DNA targets for certain bZIP proteins distinguished by an intrinsic bend.

In spite of the large amount of sequence conservation among the DNA binding segments of basic region leucine zipper (bZIP) proteins, these proteins can discriminate differently between target sequences that differ in half-site spacing. Here it is shown that the half-site spacing preferences of bZIP proteins are the result of (i) the differential intrinsic curvature in target binding sites that differ by insertion or deletion of a single base pair and (ii) the ability of some bZIP proteins to overcome this intrinsic curvature through a mechanism dependent on basic segment residues.

Fibrosis and other histological features in chronic hepatitis C virus infection: a statistical model.

AIMS: To study the inter-relation between hepatic fibrosis and other histological features of chronic hepatitis C virus (HCV) infection. METHODS: Liver biopsy specimens from 200 consecutive patients with chronic HCV infection were graded and staged separately for necro-inflammatory activity and for fibrosis. The interaction between fibrosis and other histological features was evaluated by univariate and multivariate analysis, followed by hierarchical log linear modelling. RESULTS: The most striking feature was the presence of portal tract inflammation in 177 (89%) of 200 samples. Lymphoid aggregates/follicles were observed either alone or as part of the general inflammatory infiltration of the portal tracts in 120 (60%) of 200 samples. Fatty change (macro- and microvesicular steatosis) was observed in 76 (38%) samples: mild to moderate in 60 (30%) and diffuse in 16 (8%). Bile duct damage was found in 30 (15%) of 200 specimens. Lobular activity was found in 154 (77%) of 200 samples and was significant in 44; piecemeal necrosis was present in 79 (40%). Thirty one (16%) patients had stage 0 liver fibrosis, 27 (14%) had stage 1, 69 (35%) had stage 2, 43 (22%) had stage 3, 16 (8%) had stage 4, and 12 (6%) had stage 5. On log linear analysis, piecemeal necrosis, lobular inflammation and steatosis were linked directly with fibrosis. Portal tract inflammation was linked directly and indirectly via piecemeal necrosis and lobular inflammation with fibrosis. The presence of lymphoid aggregates was associated with bile duct damage. CONCLUSIONS: Portal tract inflammation with lymphoid aggregates or follicles, together with fatty change, bile duct damage and/or lobular activity, are characteristic of chronic HCV infection, confirming previous reports. Piecemeal necrosis, lobular inflammation, portal inflammation, and steatosis are linked directly with fibrosis in this statistical model, suggesting a close inter-relation in the development of fibrosis/cirrhosis.

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.

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.

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.

A new mobility score for predicting mortality after hip fracture.

We assessed 882 patients presenting with a proximal femoral fracture by a new mobility score and by a mental test score, to determine which was of the most value in forecasting mortality at one year. Both scores gave a highly significant prediction, but the mobility score had a greater predictive value and is easier to perform.

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.

Quality-of-life improvement compared after hip and knee replacement.

Total hip and total knee arthroplasty both provide a considerable improvement in quality of life, but there is no evidence to suggest that one is more successful than the other. We studied 72 patients in a prospective trial before and after total hip or total knee replacement. We recorded scores for disability and distress derived from the Harris hip score and the British Orthopaedic Association knee assessment score, and used them to generate quality of life (QoL) scores using the Rosser Index Matrix immediately before and at one year after surgery. The patients awaiting knee replacement had significantly lower QoL scores than those awaiting hip replacement (p = 0.011). The QoL scores at one year were high and almost identical for both groups (p = 0.46). Further analysis showed that gender and weight were not significant predictors of improvement of QoL scores, but age (p = 0.03) and whether the hip or knee was replaced (p = 0.006) were significant factors.

Acoustic rhinometry in the pre-operative assessment of adenoidectomy candidates.

Claims have been made for the potential of acoustic rhinometry (AR) in the evaluation of adenoidectomy patients. Little evidence has been presented to support such claims, and evidence is accumulating that AR is inaccurate in reflecting anatomical reality in the nasopharynx. We set out to establish whether acoustic rhinometry studies could predict operative decision-making sufficiently for it to be of assistance to the clinician, despite these theoretical and practical obstacles. A total of 101 patients aged 2-13 years were examined by AR using the impulse technique. Parameters were chosen from the area-distance function to indicate nasopharyngeal volumes and areas (decongested and non-decongested). This information was compared with findings at EUA (examination under anaesthesia-obstruction categories: A-'good airway' to D-'severe obstruction'), operative decision (2 categories-'obstructive' = remove, versus 'non obstructive' = leave in situ) and parents' symptom scores. Twenty-one patients were also evaluated post-operatively. There was considerable overlap between the AR parameters in the groups classified at EUA as 'obstructive' or 'non obstructive', but this overlap diminished after decongestion. Logistic regression demonstrated that the decongested volume and area parameters were of significant predictive value with respect to operative decision (odds ratio for unit change in volume = 0.82; 95% C.I. = 0.70-0.97; p = 0.018). Parents' analogue scores for snoring and for [snoring+obstruction+ mouthbreathing] were also of significant predictive value. The presence of rhinitis diminishes the predictive value of AR. Acoustic rhinometry has potential as a pre-operative evaluation of the nasopharyngeal airway in adenoidectomy candidates, but the predictive value is low unless combined with clinical factors.

Do hydroxy-carotenoids prevent coronary heart disease? A comparison between Belfast and Toulouse.

High intakes of antioxidants in fruit, vegetables and wine are thought to protect against coronary heart disease (CHD). Because people in Toulouse have a much lower incidence of CHD compared with Belfast, the plasma concentrations of antioxidant vitamins and carotenoids in the two populations have been compared. The major difference was in some of the plasma carotenoids. Hydroxy-carotenoids were twice as high in Toulouse in both sexes, notably lutein which occurs principally in dark green vegetables and beta-cryptoxanthin which occurs chiefly in citrus fruits. In addition, alpha-carotene was 50% higher in Toulouse, gamma-tocopherol was 50% higher in Belfast. Other plasma vitamins and carotenoids were not significantly different. If antioxidants play a role in preventing CHD, then the hydroxy-carotenoids are major candidates for further investigation.

Practical aspects of acoustic rhinometry: problems and solutions.

Acoustic rhinometry now has an established place in the rhinology laboratory as a measure of nasal geometry. We aimed to investigate several aspects of technique in order to offer some guidance on preferred procedures. We studied the effects of nosepiece seal quality, nosepiece aperture diameter, angle of inclination of the wave tube (in two planes), palate position and inter-observer variation on the nasal area-distance function. One hundred nasal cavities in adults and children were examined: 50 normal and 50 pathological. Each factor was examined intensively in 20 cavities, and reproducibility data obtained on all 100 cavities. The baseline mean coefficient of variation for nasal cavity volume (V1) was 6% and for minimum cross-sectional area (MCA) was 8%. Altering the angle of incidence of the wave tube in the axial and coronal planes caused considerable change in the traces from the anterior nasal cavity, including the I- and C-notches, and affected the MCA significantly (p < 0.01, Wilcoxon signed rank test). Using a small nosepiece aperture accentuated the I-notch, and the nosepiece in some cases became the site of the minimal area. Addition of a silicone-based sealant to the standard nosepiece caused a mean reduction of 14.3% in nasal volume, if the seal quality was suspected to be suboptimal. Nasopharyngeal volume decreased by a mean of 28.6% when the palate is raised by the modified Valsalva manoeuvre, and no difference was found between quiet oral respiration and cessation of nasal respiration. Acoustic rhinometry is sensitive to minor changes in the details of technique. We recommend using an intermediate range of angles in both planes, the addition of a sealant where the nosepiece seal is suspect, use of newer improved nosepieces and synchronizing readings with either cessation of nasal respiration or with quiet oral respiration. There is a pressing need for international agreement on such details if collaboration and clinical application of acoustic rhinometry is to flourish.

Monitoring fluctuations in nasal patency in children: acoustic rhinometry versus rhinohygrometry.

Simple rhinohygrometry and passive rhinomanometry studies have suggested that the 'nasal cycle' in children is often different in pattern of that of adults and experimental animals. We aimed to establish whether this assertion was correct, using a reliable and sensitive method, acoustic rhinometry (AR), and to compare results with those of simple rhinohygrometry (RH). Healthy children with no evidence of nasal disease were examined (n = 15; age range three to 10 years; mean age six years). Simultaneous recordings using AR and RH were made on each child every 10-15 minutes over two to four hour periods. Six children underwent nine additional AR studies on separate occasions. 'Classical' reciprocal alternating patterns were evident in 80 per cent (12/15) AR and 53 per cent (8/15) RH studies, 'in concert' patterns in seven per cent (1/15) AR and 20 per cent (3/15) RH studies and 'irregular' patterns in 13 per cent (2/15) AR and 27 per cent (4/15) RH studies. The agreement between the two methods was 47 per cent, with a kappa (kappa) value of -0.17 (poor agreement compared to chance). Agreements between the acoustic rhinometry parameters were 'fair' for all data (kappa = 0.34) and excellent (kappa = 1.0) if irregular patterns were ignored. Repeated studies showed that the pattern of fluctuation varies within any particular individual. The nasal cycle is similar in pattern in children and adults, and acoustic rhinometry is currently the method of choice to further investigate and clarify this phenomenon.

Injury patterns in cyclists attending an accident and emergency department: a comparison of helmet wearers and non-wearers.

OBJECTIVES: To study circumstances of bicycle accidents and nature of injuries sustained and to determine effect of safety helmets on pattern of injuries. DESIGN: Prospective study of patients with cycle related injuries. SETTING: Accident and emergency department of teaching hospital. SUBJECTS: 1040 patients with complete data presenting to the department in one year with cycle related injuries, of whom 114 had worn cycle helmets when accident occurred. MAIN OUTCOME MEASURES: Type of accident and nature and distribution of injuries among patients with and without safety helmets. RESULTS: There were no significant differences between the two groups with respect to type of accident or nature and distribution of injuries other than those to the head. Head injury was sustained by 4/114 (4%) of helmet wearers compared with 100/928 (11%) of non-wearers (P = 0.023). Significantly more children wore helmets (50/309 (16%)) than did adults (64/731 (9%)) (P < 0.001). The incidence of head injuries sustained in accidents involving motor vehicles (52/288 (18%)) was significantly higher than in those not involving motor vehicles (52/754 (7%)) (chi 2 = 28.9, P < 0.0001). Multiple logistic regression analysis of probability of sustaining a head injury showed that only two variables were significant: helmet use and involvement of a motor vehicle. Mutually adjusted odds ratios showed a risk factor of 2.95 (95% confidence interval 1.95 to 4.47, P < 0.0001) for accidents involving a motor vehicle and a protective factor of 3.25 (1.17 to 9.06, P = 0.024) for wearing a helmet. CONCLUSION: The findings suggest an increased risk of sustaining head injury in a bicycle accident when a motor vehicle is involved and confirm protective effect of helmet wearing for any bicycle accident.

Rates of admission to hospital for asthma.

OBJECTIVE: To describe trends in hospital admission rates for asthma in England and Wales (1976-85), the East Anglian region (from 1976 to 1991-2), and Wales (1980-90). DESIGN: Descriptive study. SETTING: Hospitals in England and Wales; hospitals in the East Anglian Regional Health Authority; hospitals in Wales. MAIN OUTCOME MEASURES: Hospital admissions for asthma as principal diagnosis in England and Wales (Hospital In-patient Enquiry, 1976-85), for the East Anglian region (Hospital In-patient Enquiry, 1976-7; Hospital Activity Analysis, 1978-86; Regional Information System, 1987-8 to 1991-2), and for Wales (Hospital Activity Analysis, 1980-90). RESULTS: Rates for England and Wales as a whole showed a steady upward trend throughout the period examined. Rates in East Anglia, though they were similar to the national trends in the early years, showed a peak in 1985 (for males and females) with some indication of a decline in rates thereafter. Rates for Wales showed an upward trend until 1988 (for both males and females) after which they showed a decline. CONCLUSIONS: Interpretation of the East Anglian trends is made more difficult by the change in England in 1987 of the system for the collection of hospital admission data. The fact that the rates for the East Anglian region seem to decline before this change and other considerations suggest that the observed trends, although partly reflecting the disruption of the coding during the changeover in systems, may not be entirely artefactual. The possible roles of diagnostic transfer and changes in the delivery of care, asthma treatment, admission and readmission policies, and the severity and prevalence of asthma in changing admission rates are considered. The changing trends in admission rates for East Anglia and Wales reflect recently published trends for mortality from asthma in England.

Differences in mortality after fracture of hip: the east Anglian audit.

OBJECTIVE: To investigate differences between hospitals in clinical management of patients admitted with fractured hip and to relate these to mortality at 90 days. DESIGN: A prospective audit of process and outcome of care based on interviews with patients, abstraction from records with standard proforma, and follow up at three months. Data were analysed with chi 2 test and forward stepwise regression modelling of mortality. SETTING: All eight hospitals in East Anglia with trauma orthopaedic departments. PATIENTS: 580 consecutive patients admitted for fracture of neck of femur. MAIN OUTCOME MEASURE: Mortality at 90 days. RESULTS: Patients admitted to each hospital were similar with respect to age, sex, pre-existing illnesses, and activities of daily living before fracture. In all, 560 (97%) were treated surgically, by a range of grades of surgeon. Two hundred and sixty one patients (45%; range between hospitals 10-91%) received pharmaceutical thromboembolic prophylaxis, 502 (93%; 81-99%) perioperative antibiotic prophylaxis. The incidence of fatal pulmonary emboli differed between patients who received and those who did not receive prophylaxis against deep vein thrombosis (P = 0.001). Mortality at 90 days was 18%, differing significantly between hospitals (5-24%). One hospital had significantly better survival than the others (odds ratio 0.14; 95% confidence interval 0.04-0.48; P = 0.0016). CONCLUSIONS: No single factor or aspect of practice accounted for this protective effect. Lower mortality may be associated with the cumulative effects of several aspects of the organisation of treatment and the management of fracture of the hip, including thromboembolic pharmaceutical prophylaxis, antibiotic prophylaxis, and early mobilisation.

"Metaphylaxis" in post-partum conditions in dairy cows with butaphosphone: a trial under South African conditions.

Current literature on the prevention of the "parturition syndrome" in dairy cows using butaphosphone is summarised. A South African trial is recorded in which 2 pre-partum injections of the drug caused a significant reduction in the number of cases of parturition syndrome, as well as a marked reduction in intercalving period in the treated portion of the herd. No difference in lactation yield or culling rate was seen. The financial implication of the reduction in intercalving period is discussed.

Cattle mange: importance in South Africa and chemical control with the organophosphate phoxim.

Cattle mange causes economic losses in South Africa. Two full efficacy trials and 6 field trials with phoxim demonstrated good efficacy against 3 species of mites causing cattle mange.

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.

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.