Preformed Angiotensin II Type-1 Receptor Antibodies Are Associated With Rejection After Kidney Transplantation: A Single-Center, Cohort Study.

Antibodies against angiotensin II type-1 receptors (AT1R) have been increasingly recognized in association with rejection and poor allograft outcomes. Our goal was to define the prevalence of preformed antibodies against AT1R and evaluate the association with renal allograft outcomes in a consecutive cohort of 150 transplant recipients. IgG antibodies against AT1R were measured by enzyme-linked immunosorbent assay using cryopreserved serum samples obtained for HLA testing at the time of transplantation. Results were categorized as negative if <10 U/mL (44%), intermediate from 10 to 17 U/mL (38%), or strongly positive if >17 U/mL (18%). The presence of AT1R antibodies was inversely associated with age, dialysis status, and diabetes. We found a strong association between the presence of AT1R antibodies and acute cellular rejection using multivariate analyses, odds ratio 3.86 (95% CI, 1.03-14.47) for intermediate titers and 9.99 (95% CI, 2.6-38.4) for strongly positive titers. There was no association with HLA sensitization or C4d-positive antibody-mediated rejection. We did not observe a significant association with graft failure, allograft function, or proteinuria. Preformed AT1R antibodies are prevalent and highly associated with acute cellular rejection early after transplant, independent of anti-HLA antibodies. The presence of AT1R antibodies correlates with recipient characteristics that may denote stronger immune responses. Future studies are needed to evaluate the mechanism and causative effect of AT1R antibodies.

Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

INTRODUCTION: Heavy menstrual bleeding (HMB) diminishes individual quality-of-life and poses substantial societal burden. In HMB endometrium, inactivation of cortisol (by enzyme 11ß hydroxysteroid dehydrogenase type 2 (11ßHSD2)), may cause local endometrial glucocorticoid deficiency and hence increased angiogenesis and impaired vasoconstriction. We propose that 'rescue' of luteal phase endometrial glucocorticoid deficiency could reduce menstrual bleeding. METHODS AND ANALYSIS: DexFEM is a double-blind response-adaptive parallel-group placebo-controlled trial in women with HMB (108 to be randomised), with active treatment the potent oral synthetic glucocorticoid dexamethasone, which is relatively resistant to 11ßHSD2 inactivation. Participants will be aged over 18 years, with mean measured menstrual blood loss (MBL) for two screening cycles ≥50 mL. The primary outcome is reduction in MBL from screening. Secondary end points are questionnaire assessments of treatment effect and acceptability. Treatment will be for 5 days in the mid-luteal phases of three treatment menstrual cycles. Six doses of low-dose dexamethasone (ranging from 0.2 to 0.9 mg twice daily) will be compared with placebo, to ascertain optimal dose, and whether this has advantage over placebo. Statistical efficiency is maximised by allowing randomisation probabilities to 'adapt' at five points during enrolment phase, based on the response data available so far, to favour doses expected to provide greatest additional information on the dose-response. Bayesian Normal Dynamic Linear Modelling, with baseline MBL included as covariate, will determine optimal dose (re reduction in MBL). Secondary end points will be analysed using generalised dynamic linear models. For each dose for all end points, a 95% credible interval will be calculated for effect versus placebo. ETHICS AND DISSEMINATION: Dexamethasone is widely used and hence well-characterised safety-wise. Ethical approval has been obtained from Scotland A Research Ethics Committee (12/SS/0147). Trial findings will be disseminated via open-access peer-reviewed publications, conferences, clinical networks, public lectures, and our websites. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98.

Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.

BACKGROUND: Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF. METHODS: In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured. RESULTS: Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response. CONCLUSIONS: pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.

Humoral immunomodulatory effect of influenza vaccine in potential blood donors: implications for transfusion safety.

BACKGROUND: Generalised immune stimulation may follow vaccination causing increased antibody titres of nonvaccine-related antibodies or bystander antibodies, including those to human leukocyte antigens (HLA) and ABO blood group antigens. HLA antibodies may lead to transfusion-related acute lung injury. High-titre ABO antibodies may cause acute haemolytic transfusion reactions after plasma-incompatible platelet transfusion. It is unknown if these antibodies can be stimulated by vaccination in otherwise normal subjects. METHODS: Blood samples of healthy volunteers who received the 2009 influenza vaccine were analysed for HLA and ABO antibodies before and 14 days after vaccination (n = 86). Age, gender and history of exposure to foreign tissue, through pregnancy, blood transfusion or tissue transplant were collected. Results were analysed with descriptive statistics, paired t-test and χ(2) test. RESULTS: There was no increase in HLA or ABO antibody levels after vaccination (P = not significant). Forty per cent of subjects (n = 35) had previously formed HLA antibody and 16% (7 males and 7 females) had HLA sensitisation but did not report foreign tissue exposure. The average panel reactive antibody of the HLA sensitised but nonexposed subjects was lower in males than females (3.4 and 28.6%, respectively, P = 0.015, t-test), suggesting that some females may have had unrecognised pregnancy. CONCLUSIONS: HLA or ABO antibodies did not appear to be stimulated by the 2009 influenza vaccine. Female blood donors with putatively unrecognised pregnancies may have higher risk for HLA sensitisation than previously thought. Further study using different vaccine formulations may lead to better understanding of the risks of bystander antibodies in the blood donor population.

Tamoxifen resistance in early breast cancer: statistical modelling of tissue markers to improve risk prediction.

BACKGROUND: For over two decades, the Nottingham Prognostic Index (NPI) has been used in the United Kingdom to calculate risk scores and inform management about breast cancer patients. It is derived using just three clinical variables - nodal involvement, tumour size and grade. New scientific methods now make cost-effective measurement of many biological characteristics of tumour tissue from breast cancer biopsy samples possible. However, the number of potential explanatory variables to be considered presents a statistical challenge. The aim of this study was to investigate whether in ER+ tamoxifen-treated breast cancer patients, biological variables can add value to NPI predictors, to provide improved prognostic stratification in terms of overall recurrence-free survival (RFS) and also in terms of remaining recurrence free while on tamoxifen treatment (RFoT). A particular goal was to enable the discrimination of patients with a very low risk of recurrence. METHODS: Tissue samples of 401 cases were analysed by microarray technology, providing biomarker data for 72 variables in total, from AKT, BAD, HER, MTOR, PgR, MAPK and RAS families. Only biomarkers screened as potentially informative (i.e., exhibiting univariate association with recurrence) were offered to the multivariate model. The multiple imputation method was used to deal with missing values, and bootstrap sampling was used to assess internal validity and refine the model. RESULTS: Neither the RFS nor RFoT models derived included Grade, but both had better predictive and discrimination ability than NPI. A slight difference was observed between models in terms of biomarkers included, and, in particular, the RFoT model alone included HER2. The estimated 7-year RFS rates in the lowest-risk groups by RFS and RFoT models were 95 and 97%, respectively, whereas the corresponding rate for the lowest-risk group of NPI was 89%. CONCLUSION: The findings demonstrate considerable potential for improved prognostic modelling by incorporation of biological variables into risk prediction. In particular, the ability to identify a low-risk group with minimal risk of recurrence is likely to have clinical appeal. With larger data sets and longer follow-up, this modelling approach has the potential to enhance an understanding of the interplay of biological characteristics, treatment and cancer recurrence.

Economic evaluation of diagnosing and excluding ectopic pregnancy.

BACKGROUND: The diagnosis of ectopic pregnancy in women presenting in early pregnancy is often protracted, relying on costly investigations that are psychologically burdensome to the patient. The aim of this study was to evaluate the financial costs to the health services in Scotland of the current methods used to diagnose and exclude ectopic pregnancy, and compare these with that of a theoretical single diagnostic serum biomarker. METHODS: We conducted a retrospective cost-description analysis (with and without costs of diagnostic laparoscopy) of the health-care costs incurred by all patients presenting to a large Scottish teaching hospital between June and September 2006 with pain and bleeding in early pregnancy, where ectopic pregnancy was not excluded. Additionally, a cost minimization analysis was performed for the costs of current ectopic pregnancy investigations versus those of a theoretical single diagnostic serum biomarker. This included sensitivity analyses where the biomarker was priced at increasing values and assumed to have less than 100% diagnostic sensitivity and specificity. RESULTS: About 175 patients were eligible to be included in the analysis. Forty-seven per cent of patients required more than three visits to diagnose or exclude ectopic pregnancy. The total yearly cost for diagnosing and excluding ectopic pregnancy was 197K pound sterling for the hospital stated, and was estimated to be 1364K pound sterling for Scotland overall. Using a theoretical diagnostic serum biomarker we calculated that we could save health services up to 976K pound sterling (lowest saving 251K pound sterling after subanalysis) every year in Scotland. CONCLUSIONS: Ectopic pregnancy is expensive to diagnose and exclude, and the investigation process is often long and might involve significant psychological morbidity. The development of a single diagnostic serum biomarker would minimize this morbidity and lead to significant savings of up to 1 million pounds per year in Scotland.

Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding.

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, during early months of use unscheduled vaginal bleeding is common, sometimes leading to discontinuation. This study aimed to determine whether intermittent administration of progesterone receptor modulator CDB-2914 would suppress unscheduled bleeding during the first 4 months after insertion of the LNG-IUS. METHODS: CDB-2914 150 mg, in divided doses, or placebo tablets, were administered over three consecutive days starting on Days 21, 49 and 77 after LNG-IUS insertion, in a double-blind randomized controlled trial of women aged 19-49 years, newly starting use of LNG-IUS. Daily bleeding diaries were completed for 6 months, and summarized across blocks as percentage days bleeding/spotting (BS%). RESULTS: Of 69 women randomized to receive CDB-2914, and 67 placebo, 61 and 55, respectively, completed the trial. BS% decreased with time in both arms, but showed a much steeper treatment-phase gradient in the placebo arm (P < 0.0001), so that a benefit of CDB-2914 in the 28 days after first treatment (-11% points, 95% CI -19 to -2), converted to a disadvantage by 64 days after the third treatment (+10% points, 95% CI 1-18). CONCLUSIONS: The effect of CDB-2914 on BS% was initially beneficial but then by third treatment was disadvantageous. Nevertheless, only 3% (4/136) of all women discontinued LNG-IUS. These findings give insight into possible mechanisms and suggest future research directions. ISRCTN Trial no. ISRCTN58283041; EudraCT no. 2006-006511-72.

Implementation of NICE recommendation for a policy of routine antenatal anti-D prophylaxis: a survey of UK maternity units.

The aim of this study was to determine how many UK maternity units have implemented National Institute for Clinical Excellence (NICE) guidance for routine antenatal anti-D prophylaxis (RAADP). In May 2002, the NICE recommended a policy of RAADP for RhD-negative pregnant women. The policy has the potential to reduce maternal sensitization and prevent deaths from haemolytic disease of the foetus and newborn, but implementation entails considerable clinical, financial and organizational challenges. A postal survey of all 324 UK maternity units was completed in 2005.Responses were received from 91% of units (294 of 324). RAADP was offered by 220 of 294 (75%) and in England and Wales 19% of those offered a single-dose regime. At 12% of maternity units, routine paternal blood group testing was offered. For 84% of maternity units, staff education was offered at the time of implementation. Written patient information was provided at 97% of maternity units and 147 of 217 (69%) returned a copy. We received 60 different leaflets. Three years after NICE guidance was issued, one in four maternity units did not offer RAADP. Among those that do offer RAADP, practice with regard to anti-D administration, paternal testing, provision of written information and staff education varied. Unit and clinician level research is required to understand why.

Effectiveness of Medifast supplements combined with obesity pharmacotherapy: a clinical program evaluation.

PURPOSE: To evaluate the long-term impact of Medifast meal-replacement supplements (MMRS) combined with appetite suppressant medication (ASM) among participants who received 52 weeks of treatment. METHODS: We conducted a systematic program evaluation of weight loss data from a medically-supervised weight control program combining the use of MMRS and ASM. Data were obtained and analyzed from 1,351 patient (BMI> or =25) medical charts who had participated for at least 12 weeks of treatment. Outcomes included weight loss (kg) and percent weight loss from baseline and at 12, 24, and 52 weeks. Both completers and intention-to-treat analyses were conducted. Completers' (i.e., those with complete data for 52 weeks) outcomes were evaluated after stratification for reported adherence to the MMRS and ASM. RESULTS: Participants who completed 52 weeks of treatment experienced substantial weight losses at 12 (-9.4+/-5.7 kg), 24 (-12.0+/-8.1 kg), and 52 weeks (-12.4+/-9.2 kg) and all measures were significantly different from baseline weight (p<0.001 for all contrasts) for both true completers (n=324) and for ITT analysis (n=1,351). Fifty percent of patients remained in the program at 24 weeks and nearly 25% were still participating at one year. CONCLUSIONS: This weight loss program using a combination of MMRS and ASM produced significant and sustained weight losses at 52 weeks. Results were better than those typically reported for obesity pharmacotherapy in both short- and long-term studies and also better than those reported for partial meal replacement programs. Program retention at one year was similar to that reported in many controlled drug trials and better than most commercial programs reported in the literature.

Factors affecting adequacy of Pipelle and Tao Brush endometrial sampling.

OBJECTIVE: To compare factors influencing adequacy of endometrial samples obtained using two outpatient sampling devices--Pipelle and Tao Brush. DESIGN: Pragmatic unblinded trial with investigation schedule randomised separately within two groups according to endometrial cancer risk. SETTING: Gynaecology outpatient clinic of a large city hospital in Edinburgh, Scotland. POPULATION: All women referred to a gynaecology outpatient clinic during a 28-month period complaining of abnormal vaginal bleeding. METHODS: Women were assigned to two 'risk groups' for endometrial cancer ('high risk' for postmenopausal women and 'moderate risk' for premenopausal women aged over 40 years or with other risk factors). Women in each risk group had both types of biopsy and were randomised to two outpatient visualisations: hysteroscopy and/or transvaginal ultrasound scan. MAIN OUTCOME MEASURES: Completion of the investigation, adequacy of sample and acceptability of investigation to women. RESULTS: In 200 high-risk women, adequate samples were significantly more likely to be obtained by Tao Brush than Pipelle (P < 0.001). Nulliparity was strongly associated with failed insertion for both devices (P < 0.001). Inadequate samples were strongly associated with postmenopausal status only for Pipelle (P < 0.001), and among premenopausal women, for both samplers, with nulliparity (P < 0.001). A significantly greater proportion of women preferred the Tao Brush to the Pipelle endometrial sampler (P < 0.001). CONCLUSIONS: In postmenopausal women, Tao Brush sampling offers advantages over use of Pipelle, and the former should be considered as an alternative or additional sampling device in this group of women.

What is the impact of change in diagnostic test method on surveillance data trends in Chlamydia trachomatis infection?

OBJECTIVE: To describe the impact of change from culture to more sensitive nucleic acid amplification testing (NAAT) tests on the detection of Chlamydia trachomatis in a genitourinary medicine (GUM) clinic population. METHODS: Data were collected between January 1992 and December 2003 on results of C trachomatis tests on male and female attenders at the Lothian GUM clinic (n = 81 590). Routine diagnosis switched from culture to NAAT methods in September 1998. Association of test result with age, sex, year of test, and test type was analysed using logistic regression. RESULTS: 6.1% (95% CI: 5.7% to 6.5%) of women and 7.1% of men (95% CI: 6.7% to 7.5%) tested positive with culture and 9.9% of women (95% CI: 9.4% to 10.3%) and 11.1% of men (95% CI: 10.7% to 11.5%) tested positive with NAATs. This corresponds to a 56% increase for men (95% CI: 47% to 66%) and 62% for women (95% CI: 50% to 67%). Logistic regression showed that a positive test result was strongly associated with test type with or without adjustment for year of test, sex, and young age. CONCLUSIONS: The significant increase in chlamydial infections detected following a change from culture to NAATs has important implications for interpretation of trends ascertained from surveillance data. Not all of this can be a direct effect of enhanced sensitivity and there may be indirect effects that improve ascertainment of existing infections. As more laboratories switch to NAATs similar patterns of stepwise increases in positive results are expected and trend analysis based on such surveillance data might thus show an artefactual rise in chlamydia infection rates. Accumulated surveillance data should therefore include timing of introduction of NAAT, so as to take account of under-ascertainment by previous methods.

Development of a disposable pyruvate biosensor to determine pungency in onions (Allium cepa L.).

A disposable prototype pyruvate biosensor was constructed using pyruvate oxidase immobilised on mediated meldolas blue electrodes to determine pungency in onions (Allium cepa L.). The optimum operating potential was +150 mV (versus Ag/AgCl). A strong correlation between the biosensor response and untreated onion juice of known pyruvate concentration 2-12 micromol/g fresh weight (FW) was demonstrated. The biosensor was able to differentiate between low and high pungency onions. The detection limit using 1 unit of pyruvate oxidase was 1-2 micromol/g FW. Optimum concentrations of co-factors TPP, FAD and MgSO4 comprising the enzyme cocktail were determined as being 0.04, 0.1 and 30 mM, respectively.

Ethnicity and peripheral arterial disease: the San Diego Population Study.

BACKGROUND: Previous studies have indicated higher rates of peripheral arterial disease (PAD) in blacks than in non-Hispanic whites (NHWs), with limited information available for Hispanics and Asians. The reason for the PAD excess in blacks is unclear. METHODS AND RESULTS: Ethnic-specific PAD prevalence rates were determined in a randomly selected defined population that included 4 ethnic groups; NHWs, blacks, Hispanics, and Asians. A total of 2343 participants aged 29 to 91 years were evaluated. There were 104 cases of PAD (4.4%). In weighted logistic models with NHWs as the reference group and containing demographic factors only, blacks had a higher PAD prevalence than NHWs (OR=2.30, P<0.024), whereas PAD rates in Hispanics and Asians, although somewhat lower, were not significantly different from NHWs. Blacks had significantly more diabetes and hypertension than NHWs and a significantly higher body mass index. Inclusion of these variables and other PAD risk factors in the model did not change the effect size for black ethnicity (OR=2.34, P=0.048). A model containing interaction terms for black ethnicity and each of the other risk factors revealed no significant interaction terms, which indicates no evidence that blacks were more "susceptible" than NHWs to cardiovascular disease risk factors. CONCLUSIONS: Black ethnicity was a strong and independent risk factor for PAD, which was not explained by higher levels of diabetes, hypertension, and body mass index. There was no evidence of a greater susceptibility of blacks to cardiovascular disease risk factors as a reason for their higher PAD prevalence. Thus, the excess risk of PAD in blacks remains unexplained and requires further study.

The Middlesex University rehabilitation robot.

This paper describes the development of an electrically powered wheelchair-mounted manipulator for use by severely disabled persons. A detailed review is given explaining the specification. It describes the construction of the device and its control architecture. The prototype robot used several gesture recognition and other input systems. The system has been tested on disabled and non-disabled users. They observed that it was easy to use but about 50% slower than comparable systems before design modifications were incorporated. The robot has a payload of greater than 1 kg with a maximum reach of 0.7-0.9 m.

Piezoelectric sensors for dioxins: a biomimetic approach.

The aim of this work was to design a fast, cheap and easy to use analytical system for dioxins. Piezoelectric sensors coupled with the pentapeptides as biomimetic traps (the receptors), selective for the dioxins, were used for the realisation of this analytical system. A methodology to select specific receptors among all possible pentapeptides randomly generated was represented by the use of molecular modelling software. Three peptides called later on A, B and C (A:[N]Asn-Phe-Gln-Gly-Ile[C]; B:[N]Asn-Phe-Gln-Gly-Gln[C]; C:[N]Asn-Phe-Gln-Gly-Phe[C]), were selected and evaluated for their potential usage as artificial receptors in solid-gas analysis by using a quartz crystal microbalance (QCM) sensors array. The peptide sequences were functionalised by two terminal cysteine residues in order to achieve a covalent interaction with the QCM gold surface. A manganese-porphyrin complex and two other pentapeptides, a pentaglutamine (pentapeptide D) and a pentalysine (pentapeptide E), were used as negative control sensors. The QCM sensors (A, B and C) gave a good linearity against different sample concentrations of the 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD) and a mixture of dioxins. In particular, the selectivity against 2,3,7,8-TCDD was nicely correlated to the estimated binding energy of the receptors calculated by computational modelling. The cross-reactivity of the system was quantified using commercial polychlorinated biphenyls (PCBs) mixtures (dioxin-like compounds).

Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

OBJECTIVES: To compare three outpatient methods of endometrial evaluation in terms of performance, patient acceptability and cost-effectiveness. DESIGN: Pragmatic unblinded trial randomised separately within three groups determined by risk of endometrial cancer. SETTING: The gynaecology outpatient clinic of a large city hospital in Edinburgh, Scotland. PARTICIPANTS: Women referred for investigation and management of abnormal bleeding between January 1999 and May 2001. INTERVENTIONS: Investigations were: blind biopsy alone, hysteroscopy with biopsy, ultrasound evaluation including transvaginal ultrasound, and, in the low-risk group, the option of no investigation. Within this design, two devices for obtaining endometrial biopsy were compared, the Pipelle sampler and the Tao brush. MAIN OUTCOME MEASURES: Successful (informative) completion of the investigation, acceptability of the investigation method to women, women's satisfaction with clinic care in the short term and at 10 months and 2 years of follow-up, and cost-effectiveness to the end of investigation. RESULTS: Minor adverse events (e.g. shock, patient distress) did not occur for ultrasound, but occurred in 16% and 10% of women for hysteroscopy and biopsy procedures respectively. Pipelle biopsy provided an acceptable endometrial sample for 79% of moderate-risk women, but only 43% of high-risk women. The Tao brush gave similar performance in moderate-risk women (77%), but was more successful than the Pipelle sampler in postmenopausal (high-risk) women (72%). There were significantly more successful visualizations for ultrasound than for hysteroscopy in both the low-risk and the moderate-risk group, and a similar but non-significant trend in the high-risk group. Ultrasound was significantly better than hysteroscopy at detecting fibroids, but hysteroscopy significantly better for polyps. At the 10-month follow-up, high-risk women who had been investigated by hysteroscopy (with biopsy) had the most positive views of their clinic experience, but this effect had largely disappeared by 24 months. In the moderate-risk group, the subgroup randomised to biopsy alone gave the most negative responses about their clinic experience and health now. Women wishing they had more investigation comprised 22% of moderate-risk women and 38% of low-risk women, but only 14% of postmenopausal women. At follow-up the moderate-risk women (with menstrual bleeding problems), compared with postmenopausal women, had much worse ratings for clinic experience and health now. Resource use tended to be higher in the moderate- and low-risk women. There was minimal difference in cost-effectiveness between investigation options in the high-risk group, with the option involving hysteroscopy being marginally better than ultrasound. The most cost-effective investigation in the moderate-risk group was biopsy alone and in the low-risk group ultrasound. CONCLUSIONS: Decision-making about investigation would be clarified if postmenopausal women were studied separately from premenopausal women with menstrual bleeding problems. For postmenopausal women exclusion of cancer is a main objective, so once investigation has been completed discharge follows, but in the woman with abnormal menstrual bleeding, even if serious pathology is excluded, the original presenting symptoms require management. About 60% of premenopausal women with abnormal bleeding reported that their symptoms were not 'much improved' at 10 months. Research is needed to understand this phenomenon, and to explore ways to integrate patient factors into optimising evaluation and treatment. The significance of benign pathologies in this group also requires clarification. Given the relatively small differences observed in cost-effectiveness, there is justification for allowing other issues (such as clinician preferences and women's perspectives) to influence decisions as to the investigation method. There is scope to make better use of patient factors to inform decisions as to the most efficient and acceptable method of investigation for an individual woman. Additional analyses, using data available as a result of this study, will contribute to this agenda.

Subclavian artery stenosis: prevalence, risk factors, and association with cardiovascular diseases.

OBJECTIVES: The objective was to assess the prevalence of subclavian artery stenosis (SS) in four cohorts (two free-living and two clinical populations) and determine both risk factors for this condition and the association with other cardiovascular conditions. BACKGROUND: The prevalence of SS in the general population is unknown, and its association with risk factors and other cardiovascular diseases is not well-established. METHODS: A total of 4,223 subjects (2,975 from two free-living cohorts and 1,248 from two clinical cohorts) were included in this cross-sectional analysis. Subclavian artery stenosis was defined as > or =15 mm Hg interarm pressure difference. RESULTS: The prevalence of SS was 1.9% in the free-living cohorts and 7.1% in the clinical cohorts; SS was significantly (p < 0.05) associated with past smoking (odds ratio [OR] = 1.80), current smoking (OR = 2.61), and higher levels of systolic blood pressure (OR = 1.90 per 20 mm Hg). Higher levels of high-density lipoprotein (HDL) cholesterol were inversely and significantly associated with SS (OR = 0.87 per 10 mg/dl). In regression analyses relating SS to other cardiovascular diseases, the only significant finding was with peripheral arterial disease (PAD) (OR = 5.11, p < 0.001). CONCLUSIONS: Significant SS is present in approximately 2% of the free-living population and 7% of the clinical population. Additionally, SS is correlated with current and past smoking histories, systolic blood pressure, HDL levels (inversely), and the presence of PAD. These findings suggest that bilateral brachial blood pressure measurements should routinely be performed in patients with an elevated risk profile, both to screen for SS, and to avoid missing a hypertension or PAD diagnosis because of unilateral pressure measurement in an obstructed arm.

The methamphetamine burn patient.

Early aggressive fluid resuscitation has significantly decreased the morbidity and mortality associated with volume losses from large burns. Although most patients are adequately resuscitated using the Parkland formula, we noted increased fluid requirements for shock resuscitation in patients involved in methamphetamine laboratory explosions. Because predominant users are young healthy individuals in their 20s and 30s, we had not anticipated burn shock resuscitation failures in this patient group. We reviewed our experience with burn patients with documented methamphetamine use to determine whether this patient group presents new dilemmas to the burn surgeon. A 2-year retrospective study of 30 patients (15 methamphetamine users, 15 controls) revealed that the methamphetamine burn patient requires two to three times the standard Parkland formula resuscitation. In this study, methamphetamine burns larger than 40% TBSA had a 100% mortality.

About time: diagnostic guidelines that help clinicians.

Clinical guidelines often make recommendations on the use of diagnostic tests. Compared with sensitivity and specificity, the use of pre- and post-test probabilities allows a more explicit and rational selection and interpretation of diagnostic tests. Ideally, clinical guidelines relating to diagnosis should routinely incorporate this information to enhance individualised decision making. We report our experience of incorporating pre- and post-test probabilities into a guideline on the investigation of women with postmenopausal bleeding developed by the Scottish Intercollegiate Guidelines Network. Issues relating to their application are highlighted, including the limitations of available evidence on diagnostic tests and prevalence of disease, acceptability to guideline users, and the uncertain impact on actual clinical decision making. Despite these potential difficulties, the incorporation of data on pre- and post-test probabilities into the development and presentation of guideline recommendations may offer an important opportunity to make clinical decision making more transparent for both clinicians and patients.