Validation of the continuous glucose monitoring sensor in preterm infants.

OBJECTIVE: Recent studies have highlighted the need for improved methods of monitoring glucose control in intensive care to reduce hyperglycaemia, without increasing the risk of hypoglycaemia. Continuous glucose monitoring is increasingly used in children with diabetes, but there are little data regarding its use in the preterm infant, particularly at extremes of glucose levels and over prolonged periods. This study aimed to assess the accuracy of the continuous glucose monitoring sensor (CGMS) across the glucose profile, and to determine whether there was any deterioration over a 7 day period. DESIGN: Prospectively collected CGMS data from the NIRTURE Trial was compared with the data obtained simultaneously using point of care glucose monitors. SETTING: An international multicentre randomised controlled trial. PATIENTS: One hundred and eighty-eight very low birth weight control infants. OUTCOME MEASURES: Optimal accuracy, performance goals (American Diabetes Association consensus), Bland Altman, Error Grid analyses and accuracy. RESULTS: The mean (SD) duration of CGMS recordings was 156.18 (29) h (6.5 days), with a total of 5207 paired glucose levels. CGMS data correlated well with point of care devices (r=0.94), with minimal bias. It met the Clarke Error Grid and Consensus Grid criteria for clinical significance. Accuracy of single readings to detect set thresholds of hypoglycaemia, or hyperglycaemia was poor. There was no deterioration over time from insertion. CONCLUSIONS: CGMS can provide information on trends in glucose control, and guidance on the need for blood glucose assessment. This highlights the potential use of CGMS in optimising glucose control in preterm infants.

Unprovoked recurrent venous thrombosis: prediction by D-dimer and clinical risk factors.

BACKGROUND: The aim of the study was to determine the predictive value of D-dimer measurement for unprovoked recurrent venous thrombosis and the influence of sex, age and type of first event (unprovoked or provoked). METHODS: Prospective cohort study of 272 patients with a first episode of venous thrombosis that was unprovoked or provoked by a non-surgical trigger. FINDINGS: The cumulative rate of unprovoked recurrence in patients with a positive D-dimer was 20% at 5 years [5.5/100 patient-years, 95% confidence interval (CI) 3.7-7.8] and in patients with a negative D-dimer 17% (4.1/100 patient-years, 95% CI 2.3-6.9). The rates are not different (hazard ratio 1.3, 95% CI 0.7-2.5). After adjustment for clinical risk factors a positive D-dimer result was significantly associated with an increased risk of unprovoked recurrent thrombosis (hazard ratio 2.0, 95% CI 1.01-3.9). The strongest indicator of risk of recurrence was male sex (hazard ratio 3.3 unadjusted and 2.9 after adjustment). The only determinant of D-dimer in a linear regression model was age (P < 0.001). CONCLUSIONS: The analysis indicates that clinical risk factors confound the association between D-dimer and risk of recurrence and when adjusted for these confounders a positive D-dimer result is significantly associated with unprovoked recurrence. The clinical utility of D-dimer measurement in individual patients should be interpreted in conjunction with clinical risk factors.

A randomized, controlled trial of routine early abdominal computed tomography in patients presenting with non-specific acute abdominal pain.

AIM: To compare the effect of an initial early computed tomography (CT) examination versus standard practice (SP) on the length of hospital stay, diagnostic accuracy, and mortality of adults presenting with acute abdominal pain. MATERIALS AND METHODS: Two hundred and five adults presenting with acute abdominal pain were randomized to undergo an early CT examination or current SP, which comprised supine abdominal and erect chest radiography. One hundred and ninety-eight patients (99 in each arm) were included in the analysis. The primary endpoint was the duration of inpatient stay; secondary endpoints were diagnostic certainty and mortality. RESULTS: There was no significant difference in the length of hospital stay between the two arms (p=0.20). At randomization 36% (35 of 96) of CT patients and 49% (48 of 98) of SP patients were correctly diagnosed; 24h after randomization the correct diagnosis had been established in 84% of CT patients and 73% of SP patients. This refinement in diagnostic certainty was significantly better in the CT group (p<0.001). There was no difference in mortality between the two trial arms (p=0.31). CONCLUSION: Early abdominal CT in patients with acute abdominal pain improves diagnostic certainty, but does not reduce the length of hospital stay and 6 month mortality.

Analysis of diagnostic confidence and diagnostic accuracy: a unified framework.

Diagnostic confidence has been used as a measure of diagnostic efficacy, but this measure in isolation fails to take into account incorrect diagnoses. Conventional analytical approaches of diagnostic confidence ignore associated diagnostic accuracy. To address this limitation, we introduce a unifying framework which incorporates diagnostic confidence, changes in diagnoses and ultimate accuracy. The framework is illustrated using data from a study in which 62 patients with acute abdominal pain prospectively underwent CT. Admitting surgeons documented their diagnoses and graded their diagnostic confidences (on a 5-point scale) on admission and again after CT. Our approach, unlike conventional analyses, incorporates knowledge of final diagnoses, obtained from surgery or 6 months follow up, in assessing the impact of the test (on a 9-point scale). Changes in pre- and post-CT confidence scores were assessed by the one-sample t-test comparing against zero change, with the test statistic acting as a standardized quantity allowing comparison between our and conventional methodological approaches. Overall, 52% (32/62) of patients were misdiagnosed on admission and 19% (12/62) had incorrect post-CT diagnoses. Diagnostic confidence following CT increased significantly compared with pre-CT confidence on applying both analytical methods, although the level of statistical significance was less marked using our approach. Mean (95% confidence interval) increase in confidence under conventional analysis was 1.32 (1.03, 1.62), with standardized score t = 8.90 [p<0.0001], whereas our method yielded 0.69 (0.25, 1.13), with standardized score t = 3.12 [p = 0.003]. Although both analytical methods led to the same inference regarding the efficacy of CT in the illustrative case study presented, they differed somewhat in degree. It is conceivable that disparate conclusions may emerge in other studies and circumstances. Failure to take adequate account of incorrect diagnoses is potentially misleading. We suggest that a comprehensive analysis of diagnostic confidence requires the incorporation of diagnostic accuracy.

Quality improvement for patients with hip fracture: experience from a multi-site audit.

PROBLEM: The first East Anglian audit of hip fracture was conducted in eight hospitals during 1992. There were significant differences between hospitals in 90-day mortality, development of pressure sores, median lengths of hospital stay, and in most other process measures. Only about half the survivors recovered their pre-fracture physical function. A marked decrease in physical function (for 31%) was associated with postoperative complications. DESIGN: A re-audit was conducted in 1997 as part of a process of continuing quality improvement. This was an interview and record based prospective audit of process and outcome of care with 3 month follow up. Seven hospitals with trauma orthopaedic departments took part in both audits. Results from the 1992 audit and indicator standards for re-audit were circulated to all orthopaedic consultants, care of the elderly consultants, and lead audit facilitators at each hospital. KEY MEASURES FOR IMPROVEMENT: Processes likely to reduce postoperative complications and improve patient outcomes at 90 days. STRATEGY FOR CHANGE: As this was a multi-site audit, the project group had no direct power to bring about changes within individual NHS hospital trusts. RESULTS: Significant increases were seen in pharmaceutical thromboembolic prophylaxis (from 45% to 81%) and early mobilisation (from 56% to 70%) between 1992 and 1997. There were reduced levels of pneumonia, wound infection, pressure sores, and fatal pulmonary embolism, but no change was recorded in 3 month functional outcomes or mortality. LESSONS LEARNT: While some hospitals had made improvements in care by 1997, others were failing to maintain their level of good practice. This highlights the need for continuous quality improvement by repeating the audit cycle in order to reach and then improve standards. Rehabilitation and long term support to improve functional outcomes are key areas for future audit and research.

Ethics, data-dependent designs, and the strategy of clinical trials: time to start learning-as-we-go?

The seeds of modern clinical trials were unwittingly sown with the first use of randomization in a 1920s agricultural field experiment. The historical development of trials is briefly reviewed here, as are multifarious pressures and problems faced by those involved with clinical trials today. These challenges include recruitment difficulties, the emerging role of patient support groups, and legal threats over informed consent, to name three. Fundamentally, they reflect an overall shift towards patient-centred, individual ethics. I suggest many problems may be overcome by increased implementation of hitherto neglected, data-dependent designs for clinical trials. Over a dozen arguments against their use are countered, primarily through ethical considerations. Benefits and costs of refining clinical trials strategy are explored hypothetically under enhanced use of such 'learn-as-you-go' designs, in contrast to traditional, equal-allocation, fixed-sample-size and frequentist-based designs. These latter methods mirror crop field trials in which one cannot make scientific progress until after gathering objective data at harvest time. Some attempts to alleviate certain problems, such as Zelen randomization to boost recruitment, or over-reliance on 'large and simple trials' to detect moderate-sized treatment effects, are discussed and found inadequate. A proposal for wider discussion is made to assist the selective introduction of 'small and complex trials,' which could simultaneously expedite medical research, satisfy the concerns of regulators, statisticians, and doctors alike, and help address the growing demands of 21st-century patients.

Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).

BACKGROUND: The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension. METHODS: We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55-80 years with hypertension (blood pressure > or = 150/95 mm Hg, or > or = 160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 mg [corrected] plus amiloride 2.5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25-50 mg or enalapril 5-10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat. FINDINGS: Primary outcomes occurred in 200 (6.3%) patients in the nifedipine group and in 182 (5.8%) in the co-amilozide group (18.2 vs 16.5 events per 1000 patient-years; relative risk 1.10 [95% CI 0.91-1.34], p=0.35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p<0.0001), but serious adverse events were more frequent in the co-amilozide group (880 vs 796, p=0.02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0.81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0.33% [-0.7 to 1.4]). INTERPRETATION: Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy.

Influence of diabetes and type of hypertension on response to antihypertensive treatment.

The aim of our investigation was to determine whether the presence of additional risk factors or type of hypertension (diastolic or isolated systolic) influences blood pressure (BP) response to treatment. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study is a double-blinded outcome comparison of calcium channel blockade with diuretics in high-risk patients aged 55 to 80 years. Dynamic randomization between nifedipine once daily and hydrochlorothiazide/amiloride was performed to ensure that approximately equal numbers of patients in the 2 groups had each of the major cardiovascular risk factors. Patients with isolated systolic hypertension were also separately randomized. Atenolol or enalapril was the mandatory second-line drug. In 5669 patients who completed the 18-week titration, BP fell from 172+/-15/99+/-9 mm Hg (mean+/-SD) while receiving placebo to 139+/-12/82+/-7 mm Hg. Twenty-six percent of patients required 2 drugs, and 4% required 3 drugs. Patients with diabetes were the most resistant to treatment, requiring second and third drugs 40% and 100% more frequently than patients without diabetes and achieving marginally the highest final BP, for any risk group, of 141+/-13/82+/-8 mm Hg. Age, smoking, gender, hypercholesterolemia, left ventricular hypertrophy, and existing atherosclerosis had little (<1 mm Hg) or no influence on BP at the end of titration, but all except smoking slightly reduced the initial response of either systolic or diastolic BP. Patients with isolated systolic hypertension were slightly more responsive than average to treatment. Our findings suggest that in patients at high absolute risk of cardiovascular complications from hypertension, the risk factors themselves do not prevent the recommended BP targets from being achieved.

Insulin response and changes in composition of non-esterified fatty acids in blood plasma of middle-aged men following isoenergetic fatty and carbohydrate breakfasts.

It was previously shown that a high plasma concentration of non-esterified fatty acids (NEFA) persisted after a fatty breakfast, but not after an isoenergetic carbohydrate breakfast, adversely affecting glucose tolerance. The higher concentration after the fatty breakfast may in part have been a result of different mobilization rates of fatty acids. This factor can be investigated as NEFA mobilized from tissues are monounsaturated to a greater extent than those deposited from a typical meal. Twenty-four middle-aged healthy Caucasian men were given oral glucose tolerance tests (OGTT), and for 28 d isoenergetic breakfasts of similar fat composition but of low (L) or moderate (M) fat content. The composition of NEFA in fasting and postprandial plasma was determined on days 1 and 29. No significant treatment differences in fasting NEFA composition occurred on day 29. During the OGTT and 0-1 h following breakfast there was an increase in plasma long-chain saturated NEFA but a decrease in monounsaturated NEFA (microg/100 microg total NEFA; P<0.001). Between 1 and 3 h following breakfast treatment differences occurred for total saturated and total monounsaturated fatty acids (microg/100 microg total NEFA; P<0.05), expressed as an increase in 18 : 1 and decreases in 16 : 0 and 17 : 0 in treatment M relative to treatment L (P<0.05). Serum insulin attained 35 and 65 mU/l in treatments M and L respectively during this period. Negative correlations were found between 16 : 0 in fasting plasma and both waist:hip circumference (P=0.0009) and insulin response curve area during OGTT (within treatment M, P=0.0001). It is concluded that a normal postprandial insulin response is associated with a rapid change in plasma saturated:monounsaturated NEFA. It is proposed that this change is the result of a variable suppression of fat mobilization, which may partly account for a large difference in postprandial total plasma NEFA between fatty and carbohydrate meals.

The Janes Surgical Society.

The Janes Surgical Society was formed in 1953 by surgeons who had undertaken their surgical training during the tenure of Dr. Robert M. Janes, Professor of Surgery at the University of Toronto from 1947 to 1957. Over the next 35 years, this unique Canadian surgical society met annually at surgical centres on this continent and abroad as well as at certain resort areas from time to time. Members of the Janes Surgical Society could be found in major clinical and academic positions across the country from St. John's to Victoria. Their annual meetings served a dual purpose: they provided a forum for the exchange of scientific knowledge and ideas by the members; and they provided an opportunity for members and their wives to socialize and renew old friendships dating back to their residency days and to establish new relationships with surgeons and their wives from other countries, including the United States, United Kingdom, France and Sweden. Unfortunately, owing to death and retirements of its members, the Society can no longer hold scientific meetings and travel to distant centres. Its sole activity is now an annual dinner in Toronto, when members and their wives gather to recall the highlights and experiences in their lives that this unique surgical society provided.

Optimisation of antihypertensive treatment by crossover rotation of four major classes.

BACKGROUND: Most comparisons of antihypertensive drugs are undertaken in parallel groups. We undertook a crossover rotation of the four main classes of antihypertensive drugs, in untreated young hypertensive patients, to assess the response rate with monotherapy achieved by a systematic rotation. METHODS: 56 patients, mean blood pressure 161/98 mm Hg, entered the rotation, of whom 36 received all four monthly cycles of treatment with an angiotensin-converting-enzyme (ACE) inhibitor (A), beta-blocker (B), calcium-channel blocker (C), and diuretic (D). Each patient's best drug was then repeated to assess repeatability. Two measures of individual variability in response were used. First, the value of rotation was measured by the increased proportion of patients reaching target blood pressure on their best drug versus their first drug. Second, we assessed whether the responses to each drug were correlated with each other. FINDINGS: Significant variability in response was found. 20 of the 41 patients reaching target blood pressure (< or =140/90 mm Hg) failed to achieve this target on their first drug. Rotation increased from 22/56 (39%) to 41/56 (73%) the success of monotherapy (p=0.0001); in half the patients, blood-pressure on the best treatment was 135/85 mm Hg or less. There were significant correlations between the blood pressure responses to A and B (r=0.5, p<0.01), and C and D (r=0.6, p<0.001), but not between the other four pairings of treatments. The responses to the AB pair were, on average, at least 50% higher than those to the CD pair; this difference was highly significant by multivariate repeated-measures ANOVA. INTERPRETATION: There is a marked variability in hypertensive patients' response to different antihypertensive drugs. The basis may be underlying variability in types of essential hypertension. Optimisation of treatment requires systematic rotation through several therapies; however, an "AB/CD" rule is proposed in which one of each of the two pairs of treatments is initially selected to abbreviate the rotation in routine practice.

Ethics and practice: alternative designs for phase III randomized clinical trials.

For decades, biostatisticians have developed and refined the methodology for clinical trials with the intent of giving trial participants a better representation than traditional, equal-allocation, fixed sample-size designs. Despite these methodologic advances and ethical advantages, alternative or data-dependent designs for phase III clinical trials, including sequential designs, Bayesian methods, and adaptive designs, have not been widely adopted in practice. We attempt to characterize situations under which these designs are feasible and desirable from ethical and logistical standpoints. In particular, we describe the role of individual and collective ethics in designing clinical trials and argue that greater attention should be paid to the former. We give examples of those alternative designs that have been used in practice, including discussion of their strengths and shortcomings. We conclude that alternative designs are applicable in limited classes of trials and that investigators should consider them more often when planning clinical trials.

Is revision as good as primary hip replacement? A comparison of quality of life.

Primary total hip arthroplasty (THA) is one of the most effective ways of improving quality of life (QoL). We have compared the improvement in QoL in 62 patients who had a cemented revision of a THA with that of 62 primary replacements. One year after operation the median QoL score had been significantly improved in both groups; from 0.870 to 0.990 in the primary group (p < 0.0001) and from 0.870 to 0.980 in the revised group (p < 0.0001). There was no significant difference in the improvement in scores between the groups (p = 0.29). When reviewed after four years there was no difference in the pain score for either group (p = 0.89), but that for function had deteriorated significantly. This was associated with revision surgery (p = 0.018) and a low preoperative QoL score (p = 0.004). We conclude that both primary and revision operations give a significant improvement in the QoL but function after revision may be less durable than after a primary arthroplasty.

Epidemiological study of latent and recent infection by Toxoplasma gondii in pregnant women from a regional population in the U.K.

AIMS: To determine the prevalence of IgG and IgM to Toxoplasma gondii (TG) and predict the incidence of infection during pregnancy and in foetuses. METHODS: Thirteen thousand pregnant women from eastern England were tested at the time of booking for antenatal screening. Screening was carried out for the presence of IgG and IgM anti-TG, followed by confirmation with commercially available assays. RESULTS: Latent infection to TG was found in 7.7% of women and increased with age from 6.8 to 17.8%. Recent infection accounted for an additional 0.4% equally distributed across age groups. No difference was found between urban and rural place of residence. A 1-2% incidence of TG infection every 5 years of age was found. IgM-only cases were mostly false positives and were unsuitable for statistical analysis. On the basis of both IgM and IgG imputed data, TG infection was found significantly higher during the first trimester of pregnancy. Three to sixteen TG-infected foetuses per 10000 pregnancies were predicted. CONCLUSIONS: The east of England has a low prevalence of TG infection and therefore a high, at-risk population of pregnant women. Repeated screening during pregnancy would be expensive, but would detect and possibly prevent infection in approximately 10 neonates per 10000 women.

The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening.

Immunization against the human platelet antigen (HPA)-1 alloantigen is the most common cause of severe fetal and neonatal thrombocytopenia. Fetal therapy has substantial risks and its indications need better definition. Of 24,417 consecutive pregnant women, 618 (2.5%) were HPA-1a negative of whom 385 entered an observational study. All were HLA-DRB3*0101 genotyped and screened for anti-HPA-1a. Their partners and neonates were HPA-1 genotyped and the latter were assessed by cord blood platelet counts and cerebral ultrasound scans. Anti-HPA-1a was detected in 46 of 387 pregnancies (12.0%; 95% CI 8.7%-15.2%). All but one were HLA-DRB3*0101 positive (odds ratio 140; 95% CI 19-1035; P< .00001). One baby died in utero, and of 26 HPA-1a-positive babies born to women with persistent antenatal antibodies, 9 were severely thrombocytopenic (8 with a count <10 x 10(9)/L, 1 with a large porencephalic cyst), 10 were mildly thrombocytopenic, whereas 7 had normal platelet counts. Severe thrombocytopenia was significantly associated with a third trimester anti-HPA-1a titer >/= 1:32 (P = . 004), but was not observed in babies of women with either transient or postnatal-only antibodies. HPA-1a alloimmunization complicates 1 in 350 unselected pregnancies, resulting in severe thrombocytopenia in 1:1,200. HPA-1a and HLA-DRB3*0101 typing combined with anti-HPA-1a titration allows selection of the majority of pregnancies at risk of severe thrombocytopenia.

Effect of breakfast fat content on glucose tolerance and risk factors of atherosclerosis and thrombosis.

Twenty-four middle-aged healthy men were given a low-fat high-carbohydrate (5.5 g fat; L), or a moderately-fatty, (25.7 g fat; M) breakfast of similar energy contents for 28 d. Other meals were under less control. An oral glucose tolerance test (OGTT) was given at 09.00 hours on day 1 before treatment allocation and at 13.30 hours on day 29. There were no significant treatment differences in fasting serum values, either on day 1 or at the termination of treatments on day 29. The following was observed on day 29: (1) the M breakfast led to higher OGTT C-peptide responses and higher areas under the curves (AUC) of OGTT serum glucose and insulin responses compared with the OGTT responses to the L breakfast (P < 0.05); (2) treatment M failed to prevent OGTT glycosuria, eliminated with treatment L; (3) serum non-esterified fatty acid (NEFA) AUC was 59% lower with treatment L than with treatment M, between 09.00 and 13.20 hours (P < 0.0001), and lower with treatment L than with treatment M during the OGTT (P = 0.005); (4) serum triacylglycerol (TAG) concentrations were similar for both treatments, especially during the morning, but their origins were different during the afternoon OGTT when the Svedberg flotation unit 20-400 lipid fraction was higher with treatment L than with treatment M (P = 0.016); plasma apolipoprotein B-48 level with treatment M was not significantly greater than that with treatment L (P = 0.086); (5) plasma tissue plasminogen-activator activity increased after breakfast with treatment L (P = 0.0008), but not with treatment M (P = 0.80). Waist:hip circumference was positively correlated with serum insulin and glucose AUC and with fasting LDL-cholesterol. Waist:hip circumference and serum TAG and insulin AUC were correlated with factors of thrombus formation; and the OGTT NEFA and glucose AUC were correlated. A small difference in fat intake at breakfast has a large influence on circulating diurnal NEFA concentration, which it is concluded influences adversely glucose tolerance up to 6 h later.

Importance of age in chronic hepatitis C virus infection.

This study was designed to investigate the value of liver biopsy in the management of patients with chronic hepatitis C virus infection and to identify risk factors for fibrosis. It was a prospective audit of clinical, biochemical, virological and radiological features for predicting liver fibrosis in 140 consecutive patients seropositive for antibody against hepatitis C virus. Seventy-five per cent of patients were asymptomatic and 69% had no clinical signs of chronic liver disease. Serum transaminase levels were normal in 44% of patients, less than twice normal in 35% and more than twice normal in 21%. Ultrasound scan was unremarkable in 85%. Sixty-nine per cent of patients were viraemic at the time of liver biopsy. Liver histology revealed that fibrosis was absent in only 10% of patients (stage 0) while cirrhosis was evident in 7% (stage 5). Liver fibrosis was detected in 90% of patients (stage 1, 11%; stage 2, 41%; stage 3, 21%; and stage 4, 10%). Univariate analysis showed that increasing age, clinical signs of chronic liver disease and abnormal ultrasound scan findings were associated with liver fibrosis (P<0.05); however, multiple linear regression analysis of all the clinical features did not reveal a useful model (sensitivity 42% and specificity 23%) for predicting liver fibrosis. Hence, no combination of clinical, biochemical, virological or radiological data was reliable in discriminating the stage of liver fibrosis in patients with chronic hepatitis C virus infection. However, older patients, especially those with clinical signs of chronic liver disease and abnormal ultrasound scan findings, were more likely to have advanced fibrosis. We recommend liver biopsy as the single most important investigation in detecting liver fibrosis.

Diurnal trends in responses of blood plasma concentrations of glucose, insulin, and C-peptide following high- and low-fat meals and their relation to fat metabolism in healthy middle-aged volunteers.

An experiment was conducted in twelve healthy middle-aged volunteers, six of each sex, with a mean BMI of 27 kg/m2 to detect differences between morning and afternoon in postprandial blood glucose, insulin and C-peptide concentrations. These responses were measured following the consumption of isoenergetic meals that were high or low in fat content, at breakfast and at lunch. Over 4 d each subject received the high-carbohydrate (L, 5.5 g mixed fat/meal) and moderately high-fat (M, 33 g mixed fat/meal) breakfasts and lunches, in three combinations (LL, MM, LM), or they fasted at breakfast time and received a moderately high-fat lunch (NM), in three Latin squares. Each evening a standard meal was given. Plasma glucose, insulin and C-peptide responses were greater following L than M meals and within both MM and LL treatments insulin and C-peptide responses were greater following breakfast than following lunch. The incremental C-peptide response to a fatty lunch following a fast at breakfast time (NM) was similar to that to a fatty breakfast, but the incremental insulin response for the same comparison was marginally lower at lunch (P = 0.06). The relationship of C-peptide and insulin concentrations was assessed. Plasma glucose response to a fatty lunch was increased by a fatty breakfast. The relationships of these metabolic events with fat metabolism are discussed.