Simultaneous quantification of cyclosporin, tacrolimus, sirolimus and everolimus in whole blood by UHPLC-MS/MS for therapeutic drug monitoring.

The aim of this study was to develop and validate a UHPLC-MS/MS assay to quantify cyclosporin (CYC), tacrolimus (TAC), sirolimus (SIR) and everolimus (EVE) in human whole blood for therapeutic drug monitoring. Analytes were extracted from 50 µL human whole blood by protein precipitation. The separation of the drugs was performed on an Acquity UPLC BEH C18 column. Analytes were eluted with a mobile phase consisting of 2 mM ammonium acetate with 0.1% formic acid (v/v) in deionised water and 2 mM ammonium acetate with 0.1% formic acid (v/v) in methanol at a flow rate of 300 µL/min in gradient elution. The method performance was evaluated by analysing patient blood samples and/or external quality control samples [proficiency testing (PT) scheme]. The method was linear from 23.75 to 1094.0, 1.3 to 42.4, 1.3 to 47.0 and 1.2-41.6 µg/mL for CYC, TAC, SIR and EVE, respectively. The within- and between-assay reproducibility results were ˂ 11%. Results from PT and patient sample quantification were comparable to those obtained previously by an in-house validated method using protein precipitation and liquid-liquid extraction. This method showed good analytical performance for quantifying CYC, TAC, SIR and EVE in whole blood over their respective calibration ranges.

Mortality from heart failure, acute myocardial infarction and other ischaemic heart disease in England and Oxford: a trend study of multiple-cause-coded death certification.

BACKGROUND: Age-standardised death rates from acute myocardial infarction (AMI) and ischaemic heart disease (IHD) have been declining in most developed countries. However, the magnitude of such reductions and how they impact on death from heart failure are less certain. We sought to assess and compare temporal trends in mortality from heart failure, AMI and non-AMI IHD over a 30-year period in England. METHODS: We analysed death registration data for multiple-cause-coded mortality for all deaths in people aged 35 years and over in England from 1995 to 2010, population 52 million, and in a regional population (Oxford region) from 1981 to 2010, population 2.5 million, for which data on all causes of death were available. RESULTS: Considering all ages and both sexes combined, during the 30-year observation period, age-standardised and sex-standardised mortality rates based on all certified causes of death declined by 60% for heart failure, 80% for AMI and 46% for non-AMI IHD. These longer term trends observed in the Oxford region were consistent with those for the whole of England from 1995 to 2010, with no evidence of a plateau in recent years. Although proportional reductions in rates differed by age and sex, even in those aged 85 years or more, there were substantial reductions in mortality rates in the all-England data set (50%, 66% and 20% for heart failure, AMI and non-AMI IHD, respectively). CONCLUSIONS: This study shows large and sustained reductions in age-specific and sex-specific and standardised death rates from heart failure, as well as from AMI and non-AMI IHD, over a 30-year period in England.

Atrial fibrillation as a cause of death increased steeply in England between 1995 and 2010.

AIMS: To report trends in mortality rates for atrial fibrillation/flutter (AF), using all the certified causes of death mentioned on death certificates (conventionally known as 'mentions') as well as the underlying cause of death, in the national population of England (1995-2010) and in a regional population with longer coverage of all-mentions mortality (1979-2010). METHODS AND RESULTS: Analysis of death registration data in England and in the Oxford record linkage study. In England between 1995 and 2010, AF was mentioned as a cause of death (either as an underlying cause or as a contributory cause) in 192 770 registered deaths in people aged 45 years of age and over (representing 0.254% of all registered deaths in this age group). Atrial fibrillation was given as the underlying cause of death in 21.4% of all deaths in which it was mentioned (41 298 of 192 770). In England, age-standardized death rates for mentions of AF increased almost three-fold between 1995 and 2010, from 202.5 deaths per million (1995) to 554.1 deaths per million (2010), with an average annual percentage change of 6.6% (95% confidence interval: 6.3, 7.0). Mortality rates for AF did not increase substantially until the mid-1990s: rates in Oxford were 145.4 deaths per million in 1979, 178.1 in 1995, and 505.1 in 2010. CONCLUSION: Atrial fibrillation has become much more common as a certified cause of death. The reasons for this are likely to be multifactorial, with changes in demographics, lifestyle, advances in therapeutics, and altered perception of the importance of the condition by certifying doctors all likely to be contributing factors.

Certification of deaths from diabetes mellitus and obesity in England: trends into the twenty-first century.

BACKGROUND: Most cases of Type 2 diabetes are attributable to excess weight and physical inactivity. We investigated trends in mortality based on doctors' certification of diabetes and obesity. METHODS: Analysis of a national data set of all certified causes of death, i.e. underlying cause and contributing causes ('mentions'), in England 1995-2010. RESULTS: Diabetes exhibited divergent trends for mortality based on underlying cause and mentions. Underlying cause rates were 107.2 per million population [95% confidence interval (CI): 105.7-108.6] in 1995, but only 68.9/10(6) (CI: 67.9-69.9) in 2010. Mortality rates for mentions of diabetes were 403.1/10(6) (CI: 400.4-405.8) in 1995, increasing to 478.4/10(6) (CI: 475.7-481.0) in 2010. Underlying cause mortality for obesity was 3.7/10(6) (CI: 3.2-4.1) in 1995 and 7.5 (CI: 7.0-8.0) in 2010. The corresponding rates for mentions of obesity were 13.2/10(6) (CI: 12.6-13.9) and 34.5/10(6) (CI: 33.6-35.4), respectively. 24.0% of death certificates with a mention of obesity also had diabetes recorded on the same certificate. CONCLUSIONS: Multiple-cause mortality statistics provide a more accurate picture than underlying cause of the total mortality burden attributed on death certificates to diabetes and obesity. Rates for both increased substantially: analysis by underlying cause alone would have missed this for diabetes.

Trends in mortality from appendicitis and from gallstone disease in English populations, 1979-2006: study of multiple-cause coding of deaths.

OBJECTIVE: To report on trends in mortality from appendicitis and from gallstone disease. DESIGN AND SETTING: Analysis of data from death certificates including all certified causes of death, termed 'mentions', not just the underlying cause, using data from Oxford ('mentions' available from 1979 to 2006) and all England ('mentions' available from 1995 to 2006). OUTCOME MEASURES: Mortality rates across all years studied, and in periods defined by changes to national rules in selecting the underlying cause of death. RESULTS: In the Oxford region, mortality rates for appendicitis based on underlying cause fluctuated between periods defined by coding rule changes. Those based on mentions were more stable: they were 3.3 per million population in 1979-83 and 3.5 in 2001-6. Nationally, mentions-based rates fell from 3.4 per million in 1995-2000 to 3.1 in 2001-2006, a small but statistically significant decline. For gallstone disease in Oxford, rates fell in the early years but then levelled off. Mortality rates for gallstones in England actually rose slightly between 1995-2000 (15.0 deaths per million) and 2001-6 (15.6 per million). The majority of deaths from appendicitis and gallstone disease were in the elderly. CONCLUSIONS: Appendicitis and gallstones are considered to be avoidable causes of death. Mortality rates for each cause have not shown any substantial falls in the recent periods covered by this study. It is possible that deaths were not, in fact, avoidable, but audits into the circumstances of deaths from these diseases may be warranted. Mortality data based on underlying cause alone substantially underestimate deaths from these two conditions.

Mortality trends for benign prostatic hyperplasia and prostate cancer in English populations 1979-2006.

OBJECTIVE To determine mortality trends for benign prostatic hyperplasia (BPH) and prostate cancer in English populations, between 1979 and 2006. SUBJECTS AND METHODS Analysis of datasets that include both the underlying cause and all other mentioned causes on death certificates (together, termed 'mentions'): the Oxford Record Linkage Study, 1979-2006, and English national data, 1995-2006. RESULTS In the Oxford region, underlying-cause mortality from BPH fell from 45 deaths per million in 1979 to 2.4 in 2006. For mentions, the respective rates were 93 and 7.1. In England, underlying-cause mortality reduced from 9.2 deaths per million in 1995 to 4.5 deaths per million in 2006. For mentions, the rates were 20 and 9.9 deaths per million. When BPH was certified on death certificates, it was selected as the underlying cause of death on fewer than half. Underlying-cause mortality for prostate cancer in Oxford increased from 213 deaths per million in 1979 to 335 by 1991, and thereafter declined to 253 deaths per million in 2006. Mentions-mortality in Oxford followed a similar pattern. In later years, when there were comparable data for Oxford and England, the pattern of decline in England was similar to that in Oxford. Where mentioned, prostate cancer was coded as the underlying cause of death on three-quarters of death certificates. CONCLUSIONS The fall in BPH mortality, evident in statistics on underlying cause, was confirmed by statistics on all certified causes of death. The fall is dramatic in scale, likely to be attributable to clinical care, and could be regarded as an indicator of improving standards of care. Mortality for prostate cancer increased, peaking in the 1990s, then decreased in recent years in rates as measured both by underlying cause and by mentions.

Certification of obesity as a cause of death in England 1979-2006.

BACKGROUND: There is increasing recognition of the importance of obesity as a cause of death but it is uncommon for obesity to be certified on death certificates. We considered it useful to study what doctors actually do in respect of certification of obesity and to study trends, if any, in certification practice. METHODS: Analysis of two datasets that include all certified causes of death ('mentions'), not just the underlying cause-the Oxford record linkage study 1979-2006 and English national mortality data 1995-2006. RESULTS: Underlying-cause mortality identified only a quarter (26% in Oxford, 25% in England) of all deaths with obesity as a certified cause. The longstanding Oxford dataset showed that there were significant changes over time in the percentage of certificates, with mention of obesity, that were coded with obesity as the underlying cause. Changes coincided with times of national change in selection and coding rules for underlying cause mortality. In the recent English dataset from 1995-2006, mention-based death rates rose by an average annual rate of 7.5% [95% confidence intervals (CI) 6.1-8.8] for men and by 4.0% (2.3-5.7) for women. Analysis of mortality based on underlying cause alone would have missed this rise. We report on diseases commonly certified alongside obesity on death certificates in England. CONCLUSION: There is an emerging trend of increased certification of obesity as a cause of death in England. The use of underlying-cause mortality statistics alone fails to capture the majority of obesity deaths.

Trends in death certification for multiple sclerosis, motor neuron disease, Parkinson's disease and epilepsy in English populations 1979-2006.

The objective of this study is to report trends in mortality, as certified on death certificates, from multiple sclerosis (MS), motor neuron disease (MND), primary Parkinson's disease (PD), and epilepsy, analysing not only the underlying cause of death but also all certified causes for each disease. Death records in the Oxford region, 1979-2006, and England, 1996-2006, were analysed for ascertaining the trends in mortality. The percentage of deaths coded as the underlying cause changed over time, coinciding with changes to the rules for selecting the underlying cause of death. Changes over time to coding rules had a large impact on apparent trends in death rates for PD when studied by underlying cause alone. They also had significant, though smaller, effects on trends in death rates for MS, MND and epilepsy. Nationally, in the last period of the study, underlying cause mortality identified 64% of deaths with a mention of MS, 88% of MND, 56% of PD, and 48% of epilepsy. In the longstanding Oxford data from 1979 to 2006, death rates based on all certified causes of death showed no significant change for MS; an upward trend for MND (notably in women over 75), though only in the last few years of the study; a significant but small decline for PD; and no significant change for epilepsy. When mortality statistics are analysed by underlying cause only, their value is reduced. A substantial percentage of neurological deaths are missed. Time trends may be misleading. All certified causes for each disease, as well as the underlying cause, should be analysed.

Mortality rates for stroke in England from 1979 to 2004: trends, diagnostic precision, and artifacts.

BACKGROUND AND PURPOSE: Stroke mortality appears to be declining more rapidly in the UK than in many other Western countries. To understand this apparent decline better, we studied trends in mortality in the UK using more detailed data than are routinely available. METHODS: Analysis of datasets that include both the underlying cause and all other mentioned causes of death (together, termed "all mentions"): the Oxford Record Linkage Study from 1979 to 2004 and English national data from 1996 to 2004. RESULTS: Mortality rates based on underlying cause and based on all mentions showed similar downward trends. Mortality based on underlying cause alone misses about one quarter of all stroke-related deaths. Changes during the period in the national rules for selecting the underlying cause of death had a significant but fairly small effect on the trend. Overall, mortality fell by an average annual rate of 2.3% (95% confidence interval 2.1% to 2.5%) for stroke excluding subarachnoid hemorrhage; and by 2.1% (1.7% to 2.6%) per annum for subarachnoid hemorrhage. Coding of stroke as hemorrhagic, occlusive, or unspecified varied substantially across the study period. As a result, rates for hemorrhagic and occlusive stroke, affected by artifact, seemed to fall substantially in the first part of the study period and then leveled off. CONCLUSIONS: Studies of stroke mortality should include all mentions as well as the certified underlying cause, otherwise the burden of stroke will be underestimated. Studies of stroke mortality that include strokes specified as hemorrhagic or occlusive, without also considering stroke overall, are likely to be misleading. Stroke mortality in the Oxford region halved between 1979 and 2004.

Inflammatory bowel disease, peptic ulcer and diverticular disease as certified causes of death in an English population 1979-2003.

BACKGROUND: When gastrointestinal diseases are certified as causes of death, they are often not selected as the underlying cause. Until recently, only one underlying cause of death has been coded and analysed in official national statistics in England and many other countries. AIMS: To report on the total 'burden of mortality' from some common gastrointestinal diseases, and whether it has changed over time, including all certified causes of death as well as underlying causes, (i) in the Oxford region from 1979 to 2003, (ii) in England from 1996 to 2003; and to quantify the under-ascertainment of cause-specific mortality when based on underlying cause alone. METHODS: We searched death certificate data from the Oxford Record Linkage Study database, and from English national data, for specified gastrointestinal diseases certified as underlying or contributory causes of death. RESULTS: For all the conditions studied, underlying-cause-coded mortality missed a substantial percentage of all certified deaths. The extent of underestimation varied according to the periods in which different criteria were used for the selection of the underlying cause. For example, in Oxford, in the latest period 1993-2003, underlying-cause-coded mortality identified only 37% of all death certificates with ulcerative colitis, 47% of Crohn's disease, between 62 and 68% for the different types of peptic ulcer and 66% of diverticular disease. CONCLUSIONS: Studies of mortality for these diseases should take account of all certified causes as well as underlying-cause mortality. This is particularly important for analyses that go across periods of change to the rules for selecting the underlying cause of death.

Psychiatric disorders certified on death certificates in an English population.

BACKGROUND: Psychiatric disorders are sometimes certified on death certificates, but seldom selected as the underlying cause of death. The majority of deaths with a certified psychiatric cause are usually omitted from official mortality statistics, which are typically based on the underlying cause alone. AIM: To report on death rates for psychiatric disorders, as certified on death certificates, including all mentioned causes as well as the underlying cause of death. METHOD: Analysis of database including all certified causes of death in 1979-1999, in three time periods defined by coding rule changes. RESULTS: Statistics on the underlying cause of death grossly under-estimated certified psychiatric disorders. For example, in the first period of our study they missed 88% of deaths in which schizophrenia was a certified cause, 98% of affective psychosis, and 96% of depression. Over time, considering all certified causes, age-standardised death rates for schizophrenia declined, those for affective psychosis showed no change, and those for depression and dementia increased. CONCLUSION: The decline in mortality rates for schizophrenia, and the increase for depression and dementia, may reflect real changes over time in disease prevalence at death, although other explanations are possible and are discussed.

Mortality from heart failure in an English population, 1979-2003: study of death certification.

OBJECTIVE: It is widely held that there will be an epidemic of heart failure in Europe and North America as a result of increased survival from myocardial infarction and other coronary heart disease. The study objective was to discover if the decline in mortality from coronary heart disease has been accompanied by a rise in mortality from heart failure in the study population. DESIGN: Analysis of database of mortality records including all certified causes of death, not just the underlying cause, from 1979-2003. SETTING: Former Oxford NHS Region, England. PATIENTS: Data from death certificates of all who died in the population covered. MAIN RESULTS: Mortality rates for heart failure fell at very similar rates as those from coronary heart disease. In men, the average annual fall in mortality from coronary heart disease was -2.7% (95% confidence intervals -2.8 to -2.5) and that from heart failure was -2.9% (-3.2 to -2.5). In women, the average annual fall in mortality from coronary heart disease was -2.3% (-2.6 to -2.1) and that from heart failure was -2.6% (-3.0 to -2.3). CONCLUSIONS: The decline in mortality from coronary heart disease has not been accompanied by a rise in mortality from heart failure. A future epidemic of heart failure, as a consequence of the decline in mortality from coronary heart disease, seems unlikely.

Alcohol as a certified cause of death in a 'middle England' population 1979-1999: database study.

The Alcohol Harm Reduction Strategy for England, recently published, highlights current concerns about alcohol consumption in this country. We used a database to examine trends in mortality for all deaths certified as effects of alcohol from 1979-1999, including mentions as well as underlying cause, in a relatively prosperous population in southern England. Mortality, certified as direct effects of alcohol, tripled during the 21 years of study; and mortality rates based on mentions were about double those based on underlying cause. The increase in recent years in mortality based on mentions was considerably greater than that based on underlying cause. Data on age, sex and occupational social class show that people whose alcohol intake kills them are from a broad cross-section of society.

Mortality rates for common respiratory diseases in an English population 1979-1998: artefact and substantive trends.

We analysed a mortality database in which all causes of death on each death certificate were coded, as well as underlying cause, to study trends from 1979 to 1998. Multiple-cause-coded death rates for pneumonia and acute bronchitis fell steadily and consistently. There were complementary rises and falls in death rates for individual chronic obstructive pulmonary diseases (COPD)--chronic bronchitis, emphysema, chronic obstructive airways disease--attributable to changes in clinical terminology. Judged by underlying cause, death rates for COPD were lower than those for lung cancer; but, judged by all mentions, death rates for COPD were appreciably higher than for lung cancer. Death rates for COPD, like lung cancer, fell over time in women under 65 years of age and in men; and increased in older women. For all respiratory diseases studied, except lung cancer, the underlying cause of death alone considerably underestimated the extent of their certification on death certificates.

Trends in mortality rates comparing underlying-cause and multiple-cause coding in an English population 1979-1998.

Until recently, national coding and analysis of routine mortality statistics in most countries included only underlying cause of death. There were changes in the rules for selection and coding of underlying cause in England in 1984 and 1993. We report on trends in mortality rates in an English region from 1979 to 1998, comparing multiple-cause and underlying-cause coded rates, for individual diseases that were affected by coding changes. Among many others, these include pneumonia, venous thromboembolism, heart failure, respiratory distress syndrome, tuberculosis, diabetes, dementia, alcohol and drug abuse, epilepsy, multiple sclerosis, stroke, asthma, peptic ulcer, appendicitis, and cancers of the breast, colon and prostate. Comparisons over time of mortality rates based on underlying cause alone will be misleading when the time-period crosses years in which rules changed for selecting underlying cause.