Variation in promptness of presentation among 10,297 patients subsequently diagnosed with one of 18 cancers: Evidence from a National Audit of Cancer Diagnosis in Primary Care

This is the final published version. Available from Wiley via the DOI in this record.Cancer awareness public campaigns aim to shorten the interval between symptom onset and presentation to a doctor (the 'patient interval'). Appreciating variation in promptness of presentation can help to better target awareness campaigns. We explored variation in patient intervals recorded in consultations with general practitioners among 10,297 English patients subsequently diagnosed with one of 18 cancers (bladder, brain, breast, colorectal, endometrial, leukaemia, lung, lymphoma, melanoma, multiple myeloma, oesophageal, oro-pharyngeal, ovarian, pancreatic, prostate, renal, stomach, and unknown primary) using data from of the National Audit of Cancer Diagnosis in Primary Care (2009-2010). Proportions of patients with 'prompt'/'non-prompt' presentation (0-14 or 15+ days from symptom onset, respectively) were described and respective odds ratios were calculated by multivariable logistic regression. The overall median recorded patient interval was 10 days (IQR 0-38). Of all patients, 56% presented promptly. Prompt presentation was more frequent among older or housebound patients (p < 0.001). Prompt presentation was most frequent for bladder and renal cancer (74% and 70%, respectively); and least frequent for oro-pharyngeal and oesophageal cancer (34% and 39%, respectively, p <.001). Using lung cancer as reference, the adjusted odds ratios of non-prompt presentation were 2.26 (95% confidence interval 1.57-3.25) and 0.42 (0.34-0.52) for oro-pharyngeal and bladder cancer, respectively. Sensitivity analyses produced similar findings. Routinely recorded patient interval data reveal considerable variation in the promptness of presentation. These findings can help to prioritise public awareness initiatives and research focusing on symptoms of cancers associated with greater risk of non-prompt presentation, such as oro-pharyngeal and oesophageal cancer. What's new? A critical aspect of cancer diagnosis is how promptly patients consult a doctor after they first notice initial symptoms. Here, the authors examine differences in this so-called patient interval in English patients subsequently diagnosed with one of 18 cancers. On average, patients with bladder and renal cancer as well as older and housebound patients consulted a doctor relatively promptly while patients with oro-pharyngeal and oesophageal cancer took the longest until first presenting to a general practitioner. The authors point out that cancer awareness campaigns should encompass symptoms of oro-pharyngeal and oesophageal cancer aiming to shorten the patient interval for these cancers. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.National Institute for Health Research (NIHR)NHS Public Health Training Schem

Identifying people at higher risk of melanoma across the U.K.: a primary-care-based electronic survey

BACKGROUND: Melanoma incidence is rising rapidly worldwide among white populations. Defining higher-risk populations using risk prediction models may help targeted screening and early detection approaches. OBJECTIVES: To assess the feasibility of identifying people at higher risk of melanoma using the Williams self-assessed clinical risk estimation model in U.K. primary care. METHODS: We recruited participants from the waiting rooms of 22 general practices covering a total population of > 240 000 in three U.K. regions: Eastern England, North East Scotland and North Wales. Participants completed an electronic questionnaire using tablet computers. The main outcome was the mean melanoma risk score using the Williams melanoma risk model. RESULTS: Of 9004 people approached, 7742 (86%) completed the electronic questionnaire. The mean melanoma risk score for the 7566 eligible participants was 17·15 ± 8·51, with small regional differences [lower in England compared with Scotland (P = 0·001) and Wales (P < 0·001), mainly due to greater freckling and childhood sunburn among Scottish and Welsh participants]. After weighting to the age and sex distribution, different potential cut-offs would allow between 4% and 20% of the population to be identified as higher risk, and those groups would contain 30% and 60%, respectively of those likely to develop melanoma. CONCLUSIONS: Collecting data on the melanoma risk profile of the general population in U.K. primary care is both feasible and acceptable for patients in a general practice setting, and provides opportunities for new methods of real-time risk assessment and risk stratified cancer interventions

Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study

This is the final version. Available on open access from Elsevier via the DOI in this recordBackground Pancreatic cancer is the tenth most common cancer in the UK; however, outcomes are poor, in part due to late diagnosis. We aimed to identify symptoms and other clinical and sociodemographic factors associated with pancreatic cancer diagnosis and diagnostic intervals. Methods We did this prospective cohort study at seven hospitals in two regions in England. We recruited participants aged 40 years or older who were referred for suspicion of pancreatic cancer. Data were collected by use of a patient questionnaire and primary care and hospital records. Descriptive and regression analyses were done to examine associations between symptoms and patient factors with the total diagnostic interval (time from onset of the first symptom to the date of diagnosis), comprising patient interval (time from first symptom to first presentation) and health system interval (time from first presentation to diagnosis). Findings We recruited 391 participants between Jan 1, 2011, and Dec 31, 2014 (24% response rate). 119 (30%) participants were diagnosed with pancreatic cancer (41 [34%] had metastatic disease), 47 (12%) with other cancers, and 225 (58%) with no cancer. 212 (54%) patients had multiple first symptoms whereas 161 (41%) patients had a solitary first symptom. In this referred population, no initial symptoms were reported more frequently by patients with cancer than by those with no cancer. Several subsequent symptoms predicted pancreatic cancer: jaundice (51 [49%] of 105 patients with pancreatic cancer vs 25 [12%] of 211 patients with no cancer; p<0·0001), fatigue (48/95 [51%] vs 40/155 [26%]; p=0·0001), change in bowel habit (36/87 [41%] vs 28/175 [16%]; p<0·0001), weight loss (55/100 [55%] vs 41/184 [22%]; p<0·0001), and decreased appetite (41/86 [48%] vs 41/156 [26%]; p=0·0011). There was no difference in any interval between patients with pancreatic cancer and those with no cancer (total diagnostic interval: median 117 days [IQR 57–234] vs 131 days [IQR 66–284]; p=0·32; patient interval 18 days [0–37] vs 15 days [1–62]; p=0·22; health system interval 76 days [28–161] vs 79 days [30–156]; p=0·68). Total diagnostic intervals were shorter when jaundice (hazard ratio [HR] 1·38, 95% CI 1·07–1·78; p=0·013) and decreased appetite (1·42, 1·11–1·82; p=0·0058) were reported as symptoms, and longer in patients presenting with indigestion (0·71, 0·56–0·89; p=0·0033), back pain (0·77, 0·59–0·99; p=0·040), diabetes (0·71, 0·52–0·97; p=0·029), and self-reported anxiety or depression, or both (0·67, 0·49–0·91; p=0·011). Health system intervals were likewise longer with indigestion (0·74, 0·58–0·95; p=0·0018), back pain (0·76, 0·58–0·99; p=0·044), diabetes (0·63, 0·45–0·89; p=0·0082), and self-reported anxiety or depression, or both (0·63, 0·46–0·88; p=0·0064), but were shorter with male sex (1·41, 1·1–1·81; p=0·0072) and decreased appetite (1·56, 1·19–2·06; p=0·0015). Weight loss was associated with longer patient intervals (HR 0·69, 95% CI 0·54–0·89; p=0·0047). Interpretation Although we identified no initial symptoms that differentiated people diagnosed with pancreatic cancer from those without pancreatic cancer, key additional symptoms might signal the disease. Health-care professionals should be vigilant to the possibility of pancreatic cancer in patients with evolving gastrointestinal and systemic symptoms, particularly in those with diabetes or mental health comorbidities. Funding National Institute for Health Research and Pancreatic Cancer Action.National Institute for Health Research (NIHR

Diagnosis of cancer as an emergency: a critical review of current evidence

Many patients with cancer are diagnosed through an emergency presentation, which is associated with inferior clinical and patient-reported outcomes compared with those of patients who are diagnosed electively or through screening. Reducing the proportion of patients with cancer who are diagnosed as emergencies is, therefore, desirable; however, the optimal means of achieving this aim are uncertain owing to the involvement of different tumour, patient and health-care factors, often in combination. Most relevant evidence relates to patients with colorectal or lung cancer in a few economically developed countries, and defines emergency presentations contextually (that is, whether patients presented to emergency health-care services and/or received emergency treatment shortly before their diagnosis) as opposed to clinically (whether patients presented with life-threatening manifestations of their cancer). Consistent inequalities in the risk of emergency presentations by patient characteristics and cancer type have been described, but limited evidence is available on whether, and how, such presentations can be prevented. Evidence on patients' symptoms and health-care use before presentation as an emergency is sparse. In this Review, we describe the extent, causes and implications of a diagnosis of cancer following an emergency presentation, and provide recommendations for public health and health-care interventions, and research efforts aimed at addressing this under-researched aspect of cancer diagnosis

Cosmic Hydrogen Was Significantly Neutral a Billion Years After the Big Bang

The ionization fraction of cosmic hydrogen, left over from the big bang, provides crucial fossil evidence for when the first stars and quasar black holes formed in the infant universe. Spectra of the two most distant quasars known show nearly complete absorption of photons with wavelengths shorter than the Ly-alpha transition of neutral hydrogen, indicating that hydrogen in the intergalactic medium (IGM) had not been completely ionized at a redshift z~6.3, about a billion years after the big bang. Here we show that the radii of influence of ionizing radiation from these quasars imply that the surrounding IGM had a neutral hydrogen fraction of tens of percent prior to the quasar activity, much higher than previous lower limits of ~0.1%. When combined with the recent inference of a large cumulative optical depth to electron scattering after cosmological recombination from the WMAP data, our result suggests the existence of a second peak in the mean ionization history, potentially due to an early formation episode of the first stars.Comment: 14 Pages, 2 Figures. Accepted for publication in Nature. Press embargo until publishe

Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.

Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed "CpG beacons") as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10(-3)) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10(-3)). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs

Sri Lankan tsunami refugees: a cross sectional study of the relationships between housing conditions and self-reported health

BACKGROUND: On the 26th December 2004 the Asian tsunami devastated the Sri Lankan coastline. More than two years later, over 14,500 families were still living in transitional shelters. This study compares the health of the internally displaced people (IDP), living in transitional camps with those in permanent housing projects provided by government and non-government organisations in Sri Lanka. METHODS: This study was conducted in seven transitional camps and five permanent housing projects in the south west of Sri Lanka. Using an interviewer-led questionnaire, data on the IDPs' self-reported health and housing conditions were collected from 154 participants from transitional camps and 147 participants from permanent housing projects. Simple tabulation with non-parametric tests and logistic regression were used to identify and analyse relationships between housing conditions and the reported prevalence of specific symptoms. RESULTS: Analysis showed that living conditions were significantly worse in transitional camps than in permanent housing projects for all factors investigated, except 'having a leaking roof'. Transitional camp participants scored significantly lower on self-perceived overall health scores than those living in housing projects. After controlling for gender, age and marital status, living in a transitional camp compared to a housing project was found to be a significant risk factor for the following symptoms; coughs OR: 3.53 (CI: 2.11-5.89), stomach ache 4.82 (2.19-10.82), headache 5.20 (3.09-8.76), general aches and pains 6.44 (3.67-11.33) and feeling generally unwell 2.28 (2.51-7.29). Within transitional camp data, the only condition shown to be a significant risk factor for any symptom was household population density, which increased the risk of stomach aches 1.40 (1.09-1.79) and headaches 1.33 (1.01-1.77). CONCLUSION: Internally displaced people living in transitional camps are a vulnerable population and specific interventions need to be targeted at this population to address the health inequalities that they report to be experiencing. Further studies need to be conducted to establish which aspects of their housing environment predispose them to poorer health

Variation in 'fast-track' referrals for suspected cancer by patient characteristic and cancer diagnosis: evidence from 670 000 patients with cancers of 35 different sites.

BACKGROUND: In England, 'fast-track' (also known as 'two-week wait') general practitioner referrals for suspected cancer in symptomatic patients are used to shorten diagnostic intervals and are supported by clinical guidelines. However, the use of the fast-track pathway may vary for different patient groups. METHODS: We examined data from 669 220 patients with 35 cancers diagnosed in 2006-2010 following either fast-track or 'routine' primary-to-secondary care referrals using 'Routes to Diagnosis' data. We estimated the proportion of fast-track referrals by sociodemographic characteristic and cancer site and used logistic regression to estimate respective crude and adjusted odds ratios. We additionally explored whether sociodemographic associations varied by cancer. RESULTS: There were large variations in the odds of fast-track referral by cancer (P<0.001). Patients with testicular and breast cancer were most likely to have been diagnosed after a fast-track referral (adjusted odds ratios 2.73 and 2.35, respectively, using rectal cancer as reference); whereas patients with brain cancer and leukaemias least likely (adjusted odds ratios 0.05 and 0.09, respectively, for brain cancer and acute myeloid leukaemia). There were sex, age and deprivation differences in the odds of fast-track referral (P<0.013) that varied in their size and direction for patients with different cancers (P<0.001). For example, fast-track referrals were least likely in younger women with endometrial cancer and in older men with testicular cancer. CONCLUSIONS: Fast-track referrals are less likely for cancers characterised by nonspecific presenting symptoms and patients belonging to low cancer incidence demographic groups. Interventions beyond clinical guidelines for 'alarm' symptoms are needed to improve diagnostic timeliness

Interleukin 7 from Maternal Milk Crosses the Intestinal Barrier and Modulates T- Cell Development in Offspring

Background Breastfeeding protects against illnesses and death in hazardous environments, an effect partly mediated by improved immune function. One hypothesis suggests that factors within milk supplement the inadequate immune response of the offspring, but this has not been able to account for a series of observations showing that factors within maternally derived milk may supplement the development of the immune system through a direct effect on the primary lymphoid organs. In a previous human study we reported evidence suggesting a link between IL-7 in breast milk and the thymic output of infants. Here we report evidence in mice of direct action of maternally-derived IL-7 on T cell development in the offspring. Methods and Findings  We have used recombinant IL-7 labelled with a fluorescent dye to trace the movement in live mice of IL-7 from the stomach across the gut and into the lymphoid tissues. To validate the functional ability of maternally derived IL- 7 we cross fostered IL-7 knock-out mice onto normal wild type mothers. Subsets of thymocytes and populations of peripheral T cells were significantly higher than those found in knock-out mice receiving milk from IL-7 knock-out mothers. Conclusions/Significance Our study provides direct evidence that interleukin 7, a factor which is critical in the development of T lymphocytes, when maternally derived can transfer across the intestine of the offspring, increase T cell production in the thymus and support the survival of T cells in the peripheral secondary lymphoid tissue

In Situ Proteolysis to Generate Crystals for Structure Determination: An Update

For every 100 purified proteins that enter crystallization trials, an average of 30 form crystals, and among these only 13–15 crystallize in a form that enables structure determination. In 2007, Dong et al reported that the addition of trace amounts of protease to crystallization trials—in situ proteolysis—significantly increased the number of proteins in a given set that produce diffraction quality crystals. 69 proteins that had previously resisted structure determination were subjected to crystallization with in situ proteolysis and ten crystallized in a form that led to structure determination (14.5% success rate). Here we apply in situ proteolysis to over 270 new soluble proteins that had failed in the past to produce crystals suitable for structure determination. These proteins had produced no crystals, crystals that diffracted poorly, or produced twinned and/or unmanageable diffraction data. The new set includes yeast and prokaryotic proteins, enzymes essential to protozoan parasites, and human proteins such as GTPases, chromatin remodeling proteins, and tyrosine kinases. 34 proteins yielded deposited crystal structures of 2.8 Å resolution or better, for an overall 12.6% success rate, and at least ten more yielded well-diffracting crystals presently in refinement. The success rate among proteins that had previously crystallized was double that of those that had never before yielded crystals. The overall success rate is similar to that observed in the smaller study, and appears to be higher than any other method reported to rescue stalled protein crystallography projects