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1.  Treatment decisions and survival for people with small-cell lung cancer 
British Journal of Cancer  2014;110(4):908-915.
Background:
Chemotherapy improves survival for many patients with SCLC, and hence it is important to understand variations in practice and outcomes for this treatment strategy.
Methods:
We used the National Lung Cancer Audit and Hospital Episodes Statistics to determine the proportion of patients who received chemotherapy for SCLC, and assess the effects of patient and organisational factors on the odds of receiving chemotherapy and of completing four cycles. We calculated median survival and used Cox regression to determine factors that predicted survival.
Results:
Of 15 091 cases of SCLC, 70% received at least one cycle of chemotherapy. More deprived people were less likely to receive chemotherapy, but patients were more likely to receive chemotherapy, and to complete ⩾four cycles, if they were referred to the lung cancer team by their GP. Median survival for those treated with chemotherapy was 12.9 months for limited and 7.3 months for extensive stage disease.
Conclusions:
The Linked NLCA and HES data provide real-life measures of survival in people treated with chemotherapy and show how this is influenced by patient and tumour characteristics. These data show the characteristics of patients who are less likely to complete a full course of treatment, an adverse predictor of survival.
doi:10.1038/bjc.2013.812
PMCID: PMC3929890  PMID: 24398511
lung neoplasm; small cell; survival; chemotherapy; radiotherapy
2.  Lung cancer survival in England: trends in non-small-cell lung cancer survival over the duration of the National Lung Cancer Audit 
British Journal of Cancer  2013;109(8):2058-2065.
Background:
In comparison with other European and North American countries, England has poor survival figures for lung cancer. Our aim was to evaluate the changes in survival since the introduction of the National Lung Cancer Audit (NLCA).
Methods:
We used data from the NLCA to identify people with non-small-cell lung cancer (NSCLC) and stratified people according to their performance status (PS) and clinical stage. Using Cox regression, we calculated hazard ratios (HRs) for death according to the year of diagnosis from 2004/2005 to 2010; adjusted for patient features including age, sex and co-morbidity. We also assessed whether any changes in survival were explained by the changes in surgical resection rates or histological subtype.
Results:
In this cohort of 120 745 patients, the overall median survival did not change; but there was a 1% annual improvement in survival over the study period (adjusted HR 0.99, 95% confidence interval (CI) 0.98–0.99). Survival improvement was only seen in patients with good PS and early stage (adjusted HR 0.97, 95% CI 0.95–0.99) and this was partly accounted for by changes in resection rates.
Conclusion:
Survival has only improved for a limited group of people with NSCLC and increasing surgical resection rates appeared to explain some of this improvement.
doi:10.1038/bjc.2013.572
PMCID: PMC3798968  PMID: 24052044
lung neoplasm; survival; thoracic surgery; England
4.  How do patient and hospital features influence outcomes in small-cell lung cancer in England? 
British Journal of Cancer  2011;105(6):746-752.
Background:
Our aim was to systematically determine how features of patients and hospitals influence access to chemotherapy and survival for people with small-cell lung cancer in England.
Methods:
We linked the National Lung Cancer Audit and Hospital Episode Statistics and used multiple logistic and Cox regression analyses to assess the influence of patient and hospital features on small-cell lung cancer outcomes.
Results:
There were 7845 patients with histologically proven small-cell lung cancer. Sixty-one percent (4820) of the patients received chemotherapy. Increasing age, worsening performance status, extensive stage and greater comorbidity all reduced the likelihood of receiving chemotherapy. There was wide variation in access to chemotherapy between hospitals in general and patients first seen in centres with a strong interest in clinical trials had a higher odds of receiving chemotherapy (adjusted odds ratio 1.42, 95% confidence interval (CI) 1.06, 1.90). Chemotherapy was associated with a lower mortality rate (adjusted hazard ratio 0.51, 95% CI 0.46, 0.56).
Conclusion:
Patients first seen at a hospital with a keen interest in clinical trials are more likely to receive chemotherapy, and chemotherapy was associated with improved survival.
doi:10.1038/bjc.2011.310
PMCID: PMC3171016  PMID: 21829191
small-cell lung cancer; chemotherapy; survival; epidemiology
5.  Dietary consistency and the midline sutures in growing pigs 
Objectives
The purpose of this study was to investigate the effects of reduced masticatory function on midline suture growth and morphology in growing pigs.
Setting and Sample Population
The sample was 20 pigs separated into 2 dietary groups, and raised at the Department of Antrhopology, Harvard University. Midline suture specimes were analyzed at the Department of Orthodontics, University of Washington.
Materials and Methods
Ten farm pigs and 10 minipigs, all male, were randomly assigned to hard (n=9) and soft diet (n=11) groups. Fluorochromic mineral labels were administered to document bone apposition, and the animals were sacrificed after 12 weeks. Undecalcified sections of the interfrontal, interparietal, internasal and intermaxillary sutures were evaluated for bone quantity and sutural thickness, interdigitation ratio and growth rate.
Results
Soft diet pigs were characterized by a slower rate of weight gain, and less bone than their hard diet counterparts. Even after correction for weight gain, soft diet pigs had reduced suture growth rate and thickness. However, no difference in interdigitation ratio was detected between dietary groups.
Conclusion
Restriction to a soft diet reduces midline suture growth and bone apposition in the growing pig.
doi:10.1111/j.1601-6343.2010.01483.x
PMCID: PMC3384692  PMID: 20477970
Dietary consistency; pig; skull; soft diet; suture growth
6.  THE EFFECT OF TAX PREFERENCES ON HEALTH SPENDING 
National tax journal  2011;64(3):795-816.
In this paper, we estimate the effect of the tax preference for health insurance on health care spending using data from the Medical Expenditure Panel Surveys from 1996–2005. We use the fact that Social Security taxes are only levied on earnings below a statutory threshold to identify the impact of the tax preference. Because employer-sponsored health insurance premiums are excluded from Social Security payroll taxes, workers who earn just below the Social Security tax threshold receive a larger tax preference for health insurance than workers who earn just above it. We find a significant effect of the tax preference, consistent with previous research.
PMCID: PMC3322613  PMID: 22500056
tax preference; health insurance; health spending
7.  A comparison of non-homogeneous Markov regression models with application to Alzheimer’s disease progression 
Journal of applied statistics  2011;38(10):2313-2326.
Markov regression models are useful tools for estimating the impact of risk factors on rates of transition between multiple disease states. Alzheimer’s disease (AD) is an example of a multi-state disease process in which great interest lies in identifying risk factors for transition. In this context, non-homogeneous models are required because transition rates change as subjects age. In this report we propose a non-homogeneous Markov regression model that allows for reversible and recurrent disease states, transitions among multiple states between observations, and unequally spaced observation times. We conducted simulation studies to demonstrate performance of estimators for covariate effects from this model and compare performance with alternative models when the underlying non-homogeneous process was correctly specified and under model misspecification. In simulation studies, we found that covariate effects were biased if non-homogeneity of the disease process was not accounted for. However, estimates from non-homogeneous models were robust to misspecification of the form of the non-homogeneity. We used our model to estimate risk factors for transition to mild cognitive impairment (MCI) and AD in a longitudinal study of subjects included in the National Alzheimer’s Coordinating Center’s Uniform Data Set. Using our model, we found that subjects with MCI affecting multiple cognitive domains were significantly less likely to revert to normal cognition.
doi:10.1080/02664763.2010.547567
PMCID: PMC3299197  PMID: 22419833
Alzheimer’s disease; interval censoring; Markov process; mild cognitive impairment; non-homogeneous; panel data
8.  The Effect of Massachusetts’ Health Reform on Employer-Sponsored Insurance Premiums* 
In this paper, we use publicly available data from the Medical Expenditure Panel Survey - Insurance Component (MEPS-IC) to investigate the effect of Massachusetts’ health reform plan on employer-sponsored insurance premiums. We tabulate premium growth for private-sector employers in Massachusetts and the United States as a whole for 2004 – 2008. We estimate the effect of the plan as the difference in premium growth between Massachusetts and the United States between 2006 and 2008—that is, before versus after the plan—over and above the difference in premium growth for 2004 to 2006. We find that health reform in Massachusetts increased single-coverage employer-sponsored insurance premiums by about 6 percent, or $262. Although our research design has important limitations, it does suggest that policy makers should be concerned about the consequences of health reform for the cost of private insurance.
doi:10.2202/1558-9544.1204
PMCID: PMC3251220  PMID: 22229023
health reform
9.  THE EFFECT OF MEDICARE COVERAGE FOR THE DISABLED ON THE MARKET FOR PRIVATE INSURANCE 
Journal of health economics  2010;29(3):418-425.
We investigate whether the removal of high-cost individuals from private insurance markets leads to greater coverage for individuals who are similar but not as high cost. Using data on insurance coverage from the Panel Study of Income Dynamics, we estimate the effect of the extension of Medicare to the disabled on the private insurance coverage of non-disabled individuals. We find that the insurance coverage of individuals who had a health condition that limited their ability to work increased significantly in states with high versus low rates of disability.
doi:10.1016/j.jhealeco.2010.02.002
PMCID: PMC2866628  PMID: 20363519
10.  Lrp4 is a Receptor for Agrin and Forms a Complex with MuSK 
Cell  2008;135(2):334-342.
SUMMARY
Neuromuscular synapse formation requires a complex exchange of signals between motor neurons and skeletal muscle fibers, leading to the accumulation of postsynaptic proteins, including acetylcholine receptors in the muscle membrane and specialized release sites, or active zones in the presynaptic nerve terminal. MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, and Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors are a major cause of a group of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). How Agrin activates MuSK and stimulates synaptic differentiation is not known and remains a fundamental gap in our understanding of signaling at neuromuscular synapses. Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK and mediates MuSK activation by Agrin.
doi:10.1016/j.cell.2008.10.002
PMCID: PMC2933840  PMID: 18848351
11.  Association of MDMA/ecstasy and other substance use with self-reported sexually transmitted diseases among college-aged adults: a national study 
Public health  2009;123(8):557-564.
SUMMARY
Objectives
MDMA/ecstasy use among college students has increased and reportedly leads to risky sexual behaviours. However, little is known about its association with sexually transmitted diseases (STDs). To evaluate this public health concern, this study examined the association between substance use (particularly MDMA) and self-reported STDs (chlamydia, gonorrhoea, herpes and syphilis) among college students and non-students aged 18–22 years (n=20,858).
Study design
A cross-sectional data analysis of a national survey.
Methods
Data were drawn from the 2005–2006 National Surveys on Drug Use and Health; a nationally representative survey of non-institutionalized Americans. Self-reported STDs and substance use were assessed by the audio computer-assisted self-interviewing method. The association between MDMA use and STDs was determined while taking into account young adults’ use of other substances, healthcare utilization and sociodemographic characteristics.
Results
Overall, 2.1% of college students and 2.5% of non-students reported contracting an STD in the past year. MDMA use in the past year was not associated with STDs. Among non-students, onset of MDMA use before 18 years of age increased the odds of past-year STDs. In both groups, alcohol use, marijuana use, female gender and African American race increased the odds of both past-year and lifetime STDs. Additional analyses indicated that, regardless of college-attending status, greater odds of past-year STDs were noted among users of alcohol and drugs, and users of alcohol alone, but not among users of drugs alone.
Conclusions
Alcohol use is a robust correlate of STDs. Irrespective of college-attending status, young women and African Americans have a higher rate of STDs than young men and Whites.
doi:10.1016/j.puhe.2009.06.012
PMCID: PMC2757289  PMID: 19656538
Alcohol use; College students; Epidemiology; MDMA; Sexually transmitted diseases
12.  Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK 
Thorax  2006;61(11):980-985.
Background
Idiopathic pulmonary fibrosis (IPF) and sarcoidosis are common diagnoses in patients attending chest clinics, but little is known about the epidemiology of these diseases. We used data from a general practice database to provide information on the current incidence of IPF and sarcoidosis in the UK.
Methods
Data were extracted for all patients with a diagnosis of IPF or sarcoidosis between 1991 and 2003. The whole population of the database was used to calculate disease incidence stratified by age, sex, region, and time period. Poisson regression was used to compare the incidence between populations and Cox regression was used to compare survival between populations.
Results
920 cases of IPF (mean age 71 years, 62% male) and 1019 cases of sarcoidosis (mean age 47 years, 47% male) were identified. The overall incidence rate per 100 000 person‐years was 4.6 for IPF and 5.0 for sarcoidosis. The incidence of IPF increased progressively between 1991 and 2003 (p<0.00001), and was highest in Northern England and Scotland (p<0.0001). The survival of patients with IPF was stable over time. In contrast, the incidence of sarcoidosis was highest in London, West Midlands and Northern Ireland and remained stable over time.
Conclusions
The incidence of IPF has more than doubled between 1990 and 2003; this is not due to the ageing of the UK population or an increased ascertainment of milder cases. The incidence of sarcoidosis has not changed during this time period. Our findings suggest that more than 4000 new cases of IPF and 3000 new cases of sarcoidosis are currently diagnosed each year in the UK.
doi:10.1136/thx.2006.062836
PMCID: PMC2121155  PMID: 16844727
idiopathic pulmonary fibrosis; sarcoidosis; epidemiology
13.  Is an internal comparison better than using national data when estimating mortality in longitudinal studies? 
Background
Discrepancies between the results of different studies looking at mortality in similar disease cohorts led us to consider the impact of methodology upon outcome.
Methods
Cohort studies were carried out using age, sex, practice, and calendar time matched control groups in the general practice research database. Data were used on all subjects with inflammatory bowel disease, coeliac disease, or Barrett's oesophagus. Mortality data for the population of England and Wales were obtained from the UK Office for National Statistics. The study compared hazard ratios (HR) for mortality using the matched controls to those found when an indirect standardisation to the mortality experience of England and Wales was carried out.
Results
For all three conditions the mortality risk was slightly lower when the national population data were used compared with the internal comparison group (coeliac disease HR 1.33 v standardised mortality ratios (SMR) 1.25, Barrett's oesophagus HR 1.32 v SMR 1.32, inflammatory bowel disease HR 1.50 v SMR 1.34).
Conclusions
A bias was found towards underestimating mortality risk when cohort studies use national population death rates as a comparator. Estimates obtained when an internal comparison group has been used are probably more appropriate.
doi:10.1136/jech.2005.041202
PMCID: PMC2566035  PMID: 16905729
inflammatory bowel disease; Barrett's oesophagus; coeliac disease; cohort studies; standardised mortality ratio; Cox regression
14.  The burden of lung disease 
Thorax  2006;61(7):557-558.
A timely reminder of the needs of people with respiratory disease in the UK
doi:10.1136/thx.2006.066050
PMCID: PMC2104658  PMID: 16807390
respiratory medicine; government policy; British Thoracic Society
15.  Oral and inhaled corticosteroids and adrenal insufficiency: a case‐control study 
Thorax  2006;61(5):405-408.
Background
Adrenal insufficiency, a well recognised complication of treatment with oral corticosteroids, has been described in association with inhaled corticosteroid use in over 60 case reports. The risk of adrenal insufficiency in people prescribed an oral or inhaled corticosteroid in the general population is not known. A study was undertaken to quantify the association between adrenal insufficiency and oral and inhaled corticosteroid exposure.
Methods
A case‐control study was performed using computerised general practice data from The Health Improvement Network.
Results
From a cohort of 2.4 million people, 154 cases of adrenal insufficiency and 870 controls were identified. There was a dose related increased risk of adrenal insufficiency in people prescribed an oral corticosteroid with an odds ratio of 2.0 (95% CI 1.6 to 2.5) per course of treatment per year. Adrenal insufficiency was associated with a prescription for an inhaled corticosteroid during the 90 day period before the diagnosis with an odds ratio of 3.4 (95% CI 1.9 to 5.9) and this effect was dose related (p for trend <0.001). After adjusting for oral corticosteroid exposure, this odds ratio was reduced to 1.6 (95% CI 0.8 to 3.2) although the dose relation remained (p for trend 0.036).
Conclusion
People prescribed an oral or inhaled corticosteroid are at a dose related increased risk of adrenal insufficiency although the absolute risk is small. This analysis suggests that the increased risk in people prescribed an inhaled corticosteroid is largely due to oral corticosteroid exposure, but inhaled corticosteroids may have an effect when they are taken at higher doses.
doi:10.1136/thx.2005.052456
PMCID: PMC2111185  PMID: 16517576
inhaled corticosteroids; adrenal insufficiency
16.  Use of nicotine replacement therapy and the risk of acute myocardial infarction, stroke, and death 
Tobacco Control  2005;14(6):416-421.
Objective: To determine whether nicotine replacement therapy (NRT) is associated with an increased risk of acute myocardial infarction, acute stroke, or death.
Design: Self control case series analysis of data from The Health Improvement Network (THIN) to estimate the relative incidence of myocardial infarction and stroke in four 14 day periods before and after the first prescription for NRT.
Setting: THIN is a computerised general practice database.
Subjects: Patients contributing data to THIN.
Interventions: Observational study of NRT.
Main outcomes: Acute myocardial infarction, acute stroke, and death.
Results: 33 247 individuals had been prescribed NRT, of whom 861 had had a myocardial infarction and 506 a stroke. There was a progressive increase in the incidence of first myocardial infarction in the 56 days leading up to the first NRT prescription (overall incidence ratio 5.55, 95% confidence interval (CI) 4.42 to 6.98), but the incidence fell after this time and was not increased in the 56 days after starting NRT (incidence ratio 1.27, 95% CI 0.82 to 1.97). The results were similar for second myocardial infarction and stroke, and for subgroups of people with pre-existing angina and hypertension. There were 960 deaths in our cohort during a mean follow up period of 2.6 years after starting NRT, with no evidence of an increased mortality in the 56 days after the NRT prescription (incidence ratio 0.86, 95% CI 0.60 to 1.23).
Conclusions: The use of NRT is not associated with any increase in the risk of myocardial infarction, stroke, or death.
doi:10.1136/tc.2005.011387
PMCID: PMC1748112  PMID: 16319366
17.  Bupropion and the risk of sudden death: a self-controlled case-series analysis using The Health Improvement Network 
Thorax  2005;60(10):848-850.
Background: Bupropion is an effective smoking cessation therapy but its use in the UK has been limited by concerns that it may increase the risk of sudden death.
Methods: Data for all patients prescribed bupropion within The Health Improvement Network (a computerised general practice database) were extracted and the self-controlled case-series method was used to estimate the relative incidence of death during the first 28 days of treatment. The incidence of seizures, a recognised adverse effect of bupropion, was also investigated during this period.
Results: A total of 9329 individuals had been prescribed bupropion (mean age 44 years, 48% male). The total person-time after the first prescription for bupropion was 17 586 years, and during this time 121 people died. Two people died within the first 28 days of treatment, which was less than expected in comparison with the remaining observation period by an incidence ratio of 0.50 (95% confidence interval (CI) 0.12 to 2.05). Twenty eight people were recorded as having a total of 45 seizures (23 before starting bupropion, two in the first 28 days of treatment, and 20 at a later point). The relative incidence of seizures during the first 28 days of treatment was 3.62 (95% CI 0.87 to 15.09), equivalent to one additional seizure per 6219 first time bupropion users.
Conclusions: Bupropion use is probably associated with an increased risk of seizures, but no evidence was found to suggest that the drug is associated with an increased risk of sudden death.
doi:10.1136/thx.2005.041798
PMCID: PMC1747199  PMID: 16055620
18.  Hormone replacement therapy, cancer, controversies, and women's health: historical, epidemiological, biological, clinical, and advocacy perspectives 
Routine acceptance of use of hormone replacement therapy (HRT) was shattered in 2002 when results of the largest HRT randomised clinical trial, the women's health initiative, indicated that long term use of oestrogen plus progestin HRT not only was associated with increased risk of cancer but, contrary to expectations, did not decrease, and may have increased, risk of cardiovascular disease. In June 2004 a group of historians, epidemiologists, biologists, clinicians, and women's health advocates met to discuss the scientific and social context of and response to these findings. It was found that understanding the evolving and contending knowledge on hormones and health requires: (1) considering its societal context, including the impact of the pharmaceutical industry, the biomedical emphasis on individualised risk and preventive medicine, and the gendering of hormones; and (2) asking why, for four decades, since the mid-1960s, were millions of women prescribed powerful pharmacological agents already demonstrated, three decades earlier, to be carcinogenic? Answering this question requires engaging with core issues of accountability, complexity, fear of mortality, and the conduct of socially responsible science.
doi:10.1136/jech.2005.033316
PMCID: PMC1733142  PMID: 16100311
19.  A case control study of age related macular degeneration and use of statins 
The British Journal of Ophthalmology  2005;89(9):1171-1175.
Aims: Age related macular degeneration (AMD) is the leading cause of blindness in industrialised countries. Previous studies have suggested that statins may have a protective effect against the disease; however, existing studies have had limited power to reliably detect or exclude an effect and have produced conflicting results. The authors assessed the risk of AMD associated with the use of statins.
Methods: Population based case control study using the United Kingdom General Practice Research Database. 18 007 people with diagnosed AMD were compared with 86 169 controls matched on age, sex, and general practice. The primary outcome was the odds ratio for the association between exposure to statins and AMD.
Results: The crude odds ratio for the association between any recorded exposure to statins and AMD was 1.32 (95% CI 1.17 to 1.48), but this reduced to 0.93 (95% CI 0.81 to 1.07, p = 0.33) after adjustment for consultation rate, smoking, alcohol intake, body mass index, atherosclerotic disease, hyperlipidaemia, heart failure, diabetes mellitus, hypertension, use of other cardiovascular drugs, and use of fibrates. There was no evidence that the risk varied by dose of statin, duration of use, or that the risk varied for individual statins.
Conclusion: In the short and medium term statin use is not associated with a decreased risk of AMD. Whether subgroups of patients with specific forms of AMD (particularly choroidal neovascularisation) benefit from statin therapy remains a possibility.
doi:10.1136/bjo.2004.064477
PMCID: PMC1772815  PMID: 16113375
age related macular degeneration; statins; case control
20.  Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study 
BMJ : British Medical Journal  2008;337(7662):160-163.
Objective To determine the incidence of and mortality from bullous pemphigoid and pemphigus vulgaris in the United Kingdom.
Design Retrospective historical cohort study.
Setting Computerised medical records from the health improvement network, a large population based UK general practice database.
Participants Patients with pemphigus vulgaris and bullous pemphigoid diagnostic codes and age, sex, and practice matched controls.
Main outcome measures Incidence and mortality compared with the control population by calendar period, age group, sex, geographical region, and degree of social deprivation.
Results 869 people with bullous pemphigoid and 138 people with pemphigus vulgaris were identified. The median age at presentation for bullous pemphigoid was 80 (range 23-102) years, and 534 (61%) patients were female. The median age at presentation for pemphigus vulgaris was 71 (21-102) years, and 91 (66%) patients were female. Incidences of bullous pemphigoid and pemphigus vulgaris were 4.3 (95% confidence interval 4.0 to 4.6) and 0.7 (0.6 to 0.8) per 100 000 person years. The incidence of bullous pemphigoid increased over time; the average yearly increase was 17% (incidence rate ratio=1.2, 95% confidence interval 1.1 to 1.2). An average yearly increase in incidence of pemphigus vulgaris of 11% (incidence rate ratio=1.1, 1.0 to 1.2) occurred. The risk of death for patients with bullous pemphigoid was twice as great as for controls (adjusted hazard ratio=2.3, 95% confidence interval 2.0 to 2.7). For pemphigus vulgaris, the risk of death was three times greater than for controls (adjusted hazard ratio=3.3, 2.2 to 5.2).
Conclusions Incidences of bullous pemphigoid and pemphigus vulgaris are increasing. The reasons for the changes in incidence are not clearly understood but have implications for identifying causative factors. Both disorders are associated with a high risk of death. Previous estimates may have underestimated the risk of death associated with these diseases.
doi:10.1136/bmj.a180
PMCID: PMC2483869  PMID: 18614511
21.  General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction 
Heart  2005;91(4):465-471.
Objective: To investigate the impact of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) on the risk of first acute myocardial infarction (MI).
Design: Case–control analysis and a self controlled case series.
Setting: 644 general practices throughout England, Scotland, Wales, and Northern Ireland.
Patients: Over 60 000 cases of MI and 360 000 age, sex, and practice matched controls randomly selected from the UK General Practice Research Database.
Main outcome measures: Matched odds ratios and incidence rate ratios estimating whether there is an acute or prolonged increased risk of MI after exposure to TCA and SSRI drugs and individual drugs within these families.
Results: Case–control analysis found an initial increased risk of MI after TCA exposure (for example, at 1–7 days after the first dothiepin prescription: odds ratio (OR) 1.90, 95% confidence interval (CI) 1.15 to 3.14) or SSRI exposure (for example, at 1–7 days after first fluoxetine prescription: OR 2.59, 95% CI 1.44 to 4.66). In the self controlled analysis the equivalent risk estimates were an incidence rate ratio of 1.43, 95% CI 0.92 to 2.22 for dothiepin and an incidence rate ratio of 1.66, 95% CI 1.01 to 2.71 for fluoxetine.
Conclusions: Antidepressant prescriptions are associated with an increased risk of MI. The size of these effects is similar for TCA and SSRI exposures; however, the lack of specificity between types of antidepressants and the lower risks found in the self controlled analysis suggest that these associations are more likely due to factors relating to underlying depression and health services utilisation than to specific adverse drug effects.
doi:10.1136/hrt.2004.037457
PMCID: PMC1768803  PMID: 15772201
myocardial infarction; tricyclic antidepressant; TCA; selective serotonin reuptake inhibitor; SSRI; case–control study; self controlled case series
22.  Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study 
Objective To determine the incidence of and mortality from bullous pemphigoid and pemphigus vulgaris in the United Kingdom.
Design Retrospective historical cohort study.
Setting Computerised medical records from the health improvement network, a large population based UK general practice database.
Participants Patients with pemphigus vulgaris and bullous pemphigoid diagnostic codes and age, sex, and practice matched controls.
Main outcome measures Incidence and mortality compared with the control population by calendar period, age group, sex, geographical region, and degree of social deprivation.
Results 869 people with bullous pemphigoid and 138 people with pemphigus vulgaris were identified. The median age at presentation for bullous pemphigoid was 80 (range 23-102) years, and 534 (61%) patients were female. The median age at presentation for pemphigus vulgaris was 71 (21-102) years, and 91 (66%) patients were female. Incidences of bullous pemphigoid and pemphigus vulgaris were 4.3 (95% confidence interval 4.0 to 4.6) and 0.7 (0.6 to 0.8) per 100 000 person years. The incidence of bullous pemphigoid increased over time; the average yearly increase was 17% (incidence rate ratio=1.2, 95% confidence interval 1.1 to 1.2). An average yearly increase in incidence of pemphigus vulgaris of 11% (incidence rate ratio=1.1, 1.0 to 1.2) occurred. The risk of death for patients with bullous pemphigoid was twice as great as for controls (adjusted hazard ratio=2.3, 95% confidence interval 2.0 to 2.7). For pemphigus vulgaris, the risk of death was three times greater than for controls (adjusted hazard ratio=3.3, 2.2 to 5.2).
Conclusions Incidences of bullous pemphigoid and pemphigus vulgaris are increasing. The reasons for the changes in incidence are not clearly understood but have implications for identifying causative factors. Both disorders are associated with a high risk of death. Previous estimates may have underestimated the risk of death associated with these diseases.
doi:10.1136/bmj.a180
PMCID: PMC2483869  PMID: 18614511
23.  Survival and disease progression in UK patients with lymphangioleiomyomatosis 
Thorax  2004;59(9):800-803.
Background: Lymphangioleiomyomatosis (LAM) is a rare and progressive disease of young women with no effective treatment. Previous estimates of 10 year survival, based mostly on case series or patients from tertiary centres, have ranged from 40% to 79%; no data are available on the progression of respiratory disability. In order to provide data for patients and for planning intervention studies, we have looked at the time course of LAM using a national cohort.
Methods: Time to death, time to MRC dyspnoea grades 2–5, and need for oxygen in patients on the UK LAM database were analysed using Kaplan-Meier analysis and Cox regression.
Results: Fifty seven of 72 patients responded with a median duration of follow up of 12.6 years (range 2.3–37) from the onset of symptoms. Ten year survival was 91% from onset of symptoms but varied widely with 11 patients alive after 20 years. Median time to MRC grade 3 dyspnoea (breathless walking on the flat) was 9.3 years (95% CI 5.1 to 13.4) from onset of symptoms.
Conclusions: Survival from LAM appears to be better than that reported in early studies. These data should be helpful for patients and for planning clinical trials.
doi:10.1136/thx.2004.023283
PMCID: PMC1747117  PMID: 15333859
24.  Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study 
Gut  2004;53(2):251-255.
Background: Inflammatory bowel disease (IBD) is known to be associated with reduced bone density but the extent to which this results in an increased risk of fracture and the contribution of corticosteroid therapy are unclear. We have conducted a large cohort study to address these issues.
Methods: We selected subjects within the General Practice Research Database (GPRD) with a diagnosis of IBD and up to five matched controls for each patient. We derived dates of recorded hip fractures and also information on smoking, use of corticosteroids, and a number of other drugs. We calculated the absolute risk of fracture and the relative risk as a hazard ratio corrected for available confounders by Cox regression.
Results: Seventy two hip fractures were recorded in 16 550 IBD cases and 223 in 82 917 controls. Cox modelling gave an unadjusted relative risk of hip fracture of 1.62 (95% confidence interval (CI) 1.24–2.11) for all IBD, 1.49 (1.04–2.15) for ulcerative colitis (UC) and 2.08 (1.36–3.18) for Crohn’s disease (CD). Multivariate modelling showed that both current and cumulative use of corticosteroids and use of opioid analgesics confounded this relationship. After adjusting for confounding, the relative risk was 1.41 (0.94–2.11) for UC and 1.68 (1.01–2.78) for CD.
Conclusion: The risk of hip fracture is increased approximately 60% in IBD patients. Corticosteroid use is a contributor to this, both in the long term as previously recognised and also in an acute reversible manner. The majority of hip fracture risk in IBD patients however cannot be attributed to steroid use.
doi:10.1136/gut.2003.026799
PMCID: PMC1774916  PMID: 14724159
corticosteroids; fracture; inflammatory bowel disease
25.  The developing story of antioxidants and asthma 
Thorax  2004;59(1):3-4.
PMCID: PMC1758863  PMID: 14694233

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