Symptoms of adult chronic and acute leukaemia before diagnosis: large primary care case-control studies using electronic records

This is the author accepted manuscript. The final version is available from Royal College of General Practitioners via the DOI in this record.BACKGROUND: Leukaemia is the eleventh commonest UK cancer. The four main subtypes have different clinical profiles, particularly between chronic and acute types. AIM: To identify the symptom profiles of chronic and acute leukaemia in adults in primary care. DESIGN AND SETTING: Matched case-control studies using Clinical Practice Research Datalink records. METHOD: Putative symptoms of leukaemia were identified in the year before diagnosis. Conditional logistic regression was used for analysis, and positive predictive values (PPVs) were calculated to estimate risk. RESULTS: Of cases diagnosed between 2000 and 2009, 4655 were aged ≥40 years (2877 chronic leukaemia (CL), 937 acute leukaemia (AL), 841 unreported subtype). Ten symptoms were independently associated with CL, the three strongest being: lymphadenopathy (odds ratio [OR] 22, 95% confidence interval [CI] = 13 to 36), weight loss (OR 3.0, 95% CI = 2.1 to 4.2), and bruising (OR 2.3, 95% CI = 1.6 to 3.2). Thirteen symptoms were independently associated with AL, the three strongest being: nosebleeds and/or bleeding gums (OR 5.7, 95% CI = 3.1 to 10), fever (OR 5.3, 95% CI = 2.7 to 10), and fatigue (OR 4.4, 95% CI = 3.3 to 6.0). No individual symptom or combination of symptoms had a PPV >1%. CONCLUSION: The symptom profiles of CL and AL have both overlapping and distinct features. This presents a dichotomy for GPs: diagnosis, by performing a full blood count, is easy; however, the symptoms of leukaemia are non-specific and of relatively low risk. This explains why many leukaemia diagnoses are unexpected findings.This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0608– 10045). Fiona M Walter is part-funded by an NIHR Clinician Scientist award. Richard D Neal is part-funded by Public Health Wales and Betsi Cadwaladr University Health Board. Willie Hamilton is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health

Quantifying the risk of multiple myeloma from symptoms reported in primary care patients: a large case-control study using electronic records

This is the author accepted manuscript. The final version is available from Royal College of General Practitioners via the DOI in this record.BACKGROUND: Patients with myeloma experience the longest diagnostic delays compared with patients with other cancers in the UK; 37% are diagnosed through emergency presentations. AIM: To identify and quantify the risk of myeloma from specific clinical features reported by primary care patients. DESIGN AND SETTING: Matched case-control study using General Practice Research Database primary care electronic records. METHOD: Putative clinical features of myeloma were identified and analysed using conditional logistic regression. Positive predictive values (PPVs) were calculated for the consulting population. RESULTS: A total of 2703 patients aged ≥40 years, diagnosed with myeloma between 2000 and 2009, and 12 157 age, sex, and general practice-matched controls were identified. Sixteen features were independently associated with myeloma: hypercalcaemia, odds ratio 11.4 (95% confidence interval [CI] = 7.1 to 18), cytopenia 5.4 (95% CI = 4.6 to 6.4), raised inflammatory markers 4.9 (95% CI = 4.2 to 5.8), fracture 3.1 (95% CI = 2.3 to 4.2), raised mean corpuscular volume 3.1 (95% CI = 2.4 to 4.1), weight loss 3.0 (95% CI = 2.0 to 4.5), nosebleeds 3.0 (95% CI = 1.9 to 4.7), rib pain 2.5 (95% CI = 1.5 to 4.4), back pain 2.2 (95% CI = 2.0 to 2.4), other bone pain 2.1 (95% CI = 1.4 to 3.1), raised creatinine 1.8 (95% CI = 1.5 to 2.2), chest pain 1.6 (95% CI = 1.4 to 1.8), joint pain 1.6 (95% CI = 1.2 to 2.2), nausea 1.5 (95% CI = 1.1 to 2.1), chest infection 1.4 (95% CI = 1.2 to 1.6), and shortness of breath 1.3 (95% CI = 1.1 to 1.5). Individual symptom PPVs were generally 10% for some symptoms when combined with leucopenia or hypercalcaemia. CONCLUSION: Individual symptoms of myeloma in primary care are generally low risk, probably explaining diagnostic delays. Once simple primary care blood tests are taken, risk estimates change. Hypercalcaemia and leucopenia are particularly important abnormalities, and coupled with symptoms, strongly suggest myeloma.This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0608- 10045). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Fiona M Walter is part-funded by a NIHR Clinician Scientist award. Richard D Neal is part funded by Public Health Wales and Betsi Cadwaladr University Health Board

Comparison of home fortification with two iron formulations among Kenyan children: Rationale and design of a placebo-controlled non-inferiority trial.

INTRODUCTION: Home fortification powders containing iron and other micronutrients have been recommended by World Health Organisation to prevent iron deficiency anaemia in areas of high prevalence. There is evidence, however, that home fortification at this iron dose may cause gastrointestinal adverse events including diarrhoea. Providing a low dose of highly absorbable iron (3 mg iron as NaFeEDTA) may be safer because the decreased amount of iron in the gut lumen can possibly reduce the burden of these adverse effects whilst resulting in similar or higher amounts of absorbed iron. OBJECTIVE: To show non-inferiority of home fortification with 3 mg iron as NaFeEDTA compared with 12.5 mg iron as encapsulated ferrous fumarate, with haemoglobin response as the primary outcome. DESIGN: 338 Kenyan children aged 12-36 months will be randomly allocated to daily home fortification with either: a) 3 mg iron as NaFeEDTA (experimental treatment), b) 12.5 mg iron as encapsulated ferrous fumarate (reference), or c) placebo. At baseline, after 30 days of intervention and within 100 days post-intervention, blood samples will be assessed for primary outcome (haemoglobin concentration), iron status markers, Plasmodium parasitaemia and inflammation markers. Urine and stool samples will be assessed for hepcidin concentrations and inflammation, respectively. Adherence will be assessed by self-reporting, sachet counts and by an electronic monitoring device. CONCLUSION: If daily home fortification with a low dose of iron (3 mg NaFeEDTA) has similar or superior efficacy to a high dose (12.5 mg ferrous fumarate) then it would be the preferred choice for treatment of iron deficiency anaemia in children

Radiocarbon dating of methane and carbon dioxide evaded from a temperate peatland stream

Streams draining peatlands export large quantities of carbon in different chemical forms and are an important part of the carbon cycle. Radiocarbon (14C) analysis/dating provides unique information on the source and rate that carbon is cycled through ecosystems, as has recently been demonstrated at the air-water interface through analysis of carbon dioxide (CO2) lost from peatland streams by evasion (degassing). Peatland streams also have the potential to release large amounts of methane (CH4) and, though 14C analysis of CH4 emitted by ebullition (bubbling) has been previously reported, diffusive emissions have not. We describe methods that enable the 14C analysis of CH4 evaded from peatland streams. Using these methods, we investigated the 14C age and stable carbon isotope composition of both CH4 and CO2 evaded from a small peatland stream draining a temperate raised mire. Methane was aged between 1617-1987 years BP, and was much older than CO2 which had an age range of 303-521 years BP. Isotope mass balance modelling of the results indicated that the CO2 and CH4 evaded from the stream were derived from different source areas, with most evaded CO2 originating from younger layers located nearer the peat surface compared to CH4. The study demonstrates the insight that can be gained into peatland carbon cycling from a methodological development which enables dual isotope (14C and 13C) analysis of both CH4 and CO2 collected at the same time and in the same way

Symptoms and signs of lung cancer prior to diagnosis: case-control study using electronic health records from ambulatory care within a large US-based tertiary care centre.

OBJECTIVE: Lung cancer is the most common cause of cancer-related death in the USA. While most patients are diagnosed following symptomatic presentation, no studies have compared symptoms and physical examination signs at or prior to diagnosis from electronic health records (EHRs) in the USA. We aimed to identify symptoms and signs in patients prior to diagnosis in EHR data. DESIGN: Case-control study. SETTING: Ambulatory care clinics at a large tertiary care academic health centre in the USA. PARTICIPANTS, OUTCOMES: We studied 698 primary lung cancer cases in adults diagnosed between 1 January 2012 and 31 December 2019, and 6841 controls matched by age, sex, smoking status and type of clinic. Coded and free-text data from the EHR were extracted from 2 years prior to diagnosis date for cases and index date for controls. Univariate and multivariable conditional logistic regression were used to identify symptoms and signs associated with lung cancer at time of diagnosis, and 1, 3, 6 and 12 months before the diagnosis/index dates. RESULTS: Eleven symptoms and signs recorded during the study period were associated with a significantly higher chance of being a lung cancer case in multivariable analyses. Of these, seven were significantly associated with lung cancer 6 months prior to diagnosis: haemoptysis (OR 3.2, 95% CI 1.9 to 5.3), cough (OR 3.1, 95% CI 2.4 to 4.0), chest crackles or wheeze (OR 3.1, 95% CI 2.3 to 4.1), bone pain (OR 2.7, 95% CI 2.1 to 3.6), back pain (OR 2.5, 95% CI 1.9 to 3.2), weight loss (OR 2.1, 95% CI 1.5 to 2.8) and fatigue (OR 1.6, 95% CI 1.3 to 2.1). CONCLUSIONS: Patients diagnosed with lung cancer appear to have symptoms and signs recorded in the EHR that distinguish them from similar matched patients in ambulatory care, often 6 months or more before diagnosis. These findings suggest opportunities to improve the diagnostic process for lung cancer

Bio-Benchmarking of Electronic Nose Sensors

BACKGROUND:Electronic noses, E-Noses, are instruments designed to reproduce the performance of animal noses or antennae but generally they cannot match the discriminating power of the biological original and have, therefore, been of limited utility. The manner in which odorant space is sampled is a critical factor in the performance of all noses but so far it has been described in detail only for the fly antenna. METHODOLOGY:Here we describe how a set of metal oxide (MOx) E-Nose sensors, which is the most commonly used type, samples odorant space and compare it with what is known about fly odorant receptors (ORs). PRINCIPAL FINDINGS:Compared with a fly's odorant receptors, MOx sensors from an electronic nose are on average more narrowly tuned but much more highly correlated with each other. A set of insect ORs can therefore sample broader regions of odorant space independently and redundantly than an equivalent number of MOx sensors. The comparison also highlights some important questions about the molecular nature of fly ORs. CONCLUSIONS:The comparative approach generates practical learnings that may be taken up by solid-state physicists or engineers in designing new solid-state electronic nose sensors. It also potentially deepens our understanding of the performance of the biological system

Is Incarceration a Contributor to Health Disparities? Access to Care of Formerly Incarcerated Adults

Despite the disproportionate prevalence of incarceration in communities of color, few studies have examined its contribution to health disparities. We examined whether a lifetime history of incarceration is associated with recent access to medical and dental care. We performed a secondary data analysis of the 2007 Los Angeles County Health Survey, a population-based random-digit-dialing telephone survey of county households. Any history of incarceration in a prison/jail/detention center as an adult was assessed for a random subsample. Bivariate and multivariate logistic regression analyses examined whether incarceration history was associated with access to care, controlling for other characteristics. Ten percent of our study population reported a history of incarceration. While persons with an incarceration history were similar to their peers with regard to health and insurance status, their access to medical and dental care was worse. Incarceration history was independently associated with disparities in access to care. Interventions to improve the health of communities affected by high rates of incarceration could include efforts that enable access to care for formerly incarcerated adults

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

Extragalactic Results from the Infrared Space Observatory

More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 micron band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy and spectro-photometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far- IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.Comment: 106 pages, including 17 figures. Ann.Rev.Astron.Astrophys. (in press), a gzip'd pdf file (667kB) is also available at http://www.mpe.mpg.de/www_ir/preprint/annrev2000.pdf.g