaluation of children with acute illness, and are often used to help identify those who may have serious infections. Meningococcal disease is a rapidly progressive infection that needs to be recognised early among children presenting to primary care. AIM: To determine the diagnostic value of presenting symptoms in primary care for meningococcal disease. DESIGN OF STUDY: Data on a series of presenting symptoms were collected using a parental symptoms checklist at point of care for children presenting to a GP with acute infection. Symptom frequencies were compared with existing data on the pre-hospital features of 345 children with meningococcal disease. SETTING: UK primary care. METHOD: The study recruited a total of 1212 children aged under 16 years presenting to their GP with an acute illness, of whom 924 had an acute self-limiting infection, including 407 who were reported by parents to be febrile. Symptom frequencies were compared with those reported by parents of 345 children with meningococcal disease. Main outcome measures were diagnostic characteristics of individual symptoms for meningococcal disease. RESULTS: Five symptoms have clinically useful positive likelihood ratios (LR+) for meningococcal disease: confusion (LR+ = 24.2, 95% confidence interval [CI] = 11.5 to 51.3), leg pain (LR+ = 7.6, 95% CI = 4.9 to 11.9), photophobia (LR+ = 6.5, 95% CI = 3.8 to 11.0), rash (LR+ = 5.5, 95% CI = 4.3 to 7.1), and neck pain/stiffness (LR+ = 5.3, 95% CI = 3.5 to 8.3). Cold hands and feet had limited diagnostic value (LR+ = 2.3, 95% CI = 1.9 to 3.0), while headache (LR+ = 1.0, 95% CI = 0.8 to 1.3), and pale colour (LR+ = 0.3, 95% CI = 0.2 to 0.5) did not discriminate meningococcal disease in children. CONCLUSION: This study confirms the diagnostic value of classic 'red flag' symptoms of neck stiffness, rash, and photophobia, but also suggests that the presence of confusion or leg pain in a child with an unexplained acute febrile illness should also usually prompt a face-to-face assessment to exclude meningococcal disease. Telephone triage systems and primary care clinicians should consider these as 'red flags' for serious infection

Antibiotic prescription strategies and adverse outcome for uncomplicated lower respiratory tract infections: prospective cough complication cohort (3C) study.

Objective To assess the impact on adverse outcomes of different antibiotic prescribing strategies for lower respiratory tract infections in people aged 16 years or more. Design Prospective cohort study. Setting UK general practice. Participants 28 883 patients with lower respiratory tract infection; symptoms, signs, and antibiotic prescribing strategies were recorded at the index consultation. Main Outcome Measures The main outcomes were reconsultation with symptoms of lower respiratory tract infection in the 30 days after the index consultation, hospital admission, or death. Multivariable analysis controlled for an extensive list of variables related to the propensity to prescribe antibiotics and for clustering by doctor. Results Of the 28 883 participants, 104 (0.4%) were referred to hospital for radiographic investigation or admission, or both on the day of the index consultation, or were admitted with cancer. Of the remaining 28 779, subsequent hospital admission or death occurred in 26/7332 (0.3%) after no antibiotic prescription, 156/17 628 (0.9%) after prescription for immediate antibiotics, and 14/3819 (0.4%) after a prescription for delayed antibiotics. Multivariable analysis documented no reduction in hospital admission and death after immediate antibiotics (multivariable risk ratio 1.06, 95% confidence interval 0.63 to 1.81, P=0.84) and a non-significant reduction with delayed antibiotics (0.81, 0.41 to 1.64, P=0.61). Reconsultation for new, worsening, or non-resolving symptoms was common (1443/7332 (19.7%), 4455/17 628 (25.3%), and 538/3819 (14.1%), respectively) and was significantly reduced by delayed antibiotics (multivariable risk ratio 0.64, 0.57 to 0.72, P&lt;0.001) but not by immediate antibiotics (0.98, 0.90 to 1.07, P=0.66). Conclusion Prescribing immediate antibiotics may not reduce subsequent hospital admission or death for young people and adults with uncomplicated lower respiratory tract infection, and such events are uncommon. If clinicians are considering antibiotics, a delayed prescription may be preferable since it is associated with a reduced number of reconsultations for worsening illness.</p

Large-scale community echocardiographic screening reveals a major burden of undiagnosed valvular heart disease in older people: the OxVALVE Population Cohort Study

Background Valvular heart disease (VHD) is expected to become more common as the population ages. However, current estimates of its natural history and prevalence are based on historical studies with potential sources of bias. We conducted a cross-sectional analysis of the clinical and epidemiological characteristics of VHD identified at recruitment of a large cohort of older people. Method and Results We enrolled 2500 individuals aged ≥65 years from a primary care population and screened for undiagnosed VHD using transthoracic echocardiography. Newly identified (predominantly mild) VHD was detected in 51% of participants. The most common abnormalities were aortic sclerosis (34%), mitral regurgitation (22%), and aortic regurgitation (15%). Aortic stenosis was present in 1.3%. The likelihood of undiagnosed VHD was 2-fold higher in the two most deprived socioeconomic quintiles than in the most affluent quintile, and 3-fold higher in individuals with atrial fibrillation. Clinically significant (moderate or severe) undiagnosed VHD was identified in 6.4%. In addition, 4.9% of the cohort had pre-existing VHD (a total prevalence of 11.3%). Projecting these findings using population data, we estimate that the prevalence of clinically significant VHD will double before 2050. Conclusions Previously undetected VHD affects 1 in 2 of the elderly population and is more common in lower socioeconomic classes. These unique data demonstrate the contemporary clinical and epidemiological characteristics of VHD in a large population-based cohort of older people and confirm the scale of the emerging epidemic of VHD, with widespread implications for clinicians and healthcare resources.</p