Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database.

OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.

Diagnosis and treatment of lower urinary tract symptoms suggestive of overactive bladder and bladder outlet obstruction among men in general practice in the UK.

OBJECTIVE: To assess the epidemiology and treatment of storage symptoms suggestive of overactive bladder (OAB) and voiding symptoms suggestive of bladder outlet obstruction (BOO) because of benign prostatic hyperplasia in UK general practice. PATIENTS AND METHODS: This was a retrospective analysis of data collected between 2000 and 2006 and entered in The Health Improvement Network general practice database, containing medical records for > 1 million men (aged >or= 18 years) in the UK. Using Read codes, we analysed the prevalence of storage and voiding lower urinary tract symptoms (LUTS) as well as prescribing trends for 5alpha-reductase inhibitors (5ARIs) and alpha-blockers for LUTS secondary to BOO and antimuscarinics for OAB. RESULTS: In 2006, the prevalence of diagnosed LUTS/OAB was only 0.3% and the recorded prevalence of LUTS/BOO was only 2.2%. Treatment rates also remained low throughout the study period. In the 12 months before 1 January 2006, only 25% of men diagnosed with OAB and 6-7% of men with storage LUTS received antimuscarinics, whereas 36% of men with a record of LUTS/BOO received alpha-blockers and/or 5ARIs. Alpha-blockers were prescribed to approximately 10% of men diagnosed with OAB or storage LUTS who did not have any recorded BOO diagnosis or symptoms. CONCLUSION: Diagnosis of both storage and voiding LUTS occurs at much lower rates than indicated by prevalence estimates. Despite the availability of effective prescription therapies, many men with storage and/or voiding LUTS may not be receiving appropriate treatment in UK general practice.

Treatment patterns of hypertension and dyslipidaemia in hypertensive patients at higher and lower risk of cardiovascular disease in primary care in the United Kingdom.

Few studies have investigated the presence of dyslipidaemia in hypertensive individuals. In addition, few data exist on the concurrent treatment of both conditions for the prevention of cardiovascular disease (CVD). This retrospective cohort study examined treatment patterns for hypertension and dyslipidaemia among hypertensive patients in UK primary care. We defined a population of patients aged > or =40 years from the UK General Practice Research Database. Hypertensive individuals with > or =3 additional cardiovascular risk factors (ARFs) were compared with a cohort comprising hypertensive patients with < or =2 ARFs. We analysed the prevalence of risk factors and the prevalence and incidence of treatment for hypertension, dyslipidaemia and for both conditions between January 1997 and December 2001. A total of 117 840 hypertensive patients were identified (23 655 with > or =3 ARFs, 94 185 with < or =2 ARFs) in 1997; in 2001, the number diagnosed as hypertensive was 133 683 (40 248 > or =3 ARFs, 93 435 < or =2 ARFs). The prevalence of antihypertensive treatment in the hypertensive patients with > or =3 ARFs increased during the study. In 2001, approximately one-third of hypertensive patients with > or =3 ARFs were not receiving antihypertensives. Among those patients who received such treatment, the majority received > or =2 separate agents in accordance with current guidelines. Treatment for concurrent hypertension and dyslipidaemia was initiated in <8% of patients with hypertension and > or =3 ARFs in each year. These findings demonstrate the under-recognition/undertreatment of cardiovascular risk factors in UK primary care among patients at risk of CVD.

Application of a propensity score to adjust for channelling bias with NSAIDs.

PURPOSE: To compare the relative risks of upper GI haemorrhage (UGIH) in users of Newer versus Older, non-specific NSAIDs when adjusted for channelling bias by regression on individual covariates, a propensity score and both. METHODS: Cohort study of patients prescribed NSAIDs between June 1987 and January 2000. Exposure to Newer and Older non-specific NSAIDs was identified, and risk factors evaluated for each patient. Results of multiple covariate analyses and the propensity scoring technique to assess potential channelling bias in comparisons between Newer and Older non-specific NSAIDs were compared. RESULTS: This study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to Older non-specific NSAIDs. Patients receiving Newer NSAIDs were older, more likely to have a history of GI symptoms, and at higher risk for GI complications. Adjusting for these risk factors reduced the relative risks of UGIH on meloxicam and coxibs versus Older non-specific NSAIDs to 0.84 (95%CI 0.60, 1.17) and 0.36 (0.14, 0.97) respectively. CONCLUSIONS: Channelling towards high GI risk patients occurred in the prescribing of Newer NSAIDs. Propensity scores highlighted the markedly different risk profiles of users of Newer and Older non-specific NSAID. Correcting for channelling bias, coxib exposure, but not meloxicam exposure, was associated with less UGIH than Older non-specific NSAID exposure. In the present study, corrections made by regression on a propensity score and on individual covariates were similar.

Cardiovascular prophylaxis with aspirin: costs of supply and management of upper gastrointestinal and renal toxicity.

AIMS: To determine the cost to the NHS of prescribed low-dose aspirin. METHODS: This was a population based observational cohort study. Patients from Tayside Scotland (17 244 new users of dispensed aspirin each with 10 matched comparators) were included. A pragmatic analysis totalled costs from the start to end of the study and compared these with a matched cohort of aspirin nonusers to estimate excess costs. Fastidious analyses were done of subjects with no prior history of upper gastrointestinal (UGI) or renal disease where the cost that occurred during aspirin exposure, the 30 days following aspirin exposure and subsequent nonexposure was calculated adjusting for risk factors in each period. RESULTS: Subjects took aspirin for only 1.18 of the 2.53 years follow-up (47% compliance). Aspirin use cost an additional 49.86 UK pounds per year (pragmatic analysis) made up of 1.96 UK pounds for aspirin tablets (4%), 5.49 UK pounds for dispensing costs (11%), 24.60 UK pounds for UGI complications (49%) and 17.81 UK pounds for renal complications (36%). The costs for managing complications were substantially lower in the fastidious analysis (2.66 UK pounds for UGI complications and 2.92 UK pounds for renal complications). Assuming that the antiplatelet trial meta-analysis is an accurate assessment of the benefits of aspirin, the costs of preventing one vascular event lay between 62 500 UK pounds (primary prevention, pragmatic analysis) and 867 UK pounds (secondary prevention, fastidious analysis). These costs may be underestimates due to the low compliance observed. CONCLUSIONS: Compliance with aspirin was poor. Serious adverse events were uncommon but despite this aspirin cost the NHS between 6 and 25 times the cost of aspirin tablets due to dispensing costs and the cost of managing adverse effects.

Rates of production of acetate, propionate, and butyrate in the rumen of lactating dairy cows given normal and low-roughage diets.

Five lactating dairy cows with a permanent cannula in the rumen were given (kg DM/d) a normal diet (7.8 concentrates, 5.1 hay) or a low-roughage (LR) diet (11.5 concentrates, 1.2 hay) in two meals daily in a two-period crossover design. Milk fat (g/kg) was severely reduced on diet LR. To measure rates of production of individual volatile fatty acids (VFA) in the rumen, 0.5 mCi 1-(14)C-acetic acid, 2-(14)C-propionic acid, or 1-(14)C-n-butyric acid were infused into the rumen for 22 h at intervals of 2 to 6 d; rumen samples were taken over the last 12 h. To measure rumen volume, we infused Cr-EDTA into the rumen continuously, and polyethylene glycol was injected 2 h before the morning feed. Results were very variable, so volumes measured by rumen emptying were used instead. Net production of propionic acid more than doubled on LR, but acetate and butyrate production was only numerically lower. Net production rates pooled across both diets were significantly related to concentrations for each VFA. Molar proportions of net production were only slightly higher than molar proportions of concentrations for acetate and propionate but were lower for butyrate. The net energy value (MJ/d) of production of the three VFA increased from 89.5 on normal to 109.1 on LR, equivalent to 55 and 64% of digestible energy, respectively. Fully interchanging, three-pool models of VFA C fluxes are presented. It is concluded that net production rates of VFA can be measured in non-steady states without the need to measure rumen volumes.

Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs.

BACKGROUND: Although clinical trial results suggest that meloxicam has less gastrointestinal toxicity than most other non-steroidal anti-inflammatory drugs (NSAIDs), in practice it has been associated with a large number of yellow card reports of gastrointestinal complications. AIMS: To estimate whether meloxicam and the coxibs, rofecoxib and celecoxib, have been channelled towards high risk patients, and to estimate the risk of hospitalisation for gastrointestinal haemorrhage associated with the use of these drugs, allowing for the effects of channelling. PATIENTS: Using the UK General Practice Research Database, this study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to older non-specific NSAIDs. METHODS: Cohort study of patients who received a prescription for an NSAID between June 1987 and January 2001. Exposure to newer NSAIDs (meloxicam, rofecoxib, celecoxib) and to older non-specific NSAIDs was identified. Channelling was assessed on factors including: demographic variables; diagnosis of arthritis; history of NSAID use or gastrointestinal events, including gastrointestinal haemorrhage; and use of ulcer healing drugs. RESULTS: Most risk factors for gastrointestinal haemorrhage were more prevalent among patients prescribed the newer NSAIDs. Adjusting for these risk factors reduced the relative risks of gastrointestinal haemorrhage on meloxicam and coxibs versus older non-specific NSAIDs to 0.84 (95% confidence interval 0.60, 1.17) and 0.36 (0.14, 0.97), respectively. CONCLUSIONS: Channelling towards high risk gastrointestinal patients occurred in the prescribing of newer NSAIDs. After attempting to correct for channelling bias, coxib exposure, but not meloxicam exposure, was associated with a significantly lower risk of gastrointestinal haemorrhage than older non-specific NSAID exposure.

A pharmacoeconomic comparison of misoprostol/diclofenac with diclofenac.

OBJECTIVES: To estimate the economic impact of misoprostol/diclofenac in a fixed combination tablet compared with diclofenac. DESIGN: Cohort study with a prospectively constructed, population-based, record-linkage database containing details of exposure to all community dispensed NSAIDs and all admissions to hospital for upper gastrointestinal (GI) diagnoses. Costs associated with each study drug exposure were analysed using generalized linear models. SETTING: The population of Tayside, Scotland. SUBJECTS: Subjects aged 20 years and over who received misoprostol/diclofenac or any other NSAID between January 1989 and 31 December 1995. MAIN OUTCOME MEASURES: Total costs for the number of days of exposure to diclofenac and misoprostol/diclofenac, plus costs of concomitant ulcer healing drug therapy plus endoscopy procedures plus costs of admissions to hospital for upper GI diagnoses. RESULTS: The rate of hospitalization with gastrointestinal events was 30% higher among patients receiving diclofenac than that for patients receiving misoprostol/diclofenac. Among patients who received diclofenac and an ulcer-healing drug (UHD), the event rate was more than twice that for patients receiving misoprostol/diclofenac. In patients with a prior GI history, switching from diclofenac to misoprostol/diclofenac would reduce the costs of hospitalization. The resulting savings would more than offset the extra prescription costs. In patients without a prior GI history, the greatest potential saving would arise due to reduced use of UHDs and net savings would occur in subjects aged between 60 and 70 years of age or more. CONCLUSION: Use of misoprostol/diclofenac instead of diclofenac can produce cost savings due to reduced hospitalization rates and decreased use of UHDs in subjects with a prior history of GI disease and in older subjects without prior GI disease. These findings have implications for the management of patients who require treatment with NSAIDs.

Low-dose misoprostol for the prevention of low-dose aspirin-induced gastroduodenal injury.

INTRODUCTION: The harmful effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa and the prophylactic effects of misoprostol are both dose-dependent. AIM: To investigate whether a low-dose of misoprostol is sufficient to prevent gastric mucosal injury caused by low-dose aspirin. METHODS: We conducted a double-blind placebo controlled parallel group endoscopic study in 32 evaluable volunteers. The main outcome measure was erosive injury (ulcers and superficial erosions) in the gastric mucosa over 28 days. RESULTS: Most subjects developed erosions on aspirin 300 mg daily. This was significantly reduced by misoprostol 100 microg daily. (Odds ratio 0.18, 95% CI: 0.07-0.48). There were no drug-related or gastrointestinal adverse events in subjects receiving misoprostol. CONCLUSION: Misoprostol 100 microg daily can prevent low-dose aspirin induced gastric mucosal injury without causing identifiable adverse effects.

Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.

OBJECTIVES: To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with, and after cessation of, non-steroidal anti-inflammatory drugs. DESIGN: Cohort study with a prospectively constructed, population based, record linkage database containing details of exposure to all community dispensed non-steroidal anti-inflammatory drugs and also all admissions to hospital for upper gastrointestinal diagnoses. SETTING: The population of Tayside, Scotland. SUBJECTS: 52,293 subjects aged 50 and over who received one or more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991 and 73,792 subjects who did not receive one during the same period (controls). MAIN OUTCOME MEASURES: Admission to hospital for upper gastrointestinal bleeding and perforation, and admission for other upper gastrointestinal diagnoses. RESULTS: About 2% of the non-steroidal anti-inflammatory cohort were admitted with an upper gastrointestinal event during the study period compared with 1.4% of controls. The risk of admission for upper gastrointestinal haemorrhage and perforation was constant during continuous non-steroidal anti-inflammatory exposure and carried over after the end of exposure. The results were similar for admissions for all upper gastrointestinal events. CONCLUSION: This study provides evidence that non-steroidal anti-inflammatory toxicity persists with continuous exposure. There seems to be carryover toxicity after the end of prescribing. These findings have implications for the management of patients requiring non-steroidal anti-inflammatory drugs.

The prevention and healing of acute non-steroidal anti-inflammatory drug-associated gastroduodenal mucosal damage by misoprostol.

This double-blind study assessed the acute development of NSAID-associated gastroduodenal (GD) damage and its prevention by misoprostol. Patients requiring chronic NSAID therapy were stratified into two groups depending on initial endoscopic appearance, Group I: normal (n = 223); Group II: non-ulcer lesions (n = 78). After 2 weeks of therapy with NSAID and either misoprostol 400-800 micrograms daily or placebo the incidence of severe mucosal damage (including ulcers) was significantly reduced by misoprostol (odds ratio; 95% CI). Group I: 4.52; 1.94, 10.51 (P = 0.018); Group II: 10.93; 1.09, 109.60 (P = 0.014); Groups I and II combined: 5.95; 3.23, 10.94 (P = 0.0003). Misoprostol exerted a significant protective effect against progression of minor to severe damage in Group II (P < 0.001). Endoscopic findings did not correlate significantly with gastrointestinal symptoms and misoprostol did not interfere with the NSAID efficacy. Significant GD damage occurs early in the course of NSAID treatment and misoprostol significantly reduces the incidence of such damage.

Feeding frequency for lactating cows: diurnal patterns of hormones and metabolites in peripheral blood in relation to milk-fat concentration.

1. The present paper reports the effects of dietary modifications on the diurnal pattern of concentrations of certain metabolites and hormones in the peripheral blood of lactating dairy cows. The cows were given fixed rations of hay and high-cereal concentrates in the proportions of 30:70 or 10:90 (w/w). The concentrates were given in either two or six equal meals daily; the hay was given twice daily. 2. Previous reports of the same experiment had shown that milk-fat yield and concentration were reduced by increasing the proportion of concentrates in the diet and increased by more frequent feeding of the concentrates. These changes could be explained in part by changes in rumen volatile fatty acid (VFA) proportions and mean daily concentrations of VFA, particularly propionic acid, and insulin in the peripheral blood, but these factors failed to explain all the increase in milk-fat concentration caused by more frequent feeding. 3. Analysis of blood samples taken at hourly intervals for 24 h at two stages of lactation showed that, in the cows fed six times daily, the concentrations of metabolites and hormones remained relatively constant over the day. In the cows fed twice daily, the concentrations of VFA, 3-hydroxybutyric acid and insulin all increased after both meals whereas the concentrations of glucose and growth hormone tended to fall. The concentration of non-esterified fatty acids tended to increase overnight and fall rapidly after the morning feed. The concentrations of glucagon, thyroxine and prolactin showed no clear pattern in relation to meals. The postprandial responses of propionate, insulin and growth hormone were greater with the higher concentrate diet. 4. The maximum concentration and the diurnal range of concentrations were reduced by more frequent feeding of both diets in the case of propionic acid and of the higher concentrate diet in the case of insulin, but the effects on insulin concentrations of more frequent feeding of the lower concentrate diet were smaller and not significant. The maximum concentration and the diurnal range of concentrations of growth hormone were unaffected by meal frequency. 5. It is concluded that the severity of milk-fat depression in cows fed twice daily is increased by the rapid rise in propionic acid concentration in the peripheral blood after a meal, which in turn increases insulin secretion and may be accompanied by a suppression of growth hormone release. This causes lipogenesis to be diverted towards adipose tissue at the expense of the mammary gland.(ABSTRACT TRUNCATED AT 400 WORDS)

Consequences of diagnostic errors in mastitis therapy trials.

The effect of errors that occur in the diagnosis of intramammary infectious mastitis on the precision of experiments measuring the efficacy of mastitis therapy has been investigated. Diagnostic errors within the range found by experienced workers can create large biases in the apparent cure rate of therapy particularly at cure rates of less than 0.5. Using confirmed methods of diagnosis rather than single samples and reducing the probabilities of false positive and false negative diagnoses to 0.01 and 0.05 respectively, the biases in the apparent cure rates are reduced to acceptable levels. A method is given for calculating the rates of occurrence of false positive and false negative diagnoses from the results of trials using confirmed diagnoses. These errors cannot be calculated from therapy trial data when diagnosis is based on single milk samples. Because the bias in the measurements of the cure rate is greatest at the lowest levels of elimination, estimates of spontaneous recovery in untreated quarters have the greatest error. For this reason experiments incorporating an untreated control group of infected quarters usually reduce the precision of the therapy trials. An experiment in which the efficacy of a test product is measured relative to a reference product has advantages. It minimizes the difficulties arising from scale of measurement, diagnostic errors and herd differences in response rate, and makes possible comparisons between trials. Further investigations are required on the importance of spontaneous recovery, particularly for studies of Escherichia coli therapy and dry period therapy. The results of this investigation have relevance to all types of mastitis investigation that measure the change in mastitis status of udder quarters, i.e. new infection rates.

An in-line sampling technique to measure the bacterial contamination of milk during milking.

The development of devices to sample milk at the clawpiece and at the end of the pipeline during milking are described. The results of tests to compare the bacteriological and compositional quality of milk collected from the sampling devices or from the recorder jar or milk cans were similar, demonstrating that the samples provided accurate and representative values. The use of the in-line sampling technique, whereby samples of the milk are taken at three points during its passage through the milking plant, to assess accurately the sources of bacterial contamination of bulk tank milk on farms is discussed.

Effect on milk production of controlling muscid flies, and reducing fly-avoidance behaviour, by the use of Fenvalerate ear tags during the dry period.

Fenvalerate ear tags reduced fly loads on dry dairy cattle by 95% between July and September. Fly dislodging behaviour, such as ear flicks which correlated with numbers of Musca autumnalis on the face and stamps/kicks which correlated with numbers of Stomoxys calcitrans on the legs, was also significantly reduced. There was no significant difference between the tagged and untagged groups in the total time spent grazing each day. Milk yields were not statistically significantly different, but the tagged group showed a greater increase in milk yield between lactations, of 1.45 kg/cow daily in the first 12 weeks of the lactation.