Genetic Variation at the BDNF Locus: Evidence for Association with Long-Term Outcome after Ischemic Stroke

Background and Purpose

Rates and extent of recovery after stroke vary considerably between individuals and genetic factors are thought to contribute to post-stroke outcome. Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair and has been shown to be involved in stroke severity, recovery, and outcome in animal models. Few clinical studies on BDNF genotypes in relation to ischemic stroke have been performed. The aims of the present study are therefore to investigate whether genetic variation at the BDNF locus is associated with initial stroke severity, recovery and/or short-term and long-term functional outcome after ischemic stroke.

Methods

Four BDNF tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS; 600 patients and 600 controls, all aged 18–70 years). Stroke severity was assessed using the NIH Stroke Scale (NIHSS). Stroke recovery was defined as the change in NIHSS over a 3-month period. Short- and long-term functional outcome post-stroke was assessed using the modified Rankin Scale at 3 months and at 2 and 7 years after stroke, respectively.

Results

No SNP was associated with stroke severity or recovery at 3 months and no SNP had an impact on short-term outcome. However, rs11030119 was independently associated with poor functional outcome 7-years after stroke (OR 0.66, 95% CI 0.46–0.92; P =  0.006).

Conclusions

BDNF gene variants were not major contributors to ischemic stroke severity, recovery, or short-term functional outcome. However, this study suggests that variants in the BDNF gene may contribute to poor long-term functional outcome after ischemic stroke.     

Assessment of Prosthesis Alignment after Revision Total Knee Arthroplasty Using EOS 2D and 3D Imaging: A Reliability Study

Introduction

A new low-dose X-ray device, called EOS, has been introduced for determining lower-limb alignment in 2D and 3D. Reliability has not yet been assessed when using EOS on lower limbs containing a knee prosthesis. Therefore purpose of this study was to determine intraobserver and interobserver reliability of EOS 2D and 3D knee prosthesis alignment measurements after revision total knee arthroplasty (rTKA).

Methods

Forty anteroposterior and lateral images of 37 rTKA patients were included. Two observers independently performed measurements on these images twice. Varus/valgus angles were measured in 2D (VV2D) and 3D (VV3D). Intraclass correlation coefficients and the Bland and Altman method were used to determine reliability. T-tests were used to test potential differences.

Results

Intraobserver and interobserver reliability were excellent for VV2D and VV3D. No significant difference or bias between the first and second measurements or the two observers was found. A significant mean and absolute difference of respectively 1.00° and 1.61° existed between 2D and 3D measurements.

Conclusions

EOS provides reliable varus/valgus measurements in 2D and 3D for the alignment of the knee joint with a knee prosthesis. However, significant differences exist between varus/valgus measurements in 2D and 3D.     

Assessment of the Integral Toxicity of Aquatic Medium Contamination with Oil and Oil Products Using Bacterial Tests

A biotest kit was used to assess the integral toxicity level of aquatic environment contamination with oil and oil products. The integral toxicity dynamics were also monitored during biodegradation of oil and oil products by an association of oil-degrading strains, including Acinetobacter sp., Mycobacterium flavescens, and Rhodococcussp. The following bacterial tests were used: the bioluminescence (BL) test based on Photobacterium leiognathi; electroorientation (EO), optoosmotic (OO), and growth tests; and the reducing activity (RA) test based on an Agrobacterium radiobacter culture. No significant increase in the integral toxicity level of the aquatic medium was observed when diesel fuel and kerosene contamination had been subjected to biodegradation. Although rapid biotests (EO, OO, RA, and BL) detected a pronounced increase in the integral toxicity of the aquatic environment, long-term growth biotests revealed no statistically significant increase in the toxicity level.     

Multi-Dimensional Health Assessment Questionnaire in China: Reliability,Validity and Clinical Value in Patients with Rheumatoid Arthritis

Objective

To evaluate the psychometric properties and clinical utility of Chinese Multidimensional Health Assessment Questionnaire (MDHAQ-C) in patients with rheumatoid arthritis (RA) in China.

Methods

162 RA patients were recruited in the evaluation process. The reliability of the questionnaire was tested by internal consistency and item analysis. Convergent validity was assessed by correlations of MDHAQ-C with Health Assessment Questionnaire (HAQ), the 36-item Short-Form Health Survey (SF-36) and the Hospital anxiety and depression scales (HAD). Discriminant validity was tested in groups of patients with varied disease activities and functional classes. To evaluate the clinical values, correlations were calculated between MDHAQ-C and indices of clinical relevance and disease activity. Agreement with the Disease Activity Score (DAS28) and Clinical Disease Activity Index (CDAI) was estimated.

Results

The Cronbach''s alpha was 0.944 in the Function scale (FN) and 0.768 in the scale of psychological status (PS). The item analysis indicated all the items of FN and PS are correlated at an acceptable level. MDHAQ-C correlated with the questionnaires significantly in most scales and scores of scales differed significantly in groups of different disease activity and functional status. MDHAQ-C has moderate to high correlation with most clinical indices and high correlation with a spearman coefficient of 0.701 for DAS 28 and 0.843 for CDAI. The overall agreement of categories was satisfying.

Conclusion

MDHAQ-C is a reliable, valid instrument for functional measurement and a feasible, informative quantitative index for busy clinical settings in Chinese RA patients.     

Gender Differences in 1-Year Clinical Characteristics and Outcomes after Stroke: Results from the China National Stroke Registry

Background

Previous reports have shown inconsistent results on clinical outcomes between women and men after stroke, and little is known about gender differences on outcomes in Chinese post-stroke patients. The aim of this study was to explore whether there were gender differences on clinical characteristics and outcomes in Chinese patients after ischemic stroke by using the data from the China National Stroke Registry (CNSR).

Methods and Findings

Out of 12,415 consecutively recruited patients with acute ischemic stroke in the CNSR from 2007 to 2008, 11,560 (93.1%) patients were followed up for 12 months. Their clinical characteristics and outcomes on death, recurrence, and dependency were recorded. The multivariate logistic regression was performed to determine whether there were gender differences in these outcomes. Women were older than men at baseline (67.9 vs. 64.0 years, P<0.001). Women had a higher mortality, recurrence rate, and dependency rate at 3, 6, and 12 months than men, but after adjusting for age, history of diabetes, pre-stroke dependency, stroke severity, in-hospital complications, and other confounders, there were no statistically significant differences in gender on mortality and recurrence rate at 3, 6, and 12 months; and dependency rate at 3, and 6 months. However, the dependency rate at 12 months remained significantly higher in women (odds ratio, 1.24; 95% confidence interval, 1.06 to 1.45).

Conclusions

There are many differences in clinical characteristics between women and men after ischemic stroke in China. Compared with men, women are more dependent at 12 months after stroke. This difference still exists after controlling the potential confounders.     

Reliability of Visual Assessment of Non-Contrast CT,CT Angiography Source Images and CT Perfusion in Patients with Suspected Ischemic Stroke

Background and Purpose

Good reliability of methods to assess the extent of ischemia in acute stroke is important for implementation in clinical practice, especially between observers with varying experience. Our aim was to determine inter- and intra-observer reliability of the 1/3 middle cerebral artery (MCA) rule and the Alberta Stroke Program Early CT Score (ASPECTS) for different CT modalities in patients suspected of acute ischemic stroke.

Methods

We prospectively included 105 patients with acute neurological deficit due to suspected acute ischemic stroke within 9 hours after symptom onset. All patients underwent non-contrast CT, CT perfusion and CT angiography on admission. All images were evaluated twice for presence of ischemia, ischemia with >1/3 MCA involvement, and ASPECTS. Four observers evaluated twenty scans twice for intra-observer agreement. We used kappa statistics and intraclass correlation coefficient to calculate agreement.

Results

Inter-observer agreement for the 1/3 MCA rule and ASPECTS was fair to good for non-contrast CT, poor to good for CT angiography source images, but excellent for all CT perfusion maps (cerebral blood volume, mean transit time, and predicted penumbra and infarct maps). Intra-observer agreement for the 1/3 MCA rule and ASPECTS was poor to good for non-contrast CT, fair to moderate for CT angiography source images, and good to excellent for all CT perfusion maps.

Conclusion

Between observers with a different level of experience, agreement on the radiological diagnosis of cerebral ischemia is much better for CT perfusion than for non-contrast CT and CT angiography source images, and therefore CT perfusion is a very reliable addition to standard stroke imaging.     

Assessment of Lower Limb Muscle Strength and Power Using Hand-Held and Fixed Dynamometry: A Reliability and Validity Study

Introduction

Hand-held dynamometry (HHD) has never previously been used to examine isometric muscle power. Rate of force development (RFD) is often used for muscle power assessment, however no consensus currently exists on the most appropriate method of calculation. The aim of this study was to examine the reliability of different algorithms for RFD calculation and to examine the intra-rater, inter-rater, and inter-device reliability of HHD as well as the concurrent validity of HHD for the assessment of isometric lower limb muscle strength and power.

Methods

30 healthy young adults (age: 23±5yrs, male: 15) were assessed on two sessions. Isometric muscle strength and power were measured using peak force and RFD respectively using two HHDs (Lafayette Model-01165 and Hoggan microFET2) and a criterion-reference KinCom dynamometer. Statistical analysis of reliability and validity comprised intraclass correlation coefficients (ICC), Pearson correlations, concordance correlations, standard error of measurement, and minimal detectable change.

Results

Comparison of RFD methods revealed that a peak 200ms moving window algorithm provided optimal reliability results. Intra-rater, inter-rater, and inter-device reliability analysis of peak force and RFD revealed mostly good to excellent reliability (coefficients ≥ 0.70) for all muscle groups. Concurrent validity analysis showed moderate to excellent relationships between HHD and fixed dynamometry for the hip and knee (ICCs ≥ 0.70) for both peak force and RFD, with mostly poor to good results shown for the ankle muscles (ICCs = 0.31–0.79).

Conclusions

Hand-held dynamometry has good to excellent reliability and validity for most measures of isometric lower limb strength and power in a healthy population, particularly for proximal muscle groups. To aid implementation we have created freely available software to extract these variables from data stored on the Lafayette device. Future research should examine the reliability and validity of these variables in clinical populations.     

Assessment of Intraocular Measurements in Neonatal Foals and Association with Gender,Laterality, and Body Weight: A Clinical Study

Objective of this study was to describe intraocular measurements in newly born foals (1–7 days of age) and assess the association between globe measurements and gender, laterality, and body weight. B-scan ultrasonographic biometry was performed on both eyes of 22 healthy foals (44 eyes) ages 1–7 days using a 10-MHz transducer. Intraocular measurements (anterior chamber depth, central lens thickness, vitreous chamber depth, axial globe length, longitudinal globe length, lens poles distance) were carried out using the ultrasound internal calipers. The influence of gender (male or female), laterality (right or left eye), and body weight (“light” <48 kg; “heavy” ≥48 kg) on ocular measurements was analysed by the Student t test. Values of P<0.05 were accepted as significant for all analyses. Mean anterior chamber depth was 2.2±0.5 mm (Standard Deviation); central lens thickness was 9.9±0.8 mm; vitreous chamber depth was 15.5±1.1 mm; axial globe length was 27.6±1.6 mm; longitudinal globe length was 35.8±1.2 mm, and lens poles distance was 16.4±1.0 mm. Intraocular measurements were not influenced by gender, laterality nor body weight. This study provides reference values for intraocular measurements in neonatal foals and may be useful in the diagnosis and treatment of congenital and acquired pathologies involving the globe.     

研究报告: 急性缺血性卒中患者血清脑红蛋白的动态变化及临床意义

目的 脑红蛋白（neuroglobin,Ngb）又称神经球蛋白,是一种携氧球蛋白。有研究证明Ngb在脑缺血缺氧疾病中具有神经保护作用,对氧具有高亲和力,有助于预防缺氧缺血性脑损伤,并影响急性缺血性卒中（acute ischemic stroke,AIS）的预后。本研究观察了AIS后血清Ngb水平的变化,并评估了Ngb与卒中严重程度及预后的关系。方法 前瞻性地募集AIS患者和健康对照者进行研究。在AIS患者起病后不同时间点（脑梗死发病后72 h内和第14天）及对照组中分别检测血清Ngb水平,并比较AIS患者与对照组之间的血清Ngb水平。对合并与不合并糖尿病的AIS患者的血清Ngb水平进行比较。分析患者血清Ngb水平与梗死体积及国家卫生研究院卒中量表（NIHSS）评分之间的相关性。应用受试者操作特征（ROC）曲线评估Ngb对AIS预后的预测价值。结果 AIS患者的血清Ngb水平在脑梗死后72 h内和第14天时分别为105.7（88.3,123.1）μg/L和72.8（58.7,86.9）μg/L。对照组血清Ngb水平为58.2（35.0,81.6）μg/L。AIS发病后72 h内血清Ngb水平较对照组显著升高（P<0.05）。合并与不合并糖尿病的AIS患者血清Ngb水平在发病后72 h内及第14天均无显著差异（P>0.05）。AIS发病72 h内的血清Ngb水平与NIHSS评分显著相关（Spearman相关系数=0.232,P=0.038）。在各时间点,大体积脑梗死组患者血清Ngb水平与中小体积脑梗死组相比无显著性差异（P>0.05）。ROC曲线分析表明,血清Ngb水平对AIS患者的预后具有良好的预测能力。结论 AIS发病后72 h内血清Ngb水平升高。合并与不合并糖尿病的AIS患者血清Ngb水平无显著差异。发病后72 h内的血清Ngb水平与NIHSS评分显著相关。Ngb可能作为卒中严重程度和预后的预测因子。     

Association of mTOR Polymorphisms with Cancer Risk and Clinical Outcomes: A Meta-Analysis

Genetic polymorphisms in mTOR gene may be associated with cancer risk and clinical outcomes of cancer patients by affecting mTOR gene expression or its activation. However, inconsistent results have been reported. The aim of this study is to systematically evaluate the association between mTOR polymorphisms (rs2295080, rs2536 and rs11121704) and cancer risk as well as clinical outcome by a meta-analysis. We identified 10 eligible studies and extracted data by two investigators. Based on dominant and recessive models, odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by using Stata, version 11 to evaluate the association strength. Our meta-analysis results showed that the wild genotype TT of rs2295080 polymorphism was associated with increased cancer risk under dominant model (OR = 1.24, 95%CI: 1.12–1.36, p<0.0005) in Chinese but not with clinical outcome parameters, while the TT genotype of rs11121704 was associated with poor clinical outcome parameters (OR = 1.53, 95%CI: 1.01–2.32, p = 0.044), such as death, metastasis and resistance to chemotherapy. However, rs2536 may not influence cancer susceptibility. In conclusion, this meta-analysis indicated the common polymorphisms in mTOR gene might be genetic risk factors for the carcinogenesis and clinical outcomes of cancer patients. However, further investigation on large population and different ethnicities are warranted.     

Seasonal Variation in Ischemic Stroke Incidence and Association with Climate: A Six‐Year Population‐Based Study

Questions about the seasonality of stroke remain controversial. Using a nationwide population‐based dataset, this study presents a time series analysis of seasonal patterns in ischemic stroke occurrence, along with their association with climate in Taiwan. Using data from the Taiwan National Health Insurance Research Database, a total of 168,977 visits to emergency departments between 1998 and 2003 for ischemic stroke were identified for patients ranging between 20 and 84 yrs of age. Monthly stroke incidences were calculated for 72 months, by sex and stroke subtype, and for the age groups 20–54, 55–64, 65–74, and ≥75 yrs per 100,000 of the population. We performed auto‐regressive integrated moving average (ARIMA) analysis to investigate the presence of seasonality and any association with climate for acute ischemic stroke events. We found no significant seasonal variation in the incidence of ischemic stroke for any age or sex groups. Furthermore, after adjusting for seasonality, month, and trend, the ARIMA regression model revealed only associations between ischemic stroke incidence and atmospheric pressure. We conclude that seasonality of ischemic stroke does not exist in Taiwan. Ischemic stroke incidence is, however, significantly related to atmospheric pressure.     

Visualization of the Peroxisomal Compartment in Living Mammalian Cells: Dynamic Behavior and Association with Microtubules

Peroxisomes in living CV1 cells were visualized by targeting the green fluorescent protein (GFP) to this subcellular compartment through the addition of a COOH-terminal peroxisomal targeting signal 1 (GFP–PTS1). The organelle dynamics were examined and analyzed using time-lapse confocal laser scanning microscopy. Two types of movement could be distinguished: a relatively slow, random, vibration-like movement displayed by the majority (~95%) of the peroxisomes, and a saltatory, fast directional movement displayed by a small subset (~5%) of the peroxisomes. In the latter instance, peak velocities up to 0.75 μm/s and sustained directional velocities up to 0.45 μm/s over 11.5 μm were recorded. Only the directional type of motion appeared to be energy dependent, whereas the vibrational movement continued even after the cells were depleted of energy. Treatment of cells, transiently expressing GFP–PTS1, with microtubule-destabilizing agents such as nocodazole, vinblastine, and demecolcine clearly altered peroxisome morphology and subcellular distribution and blocked the directional movement. In contrast, the microtubule-stabilizing compound paclitaxel, or the microfilament-destabilizing drugs cytochalasin B or D, did not exert these effects. High resolution confocal analysis of cells expressing GFP–PTS1 and stained with anti-tubulin antibodies revealed that many peroxisomes were associated with microtubules. The GFP–PTS1–labeled peroxisomes were found to distribute themselves in a stochastic, rather than ordered, manner to daughter cells at the time of mitosis.     

Compromised Dynamic Cerebral Autoregulation in Patients with a Right-to-Left Shunt: A Potential Mechanism of Migraine and Cryptogenic Stroke

Background and Purpose

The relationship between right-to-left shunts (RLS) and migraine and cryptogenic stroke is not well understood. In this study, we investigated whether RLS are associated with impairment of dynamic cerebral autoregulation (dCA), which may play a role in migraine and cryptogenic stroke.

Methods

Sixty-six migraineurs were enrolled in the study, including 36 non-RLS patients and 30 RLS patients. Non-invasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each patient by using transcranial Doppler and servo-controlled plethysmograph, respectively. Transfer function analysis was applied to derive autoregulatory parameters of gain, phase difference (PD), and autoregulation index.

Results

The PD in migraineurs with RLS was 50.6±22.9 degrees, which was significantly lower than that observed in the non-RLS group (67.2±18.2 degrees, P<0.001). The PD in the large RLS group (45.4±22.6 degrees) was significantly lower than that of the small RLS group (64.9±17.1 degrees, P<0.01) and non-RLS group (P<0.001); however, the PD in the small RLS group was similar to that of the non-RLS group. The PD in the permanent group (48.8±19.9 degrees) was similar to that of the latent group (52.6±26.1 degrees), and both were significantly lower than that of the non-RLS group (P<0.05). The autoregulation index results were similar to the PD findings.

Conclusions

dCA is impaired in migraineurs with large RLS, and this may represent a potential mechanism linking RLS, migraine, and cryptogenic stroke.     

Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model

Objective

To identify patient populations most in need of treatment across the prostate cancer disease continuum, we developed a novel dynamic transition model based on risk of disease progression and mortality.

Design and Outcome Measurements

We modeled the flow of patient populations through eight prostate cancer clinical states (PCCS) that are characterized by the status of the primary tumor, presence of metastases, prior and current treatment, and testosterone levels. Simulations used published US incidence rates for each year from 1990. Progression and mortality rates were derived from published clinical trials, meta-analyses, and observational studies. Model outputs included the incidence, prevalence, and mortality for each PCCS. The impact of novel treatments was modeled in three distinct scenarios: metastatic castration-resistant prostate cancer (mCRPC), non-metastatic CRPC (nmCRPC), or both.

Results and Limitations

The model estimated the prevalence of prostate cancer as 2,219,280 in the US in 2009 and 3,072,480 in 2020, and incidence of mCRPC as 36,100 and 42,970, respectively. All-cause mortality in prostate cancer was estimated at 168,290 in 2009 and 219,360 in 2020, with 20.5% and 19.5% of these deaths, respectively, occurring in men with mCRPC. The majority (86%) of incidence flow into mCRPC states was from the nmCRPC clinical state. In the scenario with novel interventions for nmCRPC states, the progression to mCRPC is reduced, thus decreasing mCRPC incidence by 12% in 2020, with a sustained decline in mCRPC mortality. A limitation of the model is that it does not estimate prostate cancer—specific mortality.

Conclusion

The model informs clinical trial design for prostate cancer by quantifying outcomes in PCCS, and demonstrates the impact of an effective therapy applied in an earlier clinical state of nmCRPC on the incidence of mCRPC morbidity and subsequent mortality.     

Cerebral Blood Volume ASPECTS Is the Best Predictor of Clinical Outcome in Acute Ischemic Stroke: A Retrospective,Combined Semi-Quantitative and Quantitative Assessment

Introduction

The capability of CT perfusion (CTP) Alberta Stroke Program Early CT Score (ASPECTS) to predict outcome and identify ischemia severity in acute ischemic stroke (AIS) patients is still questioned.

Methods

62 patients with AIS were imaged within 8 hours of symptom onset by non-contrast CT, CT angiography and CTP scans at admission and 24 hours. CTP ASPECTS was calculated on the affected hemisphere using cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps by subtracting 1 point for any abnormalities visually detected or measured within multiple cortical circular regions of interest according to previously established thresholds. MTT-CBV ASPECTS was considered as CTP ASPECTS mismatch. Hemorrhagic transformation (HT), recanalization status and reperfusion grade at 24 hours, final infarct volume at 7 days and modified Rankin scale (mRS) at 3 months after onset were recorded.

Results

Semi-quantitative and quantitative CTP ASPECTS were highly correlated (p<0.00001). CBF, CBV and MTT ASPECTS were higher in patients with no HT and mRS≤2 and inversely associated with final infarct volume and mRS (p values: from p<0.05 to p<0.00001). CTP ASPECTS mismatch was slightly associated with radiological and clinical outcomes (p values: from p<0.05 to p<0.02) only if evaluated quantitatively. A CBV ASPECTS of 9 was the optimal semi-quantitative value for predicting outcome.

Conclusions

Our findings suggest that visual inspection of CTP ASPECTS recognizes infarct and ischemic absolute values. Semi-quantitative CBV ASPECTS, but not CTP ASPECTS mismatch, represents a strong prognostic indicator, implying that core extent is the main determinant of outcome, irrespective of penumbra size.     

Health and Human Rights in Eastern Myanmar after the Political Transition: A Population-Based Assessment Using Multistaged Household Cluster Sampling

BackgroundMyanmar transitioned to a nominally civilian parliamentary government in March 2011. Qualitative reports suggest that exposure to violence and displacement has declined while international assistance for health services has increased. An assessment of the impact of these changes on the health and human rights situation has not been published.ConclusionThis large survey of health and human rights demonstrates that two years after political transition, vulnerable populations of eastern Myanmar are less likely to experience human rights violations compared to previous surveys. However, access to health services remains constrained, and risk of disease and death remains higher than the country as a whole. Efforts to address these poor health indicators should prioritize support for populations that remain outside the scope of most formal government and donor programs.     

Diagnostic Intervals and Its Association with Breast,Prostate, Lung and Colorectal Cancer Survival in England: Historical Cohort Study Using the Clinical Practice Research Datalink

Rapid diagnostic pathways for cancer have been implemented, but evidence whether shorter diagnostic intervals (time from primary care presentation to diagnosis) improves survival is lacking. Using the Clinical Practice Research Datalink, we identified patients diagnosed with female breast (8,639), colorectal (5,912), lung (5,737) and prostate (1,763) cancers between 1998 and 2009, and aged >15 years. Presenting symptoms were classified as alert or non-alert, according to National Institute for Health and Care Excellence guidance. We used relative survival and excess risk modeling to determine associations between diagnostic intervals and five-year survival. The survival of patients with colorectal, lung and prostate cancer was greater in those with alert, compared with non-alert, symptoms, but findings were opposite for breast cancer. Longer diagnostic intervals were associated with lower mortality for colorectal and lung cancer patients with non-alert symptoms, (colorectal cancer: Excess Hazards Ratio, EHR >6 months vs <1 month: 0.85; 95% CI: 0.72-1.00; Lung cancer: EHR 3-6 months vs <1 month: 0.87; 95% CI: 0.80-0.95; EHR >6 months vs <1 month: 0.81; 95% CI: 0.74-0.89). Prostate cancer mortality was lower in patients with longer diagnostic intervals, regardless of type of presenting symptom. The association between diagnostic intervals and cancer survival is complex, and should take into account cancer site, tumour biology and clinical practice. Nevertheless, unnecessary delay causes patient anxiety and general practitioners should continue to refer patients with alert symptoms via the cancer pathways, and actively follow-up patients with non-alert symptoms in the community.