Ethnic differences in success at application for consultant posts among United Kingdom physicians from 2011 to 2019: a retrospective cross-sectional observational study.

OBJECTIVES: To identify associations between success following application for consultant physician posts and demographic factors. DESIGN: Logistic regression analysis of nationwide survey data. SETTING: United Kingdom (UK) physicians with a recent certificate of completion of training (CCT). PARTICIPANTS: All UK trainee physicians who received a CCT between 2010 and 2019 were surveyed. Respondents were excluded if they had not applied for a consultant post or if application data were incomplete. MAIN OUTCOME MEASURES: The primary outcome measure was success over the entire consultant application process, i.e. shortlisted and offered the post following the first application. Secondary outcomes were: shortlisted following first application and offered a consultant post at first interview. RESULTS: From 7037 CCT holders surveyed, 50.7% responded. While 1198 (59.7%) respondents were white, 760 (37.9%) were from minority ethnic groups and 50 (3.5%) were of unknown ethnicity. Primary medical qualification (PMQ) country was the UK in 75.3% (n = 1512). On multivariable logistic regression analysis the independent negative associations with success were: minority ethnicity (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.43-0.71); p < 0.001) vs. white; PMQ from Europe (OR 0.47, 95% CI 0.28-0.79; p = 0.004) or Asia (OR 0.68, 95% CI 0.49-0.96; p = 0.027) vs. UK PMQ; year of CCT 2012 (OR 0.40, 95% CI 0.24-0.68; p = 0.001), 2013 (OR 0.39, 95% CI 0.23-0.65; p < 0.001), and 2014 (OR 0.26, 95% CI 0.15-0.43; p < 0.001) vs. 2019. Specialties associated with lower success rates included Cardiology, Endocrinology, Genitourinary medicine, Palliative care, Renal and Respiratory, compared to Acute medicine. CONCLUSIONS: Minority ethnic group candidates for consultant physician posts had lower success rates compared to white candidates after correction for important variables including specialty, time from and country of PMQ. This finding requires further evaluation to identify the causes for this variation.

The risk of oesophageal adenocarcinoma in a prospectively recruited Barrett's oesophagus cohort.

BACKGROUND: Varying rates of oesophageal adenocarcinoma (OAC) complicating Barrett's oesophagus (BO) have been reported. Recent studies and meta-analyses suggest a lower incidence, questioning the value of endoscopic surveillance. AIM: We aimed to retrospectively examine the rate of OAC, risk factors and causes of death in a prospectively recruited BO cohort. METHODS: Data from patients with BO from a cohort from 1982-2007 were studied. Patients were subdivided into surveyed, failed to attend surveillance and unfit for surveillance. Standardised mortality ratios (SMR) were calculated for common causes of death. Cox proportional hazards models were used to determine which factors were associated with progression to OAC. RESULTS: In total, 671 BO patients (61% male) were studied; 37 (76% male) were diagnosed with OAC. OAC incidence was 0.47% per annum and stable across three decades (1982-1991 0.56%, 1992-2001 0.46%, 2002-2012 0.41% (p = 0.8)). All-cause mortality was increased for the whole cohort (SMR 163(95% CI 145-183)). Mortality from OAC appeared higher in patients who failed to attend surveillance (SMR 3216(95% CI 1543-5916)) compared with surveyed (SMR 1753(95% CI 933-2998)) and those unfit for surveillance due to co-morbidity (SMR 440(95% CI 143-1025)). Multivariable analysis identified low-grade dysplasia (HR 4.4(95% CI 1.56-12.43), p = 0.005) and length of BO (HR 1.2(95% (1.1-1.3)), p < 0.001)) as associated with OAC. CONCLUSIONS: Progression to OAC appeared stable over three decades at 0.47% per annum. Patients with BO had a modest increase in all-cause mortality and a large increase in OAC mortality, particularly if fit for surveillance. Low-grade dysplasia and the length of the BO segment were associated with developing OAC.

A study of pathophysiological factors associated with gastro-esophageal reflux disease in twins discordant for gastro-esophageal reflux symptoms.

BACKGROUND: Differences in lower esophageal sphincter (LES) and peristaltic function and in transient LES relaxations (TLESR) have been described in patients with gastro-esophageal reflux disease (GERD). However, some of these differences may be the result of chronic GERD rather than being an underlying contributory factor. METHODS: Twins discordant for GERD symptoms, i.e., only one twin had GERD symptoms, underwent standard LES and esophageal body manometry, and then using a sleeve sensor prolonged LES and pH monitoring, 30 min before and 60 min after a 250 mL 1200 kcal lipid meal. KEY RESULTS: Eight monozygotic and 24 dizygotic female twins were studied. Although there was no difference in preprandial LES pressure (symptomatic 13.2 ± 7.1 mmHg vs asymptomatic 15.1 ± 6.2 mmHg, P = 0.4), LES pressure fell further postprandially in symptomatic twins (LES pressure area under the curve 465 ± 126 vs 331 ± 141 mmHg h, P < 0.01). 12/37 (32%) of acid reflux episodes in symptomatic twins occurred due to low LES pressure or deep inspiration/strain and 0/17 in asymptomatic twins (P = 0.01). There was no difference between symptomatic and asymptomatic twins in: peristaltic amplitude, ineffective esophageal body motility, hiatus hernia prevalence, or LES length. There was also no difference in TLESR frequency preprandially (symptomatic median 1(range 0-2) vs asymptomatic 0(0-2), P = 0.08) or postprandially (2.5(1-8) vs 3(1-6), P = 0.81). CONCLUSIONS & INFERENCES: Twins with GERD symptoms had lower postprandial LES pressure and given the close genetic link between the twins, it is possible that such differences are caused by GERD. Acid reflux episodes associated with a hypotensive LES were seen in symptomatic, but not in asymptomatic twins.

Laparoscopic stapled cardioplasty for failed treatment of achalasia.

BACKGROUND: Treatment of primary achalasia includes injection of botulinum toxin, pneumatic dilatation or surgical myotomy. All of these procedures have an associated failure rate. Laparoscopic stapled cardioplasty (LSC) may be an alternative to failed pneumatic dilatation and laparoscopic Heller's myotomy where oesophagectomy has previously been the only surgical option. METHODS: Selected patients with recurrent achalasia following multiple failed medical treatments, including myotomies, were managed by LSC. Patients had postoperative contrast swallows before discharge with clinical follow-up. RESULTS: All seven patients treated with LSC were discharged within 5 days. Rapid oesophageal emptying was noted on all post-LSC contrast swallows. No patient had an anastomotic leak. After 1 year, all but one patient was free from dysphagia, all had gained weight, and four patients had heartburn controlled by a proton pump inhibitor. CONCLUSION: LSC may be a useful procedure for resistant achalasia.

Subjects with prostate cancer are less likely to develop esophageal cancer: analysis of SEER 9 registries database.

Esophageal adenocarcinoma (EAC) is five times more common among men. EAC tissue exhibits an increased concentration of androgen receptors. We previously reported lower EAC incidence following prostate cancer (PC), suggesting androgen deprivation therapy may reduce EAC incidence, but were unable to demonstrate reducing incidence of EAC with time (latency effect) that would support a cumulative effect of anti-androgen treatment.The Survival Epidemiology and End Results (SEER9) dataset from 1977­2004 was therefore examined to identify subjects with a first malignant primary of PC.Subjects were followed until second primary cancer diagnosis,death, or time period end. Age- and period-adjusted standardized incidence ratios (SIR) were calculated as an estimate of relative risk of an esophageal second malignant primary. Between 1977 and 2004, 343,538 subjects (following exclusion criteria) developed PC as a first primary malignant tumor, providing 2,014,337 years of follow-up.Subsequently 604 esophageal cancers developed, with 763 expected. The incidence of EAC fell following PC [SIR0.83 (95 % CI 0.74­0.93)] with a latency effect identified with SIR 1.1 3 months to 1 year post-PC, SIR 0.85 1­5 years post-PC, and SIR 0.75 greater than five years post-PC. The incidence of esophageal squamous cell carcinoma (ESCC) after PC was also reduced [SIR, 0.79 (0.69-0.89)],with evidence of a latency effect also seen. There is a reduced risk of developing esophageal cancer, both EAC and ESCC, following PC. Androgen deprivation therapy may contribute, but changes in lifestyle following PC diagnosis and decrease in ESCC incidence are also plausible explanations.

Risk factors for gastro-oesophageal reflux disease symptoms: a community study.

AIM: To examine the prevalence of gastro-oesophageal reflux disease symptoms and potential risk factors among community subjects. METHODS: A questionnaire was sent to 4000 subjects, stratified by age, gender and ethnicity to be representative of the local population. Gastro-oesophageal reflux disease symptoms were defined as at least weekly heartburn or acid regurgitation. RESULTS: 2231 responded (59%), 691 refused to participate and seven were incomplete. 1533 (41%) were evaluable (637 male, mean age 51 years, range: 20-80). The prevalence of gastro-oesophageal reflux disease symptoms was 21%. Smoking, excess alcohol, irritable bowel syndrome, increasing body mass index, a family history of upper gastrointestinal disease, increasing Townsend deprivation index, anticholinergic drugs (all P < 0.0001), weight gain, antidepressant drugs, inhaled bronchodilators, no educational attainment (all P < 0.01), south Asian origin (P = 0.02) and manual work (P < 0.05) were associated with gastro-oesophageal reflux disease symptoms. Multivariate logistic regression revealed increasing body mass index, a family history of upper gastrointestinal disease, irritable bowel syndrome, south Asian origin (all P < 0.0001), smoking, excess alcohol, no educational attainment and anticholinergic drugs (all P < 0.01) were independently associated with gastro-oesophageal reflux disease symptoms. CONCLUSIONS: Frequent gastro-oesophageal reflux disease symptoms affect 21% of the population. Increasing body mass index, a family history of upper gastrointestinal disease, irritable bowel syndrome, south Asian origin, smoking, excess alcohol, social deprivation and anticholinergic drugs are independently associated with gastro-oesophageal reflux disease symptoms.

Cell cycle regulation in patients with intestinal metaplasia at the gastro-oesophageal junction.

BACKGROUND/AIMS: The incidence of oesophageal adenocarcinoma is increasing rapidly and this may be related to the presence of intestinal metaplasia (IM) at the gastro-oesophageal junction (GOJ). Recent studies have distinguished two subtypes of IM at the GOJ: short segment Barrett's oesophagus (SSBO) and IM at a normal squamo-columnar junction (IMNSCJ). Because abnormal expression of cell cycle regulators is common in cancer and precancerous states, cell cycle regulation was studied in patients with IM at the GOJ. METHODS: Biopsy samples and resected materials were identified from patients with SSBO (10), IMNSCJ (14), a normal SCJ with (14) and without (12) inflammation, conventional Barrett's oesophagus (BO) (12), and oesophageal adenocarcinoma (12). Sections were stained with antibodies to p21, p27, p53, Ki67, cyclin D1, and c-erbB2 and were assessed independently by two observers, using predetermined criteria. RESULTS: Patients with oesophageal adenocarcinoma showed high expression of c-erbB2, p53, p27, and Ki67. Patients with BO showed expression of c-erbB2 but little expression of other markers. Greatly increased expression of cyclin D1 was seen in patients with IMNSCJ. The expression of all other markers was similar in patients with IMNSCJ and those with SSBO. Cyclin D1 and c-erbB-2 were coexpressed in patients with SSBO and IMNSCJ, and their expression was associated with the presence of p53 and p21. CONCLUSIONS: Although the proposed aetiologies of SSBO (gastro-oesophageal reflux) and IMNSCJ (Helicobacter pylori infection) differ, the cell cycle response is similar and both may have malignant potential.

Genetic influences in gastro-oesophageal reflux disease: a twin study.

BACKGROUND: A number of families have been described which include multiple members with symptomatic, endoscopic, or complicated gastro-oesophageal reflux disease (GORD). First degree relatives of patients with GORD are more likely to suffer with GORD symptoms. These observations raise the possibility of a genetic contribution to the aetiology of GORD. AIMS: To determine the relative contribution of genetic factors to GORD by evaluating GORD symptoms in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 4480 unselected twin pairs, identified from a national volunteer twin register, were asked to complete a validated symptom questionnaire. GORD was defined as symptoms of heartburn or acid regurgitation at least weekly during the past year. RESULTS: Replies were obtained from 5032 subjects (56% response rate). A total of 1960 twin pairs were evaluable: 928 MZ pairs (86 male pairs, mean (SD) age 52 (13) (range 19-81) years) and 1032 DZ pairs (71 male pairs, mean age 52 (13) (20-82) years). The prevalence of GORD among both groups of twins was 18%. Casewise concordance rates were significantly higher for MZ than DZ twins (42% v 26%; p<0.001). Multifactorial liability threshold modelling suggests that additive genetic effects combined with unique environmental factors provide the best model for GORD. Heritability estimates suggest that 43% (95% confidence interval 32-55%) of the variance in liability to GORD is due to additive genetic factors. CONCLUSIONS: There is a substantial genetic contribution to the aetiology of GORD.

The effect of cholecystokinin antagonism on postprandial lower oesophageal sphincter function in asymptomatic volunteers and patients with reflux disease.

BACKGROUND: Postprandial acid reflux is thought to be mediated by the increase in transient lower oesophageal sphincter relaxations (TLOSR) frequency and fall in lower oesophageal sphincter (LOS) pressure seen after ingestion of a meal. Studies in animals and healthy volunteers suggest that cholecystokinin (CCK) may play a role. AIM: To study the role of CCK in postprandial LOS function using the CCK antagonist loxiglumide. SUBJECTS: 10 asymptomatic volunteers (7 male, 20-29 years) and 9 patients with symptomatic gastro-oesophageal reflux (4 male, 33-66 years). METHODS: Oesophageal, LOS and gastric pressure and oesophageal pH readings were recorded for 1 h before and 2 h after intragastric infusion of a 200 kCal, 300 mL long chain triglyceride meal. Each subject underwent two studies and received intravenous loxiglumide or placebo infusion in randomized order. RESULTS: During placebo infusion, postprandial LOS pressure fell [volunteers: 17 (9-31) to 7 (1-19) mmHg (P < 0.01), patients: 15 (6-26) to 9 (2-21) mmHg (P=0.02)] and TLOSR frequency increased [volunteers: 0 (0-1) to 2 (0-7) per hour (P=0.01), patients: 0 (0-3) to 2 (0-10) per hour (P=0.03)]. Loxiglumide infusion attenuated the postprandial fall in LOS pressure and the postprandial increase in TLOSR frequency [volunteers: 0 (0-3) per hour (P=0.04 vs. placebo), patients: 0 (0-2) per hour (P=0.03 vs. placebo)], but it had only modest effects on postprandial acid exposure [volunteers: placebo 45 (0-1725) vs. loxiglumide 0 (0-443) seconds (N.S.), patients: placebo 60 (0-3442) seconds vs. loxiglumide 31 (0-1472) seconds (N.S.)]. CONCLUSIONS: Loxiglumide inhibits TLOSR and attenuates the fall in LOS pressure following a meal, but has only modest effects on postprandial gastro-oesophageal acid reflux.

Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers.

OBJECTIVES: Studies of the relative frequency of transient lower esophageal sphincter relaxations (TLESRs) in patients with gastroesophageal reflux disease and asymptomatic controls have revealed conflicting data. We have therefore studied the frequency of TLESRs and the frequency and mechanisms of acid reflux episodes in patients with gastroesophageal reflux disease and age- and sex-matched asymptomatic controls using standardized criteria. METHODS: Ten patients with symptomatic gastroesophageal reflux disease (four male, aged 50 [30-59] yr) and 10 asymptomatic matched volunteers (four male, aged 50 [32-59] yr) were studied. Esophageal, lower esophageal sphincter, and gastric manometric and esophageal pH readings were recorded for 1 h before and 1 h after a 200-kcal, 150 ml long-chain triglyceride meal. RESULTS: TLESR frequency increased after the meal in both volunteers (median 0 [range = 0-3] to 3 [0-8] per hour,p < 0.01) and patients (1 [0-6] to 2.5 [0-9] per hour, p = 0.08). There was no significant difference in the frequency of TLESRs between volunteers and patients. TLESRs were more likely to be associated with acid reflux in patients (65% vs 37%, p = 0.03), whereas volunteers were more likely to reflux gas or liquid without acid (30% vs 3.0%, p = 0.01). CONCLUSIONS: TLESRs are no more frequent in patients with gastroesophageal reflux disease than age- and sex-matched asymptomatic volunteers. However, when TLESRs occur in patients, they are twice as likely to be associated with acid reflux.

Monitoring the lower oesophageal sphincter: sphinctometer or sleeve?

Two methods have been used to study lower oesophageal sphincter (LOS) function in gastro-oesophageal reflux disease: the sleeve sensor and the sphinctometer. Our aim was to directly compare the sleeve and sphinctometer in vivo. Ten asymptomatic volunteers were intubated with a perfused assembly incorporating a sleeve sensor, a solid-state assembly incorporating a sphinctometer and a pH probe. LOS function was recorded pre- and post-prandially. During basal periods sleeve and sphinctometer readings correlated well both within and between subjects (r2 = 0.89 (P < 0.0001)). However, the sphinctometer relaxed less during swallows (median 42 (interquartile range 27-55)% vs 73 (62-81)% (P < 0.001)), transient LOS relaxations (TLOSR) (50 (40-70)% vs 94 (88-100)% (P < 0.001)) and reflux episodes (67 (59-75)% vs 97 (91-100)% (P = 0.02)). Using criteria derived from 10 dry swallows, the expected relaxation of the sphinctometer during TLOSR was defined. The sphinctometer had an overall sensitivity ranging from 43 to 71% for the detection of TLOSR with 11-22 false positive relaxations, depending on the criteria employed. Sensitivity was particularly poor in those with low basal LOS pressure. The sphinctometer has a lower capacity to register LOS relaxations than the sleeve sensor, which limits its value in studying the pathophysiology of reflux disease.

Familial clustering of reflux symptoms.

OBJECTIVE: A number of case reports describe multiple family members with gastroesophageal reflux disease and Barrett' s esophagus. The wider importance of familial factors in gastroesophageal reflux disease has not been established. Therefore, we have studied the prevalence of reflux symptoms and medication use among relatives of patients with documented gastroesophageal reflux disease. METHODS: A postal questionnaire study of the first degree relatives of six groups of matched patients. The groups comprised patients with 1) no dyspeptic symptoms; 2) reflux symptoms and a normal pH study; 3) reflux symptoms, an abnormal pH study, and a lower esophageal sphincter (LOS) pressure more than 10 mm Hg; 4) reflux symptoms, an abnormal pH study, and a LOS pressure less than 10 mm Hg; 5) Barrett's esophagus; and 6) peptic stricture. RESULTS: Four hundred eighteen subjects replied (78% response). Infrequent reflux symptoms were equally common in all groups of relatives. Frequent reflux symptoms, however, were more common among relatives of patients with an abnormal pH study and normal (26%, p = 0.007) or low LOS pressure (27%, p = 0.01) or Barrett's esophagus (30%, p = 0.003), compared with relatives of nondyspeptic patients (9%). Frequent reflux symptoms were no more common among relatives of patients with a normal pH study (16%) or peptic stricture (18%). Reflux medication use showed a similar pattern. CONCLUSIONS: Familial clustering of reflux symptoms is seen in relatives of patients with reflux symptoms and increased esophageal acid exposure and in relatives of patients with Barrett's esophagus.

Studies of autonomic function in patients with achalasia and nutcracker oesophagus.

BACKGROUND: Post-mortem studies in patients with achalasia reveal degenerative changes in the vagus and its dorsal motor nuclei suggesting the possibility of widespread autonomic dysfunction. AIMS: To study a broad range of autonomic function in patients with achalasia and nutcracker oesophagus and in asymptomatic volunteers. SUBJECTS: Patients with a manometric diagnosis of achalasia and nutcracker oesophagus and age- and sex-matched asymptomatic volunteers. METHODS: Subjects underwent measurement of: (1) pupil cycle time estimation; (2) heart rate response to the Valsalva manoeuvre, standing and deep breathing; (3) systolic blood pressure response to standing; (4) diastolic response to sustained handgrip; (5) spectral analysis of heart rate variability; and (6) heart rate and blood pressure during the Valsalva manoeuvre. RESULTS: No significant differences were found between patients with achalasia and asymptomatic volunteers. Patients with nutcracker oesophagus, however, had longer pupil cycle times (1.2 (0.9-1.4) s versus 0.9 (0.8-1.2) s, P= 0.02) and had attenuation of both the rise in the low frequency peak of heart rate variability and the fall in the high frequency peak on standing (rise in low frequency peak - patients 26.6 (10.4-52.3)% to 42.2 (15.5-54.0)%, P = 0.46, volunteers 16.9 (8.4-37.2)% to 47.4 (21.1-66.3)%, P = 0.03; fall in high frequency peak - patients 18.1 (0.9-43.3)% to 10.1 (0.5-26.6)%, P= 0.46, volunteers 24.8 (8.5-44.4)% to 9.3 (2.6-35.6)%, P= 0.03). The rise in blood pressure during the Valsalva manoeuvre was also attenuated in patients with nutcracker oesophagus compared with asymptomatic volunteers (6.9 (1.0-9.3) mmHg versus 12.9 (11 -23.0) mmHg, P < 0.01). CONCLUSIONS: Whereas tests of cardiovascular and pupillary autonomic function are normal in patients with achalasia, patients with nutcracker oesophagus show defects in both parasympathetic and sympathetic function.

Impact of smoking cessation on salivary function in healthy volunteers.

BACKGROUND: Salivary bicarbonate and epidermal growth factor (EGF) have an important protective role in the oesophagus. The effect of smoking cessation on these aspects of salivary function is unknown. METHODS: Salivary bicarbonate secretion and EGF output were measured before and after attempted smoking cessation in 28 healthy volunteers. Urinary cotinine excretion was used to assess compliance. RESULTS: Negative correlations were found between salivary flow rate and age (rho = -0.34) and between cigarette consumption and salivary flow (rho = -0.27) and salivary bicarbonate concentrations (rho = -0.32). Smoking cessation was associated with a significant increase in salivary bicarbonate secretion (day 0, 1.7 (0.14-6.2); day 7, 3.6 (0.52-6.4); day 21, 3.3 (0.44-6.6) micromol min(-1); P < 0.01) but left salivary EGF output unchanged. CONCLUSION: Smoking cessation is associated with significant improvements in salivary bicarbonate secretion. This would benefit patients with reflux disease who stop smoking.

Mechanisms of gastro-oesophageal reflux in the lateral decubitus positions.

Gastro-oesophageal reflux is more common in the right than in the left lateral position but the reasons why are not well understood. We have therefore studied the mechanisms underlying reflux in the lateral decubitus positions in patients with reflux disease. Fifteen patients with symptomatic reflux and excessive oesophageal acid exposure were studied (nine male, age 25-63 years). Each was intubated with a perfused manometric assembly, incorporating a Dent sleeve, and a pH probe. Following a 30-min basal period, a 400-kCal meal was infused into the stomach and patients were studied for 60 min in each lateral position. Following infusion of the meal, lower oesophageal sphincter (LOS) pressure fell and transient LOS relaxation (TLOSR) frequency increased. Acid reflux episodes were more common in the postprandial period (fasting 0 (0-6) h, first postprandial hour 1 (0-9) h, P = 0.0002, second postprandial hour 1 (0-22) h, P = 0.02) and occurred more than twice as often in the right lateral position (right 3 (0-22) h, left 0 (0-10) h, P = 0.01). However, TLOSRs, swallow-related relaxations and low basal LOS pressures were equally common in both lateral positions. In patients with reflux disease, postprandial reflux is twice as common in the right lateral position. This does not relate to differences in gastro-oesophageal junctional pressure, suggesting that other aspects of barrier function or differences in the intragastric distribution of chyme may be important.

Intestinal metaplasia at the squamocolumnar junction in patients attending for diagnostic gastroscopy.

BACKGROUND: The incidence of adenocarcinoma of the oesophagus and gastric cardia is increasing rapidly. Barrett's oesophagus is the major risk factor. Intestinal metaplasia at the squamocolumnar junction in the absence of Barrett's oesophagus is common but its relation to adenocarcinoma and gastro-oesophageal reflux disease is unclear. AIMS: To study the prevalence and clinical, endoscopic, and histological associations of intestinal metaplasia at the squamocolumnar junction. METHODS: Biopsy specimens were taken from 120 randomly selected patients undergoing routine diagnostic endoscopy. Eight biopsy specimens, taken from above and below the squamocolumnar junction, gastric fundus, and gastric antrum, were stained with haematoxylin/eosin, alcian blue/periodic acid-Schiff, and Gimenez, and graded independently by one pathologist. RESULTS: Intestinal metaplasia at the squamocolumnar junction was found in 21 patients (18%). Metaplasia was associated with increasing age (p < 0.01) and antral intestinal metaplasia (p = 0.04). Logistic regression analysis revealed that age was the only independent predictor (p < 0.01). There was no association with symptomatic, endoscopic, or histological markers of gastro-oesophageal reflux disease. CONCLUSIONS: Intestinal metaplasia at the squamocolumnar junction is a common finding. It is associated with increasing age but not gastro-oesophageal reflux disease.

Variable and circadian response to a fixed high-dose (12 500 IU twice daily) subcutaneous heparin regimen after thrombolytic therapy for acute myocardial infarction.

AIM: To determine the effect of a fixed high-dose (12 500 IU twice daily) subcutaneous heparin regimen on coagulation parameters after thrombolysis with streptokinase. BACKGROUND AND METHODS: A number of large thrombolytic trials have allocated patients to fixed high-dose (12 500 IU twice daily) subcutaneous heparin with no monitoring of coagulation parameters. We hypothesized that heparin's apparent lack of benefit and increased haemorrhagic complications in these trials may be the result of inappropriate anticoagulation. We therefore studied 11 patients who received intravenous streptokinase and oral aspirin for acute myocardial infarction and were subsequently started on the above heparin regimen. Blood samples were taken for activated partial thromboplastin time (APTT) and thrombin time before streptokinase and then immediately before and 6 h after each heparin injection on days 1,4, and 6, and 3 and 6 h after streptokinase on day 5. Plasma heparin levels were also measured on all post-streptokinase samples. Plasma fibrinogen was measured before the administration of streptokinase and once daily on the other sampling days. RESULTS: Both the median APTT and thrombin time were prolonged above the normal range throughout day 1, when fibrinogen levels were depressed, with a non-significant variation between the sampling points. By day 4, however, when fibrinogen levels had returned to pre-streptokinase levels, the median (range) APTTs at 8 a.m. and 8 p.m. (pre-heparin) were similar, and below the therapeutic range, at 52 (38-76) and 48 (39-79) s (NS). Six hours after each heparin injection the APTTs were elevated, but the median (range) 2 p.m. peak of 63 (46-138) s was lower than that at 2 a.m., 125 (58-178) s (P = 0.003). A similar peak and trough, and apparent circadian, APTT response pattern was seen on days 5 and 6. The thrombin time showed the same variation, which was also mirrored in the plasma heparin levels, although the circadian effect was not as marked. CONCLUSION: There is a marked individual variation in response to fixed-dose (12 500 IU twice daily) subcutaneous heparin, with many patients inadequately anticoagulated and an obvious circadian pattern of response. These findings have important implications when considering the benefits and haemorrhagic complications of subcutaneous heparin therapy in general and following thrombolysis in particular.