Intratumoural immune signature to identify patients with primary colorectal cancer who do not require follow-up after resection: an observational study.

BACKGROUND: Following surgical and adjuvant treatment of primary colorectal cancer, many patients are routinely followed up with axial imaging (most commonly computerised tomography imaging) and blood carcinoembryonic antigen (a tumour marker) testing. Because fewer than one-fifth of patients will relapse, a large number of patients are followed up unnecessarily. OBJECTIVES: To determine whether or not the intratumoural immune signature could identify a cohort of patients with a relapse rate so low that follow-up is unnecessary. DESIGN: An observational study based on a secondary tissue collection of the tumours from participants in the FACS (Follow-up After Colorectal Cancer Surgery) trial. SETTING AND PARTICIPANTS: Formalin-fixed paraffin-embedded tumour tissue was obtained from 550 out of 1202 participants in the FACS trial. Tissue microarrays were constructed and stained for cluster of differentiation (CD)3+ and CD45RO+ T lymphocytes as well as standard haematoxylin and eosin staining, with a view to manual and, subsequently, automated cell counting. RESULTS: The tissue microarrays were satisfactorily stained for the two immune markers. Manual cell counting proved possible on the arrays, but manually counting the number of cores for the entire study was found to not be feasible; therefore, an attempt was made to use automatic cell counting. Although it is clear that this approach is workable, there were both hardware and software problems; therefore, reliable data could not be obtained within the time frame of the study. LIMITATIONS: The main limitations were the inability to use machine counting because of problems with both hardware and software, and the loss of critical scientific staff. Findings from this research indicate that this approach will be able to count intratumoural immune cells in the long term, but whether or not the original aim of the project proved possible is not known. CONCLUSIONS: The project was not successful in its aim because of the failure to achieve a reliable counting system. FUTURE WORK: Further work is needed to perfect immune cell machine counting and then complete the objectives of this study that are still relevant. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41458548. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 2. See the NIHR Journals Library website for further project information.

Bowel cancer (also known as colorectal cancer) is the fourth commonest cancer in the UK. When the cancer is confined to the bowel and/or the surrounding lymph nodes (early bowel cancer), it is typically treated with an operation to remove the cancer with or without the addition of chemotherapy. Following this treatment, many patients will be cured, but in approximately one in five patients the cancer may come back (recur) either in the bowel or in another organ (e.g. the liver). Consequently, after treatment of early bowel cancer, clinicians often follow up patients in the hope of detecting any recurrent cancer at an early and treatable stage. For the four out of five patients whose cancer will never recur, this follow-up is unnecessary and burdensome on both the NHS and the patients. Better markers are needed to inform which patients do and do not need to undergo this surveillance. Over the last decade, evidence has accumulated to show that the way that a patient's immune system responds to a cancer influences the likelihood of the cancer recurring. It is plausible that those with the most immune cells in their cancer have such a small chance of recurrence that follow-up is not necessary. To validate this in an accurately followed-up population of patients with bowel cancer, we collected cancer tissue specimens from 701 patients in the Follow-up After Colorectal Surgery (FACS) trial and developed methods to count the number of immune cells in their cancers. At present, methods are still under development to automate the process. Indeed, if this were ever to become part of routine practice in NHS laboratories, then automation would be essential.

Relationship between microbiology of throat swab and clinical course among primary care patients with acute cough: a prospective cohort study.

BACKGROUND: Acute lower respiratory tract infections (ALRTIs) account for most antibiotics prescribed in primary care despite lack of efficacy, partly due to clinician uncertainty about aetiology and patient concerns about illness course. Nucleic acid amplification tests could assist antibiotic targeting. METHODS: In this prospective cohort study, 645 patients presenting to primary care with acute cough and suspected ALRTI, provided throat swabs at baseline. These were tested for respiratory pathogens by real-time polymerase chain reaction and classified as having a respiratory virus, bacteria, both or neither. Three hundred fifty-four participants scored the symptoms severity daily for 1 week in a diary (0 = absent to 4 = severe problem). RESULTS: Organisms were identified in 346/645 (53.6%) participants. There were differences in the prevalence of seven symptoms between the organism groups at baseline. Those with a virus alone, and those with both virus and bacteria, had higher average severity scores of all symptoms combined during the week of follow-up than those in whom no organisms were detected [adjusted mean differences 0.204 (95% confidence interval 0.010 to 0.398) and 0.348 (0.098 to 0.598), respectively]. There were no differences in the duration of symptoms rated as moderate or severe between organism groups. CONCLUSIONS: Differences in presenting symptoms and symptoms severity can be identified between patients with viruses and bacteria identified on throat swabs. The magnitude of these differences is unlikely to influence management. Most patients had mild symptoms at 7 days regardless of aetiology, which could inform patients about likely symptom duration.

Circumstances of child deaths in Mali and Uganda: a community-based confidential enquiry.

BACKGROUND: Interventions to reduce child deaths in Africa have often underachieved, causing the Millennium Development Goal targets to be missed. We assessed whether a community enquiry into the circumstances of death could improve intervention effectiveness by identifying local avoidable factors and explaining implementation failures. METHODS: Deaths of children younger than 5 years were ascertained by community informants in two districts in Mali (762 deaths) and three districts in Uganda (442 deaths) in 2011-15. Deaths were investigated by interviewing parents and health workers. Investigation findings were reviewed by a panel of local health-care workers and community representatives, who formulated recommendations to address avoidable factors and, subsequently, oversaw their implementation. FINDINGS: At least one avoidable factor was identified in 97% (95% CI 96-98, 737 of 756) of deaths in children younger than 5 years in Mali and 95% (93-97, 389 of 409) in Uganda. Suboptimal newborn care was a factor in 76% (146 of 194) of neonatal deaths in Mali and 64% (134 of 194) in Uganda. The most frequent avoidable factor in postneonatal deaths was inadequate child protection (mainly child neglect) in Uganda (29%, 63 of 215) and malnutrition in Mali (22%, 124 of 562). 84% (618 of 736 in Mali, 328 of 391 in Uganda) of families had consulted a health-care provider for the fatal illness, but the quality of care was often inadequate. Even in official primary care clinics, danger signs were often missed (43% of cases in Mali [135 of 396], 39% in Uganda [30 of 78]), essential treatment was not given (39% in Mali [154 of 396], 35% in Uganda [27 of 78]), and patients who were seriously ill were not referred to a hospital in time (51% in Mali [202 of 396], 45% in Uganda [35 of 78]). Local recommendations focused on quality of care in health-care facilities and on community issues influencing treatment-seeking behaviour. INTERPRETATION: Local investigation and review of circumstances of death of children in sub-Saharan Africa is likely to lead to more effective interventions than simple consideration of the biomedical causes of death. This approach discerned local public health priorities and implementable solutions to address the avoidable factors identified. FUNDING: European Union's 7th Framework Programme for research and technological development.

Predictors of pneumonia in lower respiratory tract infections: 3C prospective cough complication cohort study.

The aim was to aid diagnosis of pneumonia in those presenting with lower respiratory tract symptoms in routine primary care.A cohort of 28 883 adult patients with acute cough attributed to lower respiratory tract infections (LRTIs) was recruited from 5222 UK practices in 2009-13. Symptoms, signs and treatment were recorded at presentation and subsequent events followed-up for 30 days by chart review. The predictive value of patient characteristics, presenting symptoms and clinical findings for the diagnosis of pneumonia in the first 7 days was established.Of the 720 out of 28 883 (2.5.%) radiographed within 1 week of the index consultation, 115 (16.0%; 0.40% of 28 883) were assigned a definite or probable pneumonia diagnosis. The significant independent predictors of radiograph-confirmed pneumonia were temperature >37.8°C (RR 2.6; 95% CI 1.5-4.8), crackles on auscultation (RR 1.8; 1.1-3.0), oxygen saturation <95% (RR 1.7; 1.0-3.1) and pulse >100·min-1 (RR 1.9; 1.1-3.2). Most patients with pneumonia (99/115, 86.1%) exhibited at least one of these four clinical signs; the positive predictive value of having at least one of these signs was 20.2% (95% CI 17.3-23.1).In routine practice, radiograph-confirmed pneumonia as a short-term complication of LRTI is very uncommon (one in 270). Pulse oximetry may aid the diagnosis of pneumonia in this setting.

Influence of the duration of penicillin prescriptions on outcomes for acute sore throat in adults: the DESCARTE prospective cohort study in UK general practice.

BACKGROUND: Guidelines recommend 10-day treatment courses for acute sore throat, but shorter courses may be used in practice. AIM: To determine whether antibiotic duration predicts adverse outcome of acute sore throat in adults in routine care. DESIGN AND SETTING: A secondary analysis of the DESCARTE (Decision rule for the Symptoms and Complications of Acute Red Throat in Everyday practice) prospective cohort study of 12 829 adults presenting in UK general practice with acute sore throat. METHOD: A brief clinical proforma was used to collect symptom severity and examination findings at presentation. Outcomes were collected by notes review, a sample also completed a symptom diary. The primary outcome was re-consultation with new/non-resolving symptoms within 1 month. The secondary outcome was 'global' poorer symptom control (longer than the median duration or higher than median severity). RESULTS: Antibiotics were prescribed for 62% (7872/12 677) of participants. The most commonly prescribed antibiotic was phenoxymethylpenicillin (76%, 5656/7474) and prescription durations were largely for 5 (20%), 7 (57%), or 10 (22%) days. Compared with 5-day courses, those receiving longer courses were less likely to re-consult with new or non-resolving symptoms (5 days 15.3%, 7 days 13.9%, 10 days 12.2%, 7-day course adjusted risk ratio (RR) 0.92 [95% confidence interval [CI] = 0.76 to 1.11] and 10-days RR 0.86 [95% CI = 0.59 to 1.23]) but these differences did not reach statistical significance. CONCLUSION: In adults prescribed antibiotics for sore throat, the authors cannot rule out a small advantage in terms of reduced re-consultation for a 10-day course of penicillin, but the effect is likely to be small.

Symptom response to antibiotic prescribing strategies in acute sore throat in adults: the DESCARTE prospective cohort study in UK general practice.

BACKGROUND: A delayed or 'just in case' prescription has been identified as having potential to reduce antibiotic use in sore throat. AIM: To determine the symptomatic outcome of acute sore throat in adults according to antibiotic prescription strategy in routine care. DESIGN AND SETTING: A secondary analysis of the DESCARTE (Decision rule for the Symptoms and Complications of Acute Red Throat in Everyday practice) prospective cohort study comprising adults aged ≥16 years presenting with acute sore throat (≤2 weeks' duration) managed with treatment as usual in primary care in the UK. METHOD: A random sample of 2876 people from the full cohort were requested to complete a symptom diary. A brief clinical proforma was used to collect symptom severity and examination findings at presentation. Outcome details were collected by notes review and a detailed symptom diary. The primary outcome was poorer 'global' symptom control (defined as longer than the median duration or higher than median symptom severity). Analyses controlled for confounding by indication (propensity to prescribe antibiotics). RESULTS: A total of 1629/2876 (57%) of those requested returned a symptom diary, of whom 1512 had information on prescribing strategy. The proportion with poorer global symptom control was greater in those not prescribed antibiotics 398/587 (68%) compared with those prescribed immediate antibiotics 441/728 (61%) or delayed antibiotic prescription 116/197 59%); adjusted risk ratio (RR) (95% confidence intervals [CI]): immediate RR 0.87 (95% CI = 0.70 to 0.96), P = 0.006; delayed RR 0.88 (95% CI = 0.78 to 1.00), P = 0.042. CONCLUSION: In the routine care of adults with sore throat, a delayed antibiotic strategy confers similar symptomatic benefits to immediate antibiotics compared with no antibiotics. If a decision is made to prescribe an antibiotic, a delayed antibiotic strategy is likely to yield similar symptomatic benefit to immediate antibiotics.

What carcinoembryonic antigen level should trigger further investigation during colorectal cancer follow-up? A systematic review and secondary analysis of a randomised controlled trial.

BACKGROUND: Following primary surgical and adjuvant treatment for colorectal cancer, many patients are routinely followed up with blood carcinoembryonic antigen (CEA) testing. OBJECTIVE: To determine how the CEA test result should be interpreted to inform the decision to undertake further investigation to detect treatable recurrences. DESIGN: Two studies were conducted: (1) a Cochrane review of existing studies describing the diagnostic accuracy of blood CEA testing for detecting colorectal recurrence; and (2) a secondary analysis of data from the two arms of the FACS (Follow-up After Colorectal Surgery) trial in which CEA testing was carried out. SETTING AND PARTICIPANTS: The secondary analysis was based on data from 582 patients recruited into the FACS trial between 2003 and 2009 from 39 NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence and followed up for 5 years. CEA testing was undertaken in general practice. RESULTS: In the systematic review we identified 52 studies for meta-analysis, including in aggregate 9717 participants (median study sample size 139, interquartile range 72-247). Pooled sensitivity at the most commonly recommended threshold in national guidelines of 5 µg/l was 71% [95% confidence interval (CI) 64% to 76%] and specificity was 88% (95% CI 84% to 92%). In the secondary analysis of FACS data, the diagnostic accuracy of a single CEA test was less than was suggested by the review [area under the receiver operating characteristic curve (AUC) 0.74, 95% CI 0.68 to 0.80]. At the commonly recommended threshold of 5 µg/l, sensitivity was estimated as 50.0% (95% CI 40.1% to 59.9%) and lead time as about 3 months. About four in 10 patients without a recurrence will have at least one false alarm and six out of 10 tests will be false alarms (some patients will have multiple false alarms, particularly smokers). Making decisions to further investigate based on the trend in serial CEA measurements is better (AUC for positive trend 0.85, 95% CI 0.78 to 0.91), but to maintain approximately 70% sensitivity with 90% specificity it is necessary to increase the frequency of testing in year 1 and to apply a reducing threshold for investigation as measurements accrue. LIMITATIONS: The reference standards were imperfect and the main analysis was subject to work-up bias and had limited statistical precision and no external validation. CONCLUSIONS: The results suggest that (1) CEA testing should not be used alone as a triage test; (2) in year 1, testing frequency should be increased (to monthly for 3 months and then every 2 months); (3) the threshold for investigating a single test result should be raised to 10 µg/l; (4) after the second CEA test, decisions to investigate further should be made on the basis of the trend in CEA levels; (5) the optimal threshold for investigating the CEA trend falls over time; and (6) continuing smokers should not be monitored with CEA testing. Further research is needed to explore the operational feasibility of monitoring the trend in CEA levels and to externally validate the proposed thresholds for further investigation. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015019327 and Current Controlled Trials ISRCTN93652154. FUNDING: The main FACS trial and this substudy were funded by the National Institute for Health Research Health Technology Assessment programme.

A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent.

BACKGROUND: Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base. OBJECTIVE: To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent. DESIGN: Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (n = 301), (2) CEA testing only (n = 300), (3) computerised tomography (CT) only (n = 299) or (4) CEA testing and CT (n = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata). SETTING: Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence. PARTICIPANTS: A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l. MAIN OUTCOME MEASURES: Primary outcome Surgical treatment of recurrence with curative intent. Secondary outcomes Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained. RESULTS: Detection of recurrence During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%; p = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%; p = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. Survival A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank p = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%. Cost-effectiveness The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy. LIMITATIONS: Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality. CONCLUSIONS: Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41458548. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.

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<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.

The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence: Results from the FACS trial.

OBJECTIVE: To evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence. BACKGROUND: Patients who have undergone curative resection for primary colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines. METHODS: A secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported. RESULTS: Of 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5µg/L achieves at best 50.0% sensitivity (95% CI: 40.1-59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2-64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5µg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5-46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others-at the 5µg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals. CONCLUSION: Our results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed.

Should all acutely ill children in primary care be tested with point-of-care CRP: a cluster randomised trial.

BACKGROUND: Point-of-care blood C-reactive protein (CRP) testing has diagnostic value in helping clinicians rule out the possibility of serious infection. We investigated whether it should be offered to all acutely ill children in primary care or restricted to those identified as at risk on clinical assessment. METHODS: Cluster randomised controlled trial involving acutely ill children presenting to 133 general practitioners (GPs) at 78 GP practices in Belgium. Practices were randomised to undertake point-of-care CRP testing in all children (1730 episodes) or restricted to children identified as at clinical risk (1417 episodes). Clinical risk was assessed by a validated clinical decision rule (presence of one of breathlessness, temperature ≥ 40 °C, diarrhoea and age 12-30 months, or clinician concern). The main trial outcome was hospital admission with serious infection within 5 days. No specific guidance was given to GPs on interpreting CRP levels but diagnostic performance is reported at 5, 20, 80 and 200 mg/L. RESULTS: Restricting CRP testing to those identified as at clinical risk substantially reduced the number of children tested by 79.9 % (95 % CI, 77.8-82.0 %). There was no significant difference between arms in the number of children with serious infection who were referred to hospital immediately (0.16 % vs. 0.14 %, P = 0.88). Only one child with a CRP < 5 mg/L had an illness requiring admission (a child with viral gastroenteritis admitted for rehydration). However, of the 80 children referred to hospital to rule out serious infection, 24 (30.7 %, 95 % CI, 19.6-45.6 %) had a CRP < 5 mg/L. CONCLUSIONS: CRP testing should be restricted to children at higher risk after clinical assessment. A CRP < 5 mg/L rules out serious infection and could be used by GPs to avoid unnecessary hospital referrals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02024282 (registered on 14th September 2012).

Blood Measurement of Carcinoembryonic Antigen Level for Detecting Recurrence of Colorectal Cancer.

CLINICAL QUESTION: What is the trade-off between sensitivity and specificity at specific carcinoembryonic antigen (CEA) thresholds for detecting recurrent colorectal cancer? BOTTOM LINE: To detect colorectal cancer recurrence, the sensitivity of CEA ranges from 68% for a threshold of 10 µg/L to 82% for a threshold of 2.5 µg/L and the specificity ranges from 97% for a threshold of 10 µg/L to 80% for a threshold of 2.5 µg/L.

Variation in Direct Access to Tests to Investigate Cancer: A Survey of English General Practitioners.

BACKGROUND: The 2015 NICE guidelines for suspected cancer recommend that English General Practitioners have direct access to diagnostic tests to investigate symptoms of cancer that do not meet the criteria for urgent referral. We aimed to identify the proportion of GPs in England with direct access to these tests. METHODS: We recruited 533 English GPs through a national clinical research network to complete an online survey about direct access to laboratory, radiology, and endoscopy tests in the three months leading up to the release of the 2015 NICE guidance. If they had direct access to a diagnostic test, GPs were asked about the time necessary to arrange a test and receive a report. Results are reported by NHS sub-region and, adjusting for sampling, for England as a whole. RESULTS: Almost all GPs reported direct access to x-ray and laboratory investigations except faecal occult blood testing (54%, 95% CI 49-59%) and urine protein electrophoresis (89%, 95% CI 84-92%). Fewer GPs had direct access to CT scans (54%, 95% CI 49-59%) or endoscopy (colonoscopy 32%, 95% CI 28-37%; gastroscopy 72%, 95% CI 67-77%). There was significant variation in direct access between NHS regions for the majority of imaging tests-for example, from 20 to 85% to MRI. Apart from x-ray, very few GPs (1-22%) could access radiology and endoscopy within the timescales recommended by NICE. The modal request to test time was 2-4 weeks for routine radiology and 4-6 weeks for routine endoscopy with results taking another 1-2 weeks. CONCLUSION: At the time that the 2015 NICE guideline was released, local investment was required to not only provide direct access but also reduce the interval between request and test and speed up reporting. Further research using our data as a benchmark is now required to identify whether local improvements in direct access have been achieved in response to the NICE targets. If alternative approaches to test access are to be proposed they must be piloted comprehensively and underpinned by robust effectiveness data.

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. METHODS 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 two-fold higher in the two most deprived socioeconomic quintiles than in the most affluent quintile, and three-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.

International variation in adherence to referral guidelines for suspected cancer: a secondary analysis of survey data.

BACKGROUND: Variation in cancer survival persists between comparable nations and appears to be due, in part, to primary care practitioners (PCPs) having different thresholds for acting definitively in response to cancer-related symptoms. AIM: To explore whether cancer guidelines, and adherence to them, differ between jurisdictions and impacts on PCPs' propensity to take definitive action on cancer-related symptoms. DESIGN AND SETTING: A secondary analysis of survey data from six countries (10 jurisdictions) participating in the International Cancer Benchmarking Partnership. METHOD: PCPs' responses to five clinical vignettes presenting symptoms and signs of lung (n = 2), colorectal (n = 2), and ovarian cancer (n = 1) were compared with investigation and referral recommendations in cancer guidelines. RESULTS: Nine jurisdictions had guidelines covering the two colorectal vignettes. For the lung vignettes, although eight jurisdictions had guidelines for the first, the second was covered by a Swedish guideline alone. Only the UK and Denmark had an ovarian cancer guideline. Survey responses of 2795 PCPs (crude response rate: 12%) were analysed. Guideline adherence ranged from 20-82%. UK adherence was lower than other jurisdictions for the lung vignette covered by the guidance (47% versus 58%; P <0.01) but similar (45% versus 46%) or higher (67% versus 38%; P <0.01) for the two colorectal vignettes. PCPs took definitive action least often when a guideline recommended a non-definitive action or made no recommendation. UK PCPs adhered to recommendations for definitive action less than their counterparts (P <0.01). There wasno association between jurisdictional guideline adherence and 1-year survival. CONCLUSION: Cancer guideline content is variable between similarly developed nations and poor guideline adherence does not explain differential survival. Guidelines that fail to cover high-risk presentations or that recommend non-definitive action may reduce definitive diagnostic action.

Impact of Contextual Factors on the Effect of Interventions to Improve Health Worker Performance in Sub-Saharan Africa: Review of Randomised Clinical Trials.

BACKGROUND: 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. METHODS AND FINDINGS: 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<5 case fatality 5% versus 10%, p<0.01; maternal in-hospital mortality 6.8/1000 versus 10.3/1000; p<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. CONCLUSIONS: 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.

C-reactive protein point-of-care testing in acutely ill children: a mixed methods study in primary care.

BACKGROUND: Point-of-care C-reactive protein (CRP) testing of adults with acute respiratory infection in primary care reduces antibiotic prescribing by 22%. The acceptability and impact of CRP testing in children is unknown OBJECTIVE: To determine the acceptability and impact of CRP testing in acutely ill children. DESIGN: Mixed methods study comprising an observational cohort with a nested randomised controlled trial and embedded qualitative study. SUBJECTS AND SETTING: Children presenting with an acute illness to general practice out-of-hours services; children with a temperature ≥38°C were randomised in the nested trial; parents and clinical staff were invited to the qualitative study. MAIN OUTCOMES: Informed consent rates; parental and staff views on testing. RESULTS: Consent to involvement in the study was obtained for 200/297 children (67.3%, 95% CI 61.7% to 72.6%); the finger-prick test might have been a contributory factor for 63 of the 97 children declining participation but it was cited as a definite factor in only 10 cases. None of the parents or staff raised concerns about the acceptability of testing, describing the pain caused as minor and transient. General practitioner views on the utility of the CRP test were inconsistent. CONCLUSIONS: CRP point-of-care testing in children is feasible in primary care and is likely to be acceptable. However, it will not reduce antibiotic prescribing and hospital referrals until general practitioners accept its diagnostic value in children. TRIAL REGISTRATION NUMBER: ISRCTN 69736109.

Site and Stage of Colorectal Cancer Influence the Likelihood and Distribution of Disease Recurrence and Postrecurrence Survival: Data From the FACS Randomized Controlled Trial.

OBJECTIVES: To describe patterns of recurrence and postrecurrence survival in a large cohort of accurately staged patients with Dukes' A-C colorectal cancer. BACKGROUND: Recurrence remains a frequent cause of mortality after the treatment of colorectal cancer with curative intent. Understanding the likelihood and site of recurrence informs adjuvant treatment and follow-up. METHODS: Retrospective cohort analysis of data from the FACS (follow-up after colorectal cancer surgery) trial after a median 4.4 years of follow-up; postrecurrence survival was calculated using the Kaplan-Meier method. RESULTS: Complete data were available for 94% of patients; 189 (17%) patients had experienced recurrence. Incidence of recurrence varied according to the site of the primary (right colon: 51/379, 14%; left colon: 68/421, 16%; rectum: 70/332, 21%; P = 0.023) and initial stage (Dukes' A: 26/249, 10%; Dukes' B: 81/537, 15%; Dukes' C: 82/346, 24%; P < 0.0001). Pulmonary recurrence was most frequently associated with rectal tumors, and multisite/other recurrence with right-sided colonic tumors. Recurrences from lower-stage tumors were more likely to be treatable with curative intent (Dukes' A: 13/26, 50%; Dukes' B: 32/81, 40%; Dukes' C: 20/82, 24%; P = 0.03). Those with rectal tumors benefited most from follow-up (proportion with treatable recurrence: rectum 30/332, 9%; left colon 23/421, 6%; right colon 12/379, 3%; P = 0.003). Both initial stage (log rank P = 0.005) and site of primary (log rank P = 0.01) influenced postrecurrence survival. CONCLUSIONS: The likelihood and site of recurrence, and survival, are influenced by the site and stage of the primary tumor. Those with rectal cancers benefited most from follow-up.ISRCTN 41458548.