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Background and Aims: Intentional weight loss may reduce symptom severity of atrial fibrillation (AF) in relatively young AF patients with overweight. We examined whether symptom severity and quality of life (QoL) are associated with weight status in the general population with AF., Methods and Results: Patients with electrocardiogram-confirmed AF completed validated questionnaires: the EuroQol 5 Dimensions QoL questionnaire and the Toronto Atrial Fibrillation Severity Scale (AFSS). The AFSS assessed the AF burden scoring on AF-related symptoms and the total AF burden measured as a combination of duration, frequency, and severity of an irregular heartbeat. Generalized liner models examined the association of body mass index (BMI) with AF severity and QoL adjusting for confounders. Between 2018 and 2019, 882 of 1901 (46%) mailed questionnaires were returned completed. Participants had a mean (SD) age of 74 (10) years old and a BMI of 27.4 (5.6) kg/m 2 . Sixteen percent reported having never experienced an irregular heartbeat. A 5 kg/m 2 higher BMI was associated with a 0.65 (95%CI: 0.25 to 1.06) higher symptom score, where 3 points represent a clinically relevant change in state. A 5 kg/m 2 higher BMI was associated with a -1.61 (95%CI: -2.72 to -0.50) lower QoL score. The coefficient of the total AF burden for a 5 kg/m 2 higher BMI was 0.17 (95% CI: -0.01 to 0.68)., Conclusion: BMI was positively associated with symptoms and negatively associated with one of the two measures of QoL, but not with the total AF burden. However, the strength of association was small and not clinically meaningful., Competing Interests: Declaration of Competing Interest DAK and PA report being investigators in a NIHR-funded trial where the weight loss intervention was donated by Nestle Health Sciences to the University of Oxford outside the submitted work. PA reports grants from Cambridge Weight Plan Ltd to the University of Oxford outside the submitted work. PA did half a day's consultancy for WW outside the submitted work and WW reimbursed his time to the University of Oxford. None of these association led to payments to them personally. The other authors report no conflicts of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

This study investigated the water balance physiology of Venezillo arizonicus, a land isopod endemic to the Southwest Desert Ecoregion of North America. Evaporative water losses were measured in two ways: gravimetric in dry air, and by perfusing animals with dry air in a respirometry chamber and monitoring downstream relative humidity (RH). The respective mean loss flux estimates were 0.140 and 0.177 μg h -1 cm -2 Pa -1 , lower than other N. American Oniscidea described to date (≥0.491 μg h -1 cm -2 Pa -1 ). Humidity monitoring revealed intermittent sharp peaks in RH, attributed to the release of maxillary urine. Whole-animal flux increased as a function of temperature, with a critical temperature (T c ) between 38 and 42 °C identifiable by a clear Arrhenius break point. Hexane-rinsed whole animals yielded straight-chain, saturated hydrocarbons (C 21 -C 33 ). The surface density of extracted alkanes (0.64 µg cm -2 ) was somewhat higher than previously determined values for mesic species, although modest compared to insects and arachnids. Dehydrated animals exposed to high RH (>88%) demonstrated active water vapor absorption (WVA) like other Crinocheta, with an extrapolated uptake threshold of approximately 85% RH (A w  = 0.85), the lowest value reported for Oniscidea. The maximum uptake flux increased linearly as a function of ambient RH. Mass-specific uptake in 100% RH was 49% d -1 , similar to values determined previously for Armadillidium vulgare and Porcellio scaber. The low WVA threshold of V. arizonicus, and the species' low permeability, are consistent with its known range in the arid desert southwest and the desiccation stress of its typical aeolian sand and seasonal wash habitats., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Since 1966 when the Cystic Fibrosis Foundation Patient Registry (CFFPR) was founded, clinicians have witnessed significant advances in both the quality and quantity of life for patients living with Cystic Fibrosis (CF). As patients with CF live longer and fuller lives, increasing encumbrances from gastrointestinal manifestations of CF will be observed. This article serves to discuss "below the diaphragm" concerns involving the large intestine (Distal Intestinal Obstruction Syndrome, Constipation, and Colorectal Cancer). Avenues for development and implementation of clinical care protocols, particularly regarding proactive management of known associated conditions and cancer screening, will continue to be refined in the coming years. It falls to the multidisciplinary CF care team to be actively engaged in addressing these concerns effectively as priority shifts from relative acuity (typically related to early nutrition and lung function) to the travails of longevity as the CF population continues to age., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Detection and treatment of heart failure (HF) can improve quality of life and reduce premature mortality. However, symptoms such as breathlessness are common in primary care, have a variety of causes and not all patients require cardiac imaging. In systems where healthcare resources are limited, ensuring those patients who are likely to have HF undergo appropriate and timely investigation is vital., Design: A decision tree was developed to assess the cost-effectiveness of using the MICE (Male, Infarction, Crepitations, Edema) decision rule compared to other diagnostic strategies to identify HF patients presenting to primary care., Methods: Data from REFER (REFer for EchocaRdiogram), a HF diagnostic accuracy study, was used to determine which patients received the correct diagnosis decision. The model adopted a UK National Health Service (NHS) perspective., Results: The current recommended National Institute for Health and Care Excellence (NICE) guidelines for identifying patients with HF was the most cost-effective option with a cost of £4400 per quality adjusted life year (QALY) gained compared to a "do nothing" strategy. That is, patients presenting with symptoms suggestive of HF should be referred straight for echocardiography if they had a history of myocardial infarction or if their NT-proBNP level was ≥400pg/ml. The MICE rule was more expensive and less effective than the other comparators. Base-case results were robust to sensitivity analyses., Conclusions: This represents the first cost-utility analysis comparing HF diagnostic strategies for symptomatic patients. Current guidelines in England were the most cost-effective option for identifying patients for confirmatory HF diagnosis. The low number of HF with Reduced Ejection Fraction patients (12%) in the REFER patient population limited the benefits of early detection., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: This study aimed to investigate whether breast volume measured preoperatively using a Kinect 3D sensor could be used to determine the most appropriate implant size for reconstruction., Methods: Ten patients underwent 3D imaging before and after unilateral implant-based reconstruction. Imaging used seven configurations, varying patient pose and Kinect location, which were compared regarding suitability for volume measurement. Four methods of defining the breast boundary for automated volume calculation were compared, and repeatability assessed over five repetitions., Results: The most repeatable breast boundary annotation used an ellipse to track the inframammary fold and a plane describing the chest wall (coefficient of repeatability: 70 ml). The most reproducible imaging position comparing pre- and postoperative volume measurement of the healthy breast was achieved for the sitting patient with elevated arms and Kinect centrally positioned (coefficient of repeatability: 141 ml). Optimal implant volume was calculated by correcting used implant volume by the observed postoperative asymmetry. It was possible to predict implant size using a linear model derived from preoperative volume measurement of the healthy breast (coefficient of determination R 2  = 0.78, standard error of prediction 120 ml). Mastectomy specimen weight and experienced surgeons' choice showed similar predictive ability (both: R 2  = 0.74, standard error: 141/142 ml). A leave one-out validation showed that in 61% of cases, 3D imaging could predict implant volume to within 10%; however for 17% of cases it was >30%., Conclusion: This technology has the potential to facilitate reconstruction surgery planning and implant procurement to maximise symmetry after unilateral reconstruction., (Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Aims: To determine the frequency of recognised morphologic facial phenotypes among the UK and US election candidates and to assess whether there is a relationship between facial morphology and success in general elections., Methods: Facial morphology analysis of prime ministerial and presidential candidates in the UK and US elections was performed. Direct facial measurements were made from frontal images and facial morphological indices calculated for all candidates. Anthropometric facial phenotype was determined and comparisons made between the elected leaders and unelected runner-up candidates. Paired candidates who had different facial types were analysed as a subgroup, with the probabilities of electoral success calculated., Results: Data were available for 45 subjects: 22 election winners and 23 unelected runner-ups. Our data showed some variation in facial morphology between the groups. The predominant facial phenotype in both groups was leptoprosopic (long and/or narrow face), accounting for 40% (n = 18). Mesoprosopic (average dimension) and euryprosopic (short and/or broad) facial type represented 31% (n = 14) and 18% (n = 8), respectively. A majority of the sample (n = 36) demonstrated a malar width to mandibular angle width ratio consistent with the modern 'power face' proportion. Subgroup analysis showed a significant association with success in an election when leptoprosopic candidates were paired against candidates of another facial phenotype (p < 0.05)., Conclusion: Leptoprosopic (long and/or narrow) facial phenotype with a wide mandibular angle width is predominant in the UK and US election candidates. Moreover, this facial phenotype appears to be associated with greater electoral success, supporting the concept of a modern political 'power face'., (Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF)., Methods: Zenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h)., Results: 96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar., Conclusions: Zenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI. NCT01641393., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

We have assessed whether HLA immunogenicity as defined by differences in donor-recipient HLA amino-acid sequence (amino-acid mismatch score, AMS; and eplet mismatch score, EpMS) and physicochemical properties (electrostatic mismatch score, EMS) enables prediction of allosensitization to HLA, and also prediction of the risk of an individual donor-recipient HLA mismatch to induce donor-specific antibody (DSA). HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The effect of AMS, EpMS, and EMS on the development of allosensitization (calculated reaction frequency [cRF]) and DSA was determined. Multivariate analyses, adjusting for time on the waiting list, maintenance on immunosuppression after transplant failure, and graft nephrectomy, showed that AMS (odds ratio [OR]: 1.44 per 10 units, 95% CI: 1.02-2.10, p = 0.04) and EMS (OR: 1.27 per 10 units, 95% CI: 1.02-1.62, p = 0.04) were independently associated with the risk of developing sensitization to HLA (cRF > 15%). AMS, EpMS, and EMS were independently associated with the development of HLA-DR and HLA-DQ DSA, but only EMS correlated with the risk of HLA-A and -B DSA development. Differences in donor-recipient HLA amino-acid sequence and physicochemical properties enable better assessment of the risk of HLA-specific sensitization than conventional HLA matching., (© 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of the American Society of Transplantation and the American Society of Transplant Surgeons.)

We report for the first time the adoptive transfer of donor HLA-specific allosensitization in two recipients following kidney transplantation from a highly sensitized donor. Kidneys from a donation after circulatory death donor were transplanted into two nontransfused, HLA-specific antibody negative males receiving their first transplant. Antibody screening 7 days after transplant showed high level de novo IgG HLA class I- and class II-specific antibodies in both recipients, with largely overlapping antibody profiles but no antibodies to donor HLA. The unusually rapid appearance of de novo alloantibodies in immunosuppressed nonsensitized recipients and absence of donor HLA-specific antibody prompted testing of stored donor serum that revealed high antibody levels with specificities very similar to those seen in both recipients, but in addition the presence of strong antibodies to each recipient HLA. Alloantibody levels gradually declined but were still detectable at 3 months. These findings suggest that alloreactive passenger B cells/plasma cells within the kidneys of highly sensitized donors may give rise to rapid development of posttransplant de novo HLA-specific alloantibodies. While the clinical significance of this phenomenon is uncertain it provides one explanation for the appearance of de novo HLA-specific antibodies directed against third party but not donor HLA., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We have analyzed the relationship between donor mismatches at each HLA locus and development of HLA locus-specific antibodies in patients listed for repeat transplantation. HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The number of HLA mismatches and the calculated reaction frequency of antibody reactivity against 10,000 consecutive deceased organ donors were determined for each HLA locus. Two-thirds of patients awaiting repeat transplantation were sensitized (calculated reaction frequency over 15%) and half were highly sensitized (calculated reaction frequency of 85% and greater). Antibody levels peaked after re-listing for repeat transplantation, were independent of graft nephrectomy and were associated with length of time on the waiting list (odds ratio 8.4) and with maintenance on dual immunosuppression (odds ratio 0.2). Sensitization was independently associated with increasing number of donor HLA mismatches (odds ratio 1.4). All mismatched HLA loci contributed to the development of HLA locus-specific antibodies (HLA-A: odds ratio 3.2, HLA-B: odds ratio 3.4, HLA-C: odds ratio 2.5, HLA-DRB1: odds ratio 3.5, HLA-DRB3/4/5: odds ratio 3.9, and HLA-DQ: odds ratio 3.0 (all significant)). Thus, the risk of allosensitization following failure of a first renal transplant increases incrementally with the number of mismatches at all HLA loci assessed. Maintenance of re-listed patients on dual immunosuppression was associated with a reduced risk of sensitization.

Coastal power stations entrain large volumes of cooling water, requiring biocidal treatment to prevent biological fouling. Discharged effluent is both heated and contaminated with residual traces of biocide and so it is necessary to quantify the impacts of this discharge. Cooling water from Heysham 2 nuclear power station, NW England, UK, is discharged to the intertidal area, via a culvert (to minimise erosion and maximise dilution and dispersion by directing the effluent into the receiving water at all states of the tide) within which the effluent is contained at low water. The culvert and surrounding coastal area support a population of blue mussels (Mytilus edulis). Mussel health was determined along a gradient of exposure, using three physiological indices: Scope for Growth, Gonad Mantle Index and Somatic Condition Index (K Factor). The Mussels within the culvert exhibited reduced physiological index values compared to an external site. A trend was identified down the length of the culvert, representing a gradient of exposure and indicating a potential negative effect on growth and reproductive output., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Donor-specific HLA alloantibodies may cause acute and chronic antibody-mediated rejection (AMR) and significantly compromise allograft survival. The clinical relevance of antibodies directed against some HLA class II antigens, particularly HLA-DP, is less clear with conflicting reports on their pathogenicity. We report two patients with high levels of pretransplant donor-specific HLA-DP antibodies who subsequently developed recurrent acute AMR and graft failure. In both cases, there were no other donor-specific HLA alloantibodies, suggesting that the HLA-DP-specific antibodies may be directly pathogenic., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Breast reduction surgery is successful in improving symptoms associated with breast hypertrophy. We sought to substantiate this in the elderly patient and ascertain how they regarded the outcome., Methods: The WHO defines elderly as 60 and over. All elderly patients undergoing BBR for breast hypertrophy over a ten-year period at a single institution were identified. Retrospective review of medical records was conducted and patients asked to complete a postal questionnaire., Results: 25/29 (86%) patients responded. 88% felt surgery improved appearance and symptoms. A statistically significant improvement in symptoms, appearance and confidence was demonstrated. 54% of patients voiced negative concerns regarding their surgery. One third were unhappy with final appearance. 2/24 regretted surgery., Conclusions: Although studies showing positive outcomes for breast reduction in breast hypertrophy are many, none have specifically looked at elderly patients. Most patients seek relief of functional symptoms. Cosmesis seems to be less an issue. That they achieve improvement in symptoms is reassuring, despite longevity of symptoms and possible concomitant musculoskeletal degeneration. However despite satisfaction with relief of symptoms, much dissatisfaction can be felt over less than perfect cosmesis. We feel attention to detail is key, even in the elderly undergoing functional procedures., (Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Complex hand injuries can be difficult to dress effectively and achieve adequate splintage of the hand in a functional position. During the past 7 years, we have had a great deal of success with topical negative-pressure dressings in the management of complex blast-related extremity war injuries. We have more recently changed to using a gauze-based system and have found this particularly useful in dressing complex hand injuries. We have been able to use this vacuum dressing system to splint the hand in a position of function. This provides an easily applied dressing that, through topical negative pressure, promotes wound healing and ensures a resting functional position, thus minimizing postoperative stiffness. We have not been able to achieve this as efficiently with standard dressings and plaster-of-Paris casts. This article details the technique of functional splinting of complex hand injuries using a gauze-based, topical negative-pressure dressing system., (Copyright © 2011. Published by Elsevier Inc.)

Background: The pre-transplant serum level of soluble CD30 (sCD30), a proteolytic derivative of the lymphocyte surface receptor CD30, has been suggested as a biomarker for immunologic risk after organ transplantation., Methods: Pre-transplant serum sCD30 levels were determined in 200 consecutive adult heart transplant recipients undertaken at a single center. Transplant outcome (acute rejection in the first 12 months and patient survival up to 5 years post-transplant) was determined., Results: Patients treated with a left ventricular assist device (LVAD) prior to transplantation (n = 28) had higher levels of sCD30 (median 64 U/ml, range 12 to 112 U/ml) than those (n = 172) with no LVAD (median 36 U/ml, range 1 to 158 U/ml, p < 0.0001). Recipients were categorized according to whether sCD30 levels were "low" (lower quartile, <24 U/ml, n = 50), "intermediate" (24 to 58 U/ml, n = 100) or "high" (upper quartile, >58 U/ml, n = 50). Neither acute rejection nor recipient survival differed according to sCD30 level, with values (mean +/- SEM) of 0.30 +/- 0.04, 0.23 +/- 0.03 and 0.30 +/- 0.05 acute rejection episodes per 100 days in the low, intermediate and high groups, respectively, with recipient survival rates at 1 year of 77.7%, 84.9% and 86% and at 5 years of 73.6%, 67.9% and 75.8%, respectively., Conclusions: Pre-transplant serum sCD30 level does not predict acute allograft rejection or recipient survival after heart transplantation, although sCD30 levels are increased by LVAD, possibly as a result of biomaterial-host immune interaction.

The objective was to measure the effect of 100% oxygen inhalation on T1 relaxation times in skeletal muscle. Healthy volunteers were scanned using three different MRI protocols while breathing medical air and 100% oxygen. Measurements of T1 were made from regions of interest (ROIs) within various skeletal muscle groups. Dynamic data of subjects breathing a sequence of air-oxygen-air allowed the calculation of characteristic wash-in and -out times for dissolved oxygen in muscle. Contrary to previous findings, a statistically significant decrease in T1 in skeletal muscle was observed due to oxygen inhalation. We report approximate baseline characteristic values for the response of skeletal muscle to oxygen inhalation. This measurement may provide new biomarkers for evaluation of oxygen delivery and consumption in normal and diseased skeletal muscle.

Background: Children with primary pulmonary hypertension (PHT) are a high-risk group who require assessment by cardiac catheterization under anaesthesia. Complications, including death, have occurred during anaesthesia in these patients, but the true risk has not been quantified., Methods: The clinical records of children with PHT undergoing general anaesthesia for pulmonary vascular resistance studies were reviewed retrospectively. Data collected included pre-catheter measures of severity of disease, details of clinical management, and complications occurring within 24 h of the start of anaesthesia., Results: During the past 5 yr, 75 consecutive patients were catheterized and usable records were available in 70. The age range was 0.1-18 yr (mean 7.1). Four children required external cardiac massage [6% (95% confident limits 1-11%)] and one of these died. Of the four, two had an arrhythmia related to the mechanical effects of catheterization, one was hypotensive during anaesthesia and the other had fatal cardiac failure in recovery. All four had severe PHT as judged by echocardiographic estimation of tricuspid regurgitant jet velocity>4 m s-1., Conclusions: Resuscitation or death occurred in 6% of cases. Any associated risk factors could not be determined because the number of complications was too small. Risks may be highest in children with severe idiopathic PHT and symptoms of chest pain, syncope, or dizziness.

Background: Contrast-enhanced MRI is of value in assessing rheumatoid pannus in the hand, but the images are not always easy to quantitate., Objective: To develop and evaluate an improved measurement of volume of enhancing pannus (VEP) in the hand in human rheumatoid arthritis (RA)., Methods: MR images of the hand and wrist were obtained for 14 patients with RA at 0, 1 and 13 weeks. Volume of enhancing pannus was measured on images created by subtracting precontrast T1-weighted images from contrast-enhanced T1-weighted images using a shuffle transformation technique. Maximum intensity projection (MIP) and 3D volume rendering of the images were used as a guide to identify the pannus and any contrast-enhanced veins., Result: Visualisation of pannus was much improved following the shuffle transform. Between 0 weeks and 1 week, the mean value of the within-subject coefficient of variation (CoV) was 0.13 and the estimated total CoV was 0.15. There was no evidence of significant increased variability within the 13-week interval for the complete sample of patients., Conclusion: Volume of enhancing pannus can be measured reproducibly in the rheumatoid hand using 3D contrast-enhanced MRI and shuffle transform.

Acute distal biceps rupture is a devastating injury in the young athlete and surgical repair offers the only chance of a full recovery. We report a new surgical technique used in 14 cases of acute distal tendon rupture in which the 'suture anchor technique' and a de-tensioning suture was employed. In this procedure the distal end of the biceps is re-attached to the radial tuberosity using a sliding whip stitch suture and the proximal part of the distal tendon repair attached to the underlying brachialis muscle with absorbable sutures. This restores correct anatomical alignment and isometric pull on the distal tendon and de-tensions the repair in the early post-operative period, allowing early rehabilitation and an early return to activity. In all cases patients regained a full pre-injury level of sporting activity at a mean period of 6.2 months (2-9 months).

Background: Disease phenotype in cystic fibrosis (CF) shows considerable heterogeneity. Atypical or mild mutations in the CFTR gene have been linked to late-onset pulmonary disease; however, few reports document the condition of the airway in infants and young children with apparent "mild" disease. Prognosis is uncertain in this group of patients and this, in turn, has led to inconsistency in management. Our initial experience of pulmonary infection in children with mild variant CF prompted a more detailed review of clinical outcome., Methods: A retrospective cohort study was carried out comparing frequency of bacterial isolates and clinical outcomes in eleven compound heterozygotes for DeltaF508 and a second mild mutation, mainly R117H, with a matched group of DeltaF508 homozygotes., Results: Staphylococcus aureus was isolated in 8 of the 11 patients with mild variant disease and Pseudomonas aeruginosa found in 7 (64%), although the frequency of positive cultures was significantly less (2.8/year) than the DeltaF508 homozygotes (6.1/year, p<0.05). Shwachman scores (median+range) were significantly higher in patients with mild mutations - 94, 74-92 vs. 88, 77-91; p<0.005); there was also a small but significant difference in chest radiograph (Chrispin-Norman) scores (median+range) (mild 5.1, 4-9, vs. severe 5.8, 3-10; p 0.04). There was little difference in lung function in terms of FEV1 (median+range) between the two groups (% predicted, mild 86.5, 68-87 vs. severe 76.0, 65-88; p 0.5)., Conclusions: Most patients with mild variant CF will have bacterial isolates from airway cultures requiring antibiotic therapy three to four times a year. Infection with both S. aureus and P. aeruginosa is common. Anti-staphylococcal prophylaxis for the first two years should be considered.

Background: Acute rejection increases the inflammatory burden of the transplanted organ and predisposes to cardiac allograft vasculopathy (CAV). In this study we aim to determine the magnitude of the association, and to differentiate between the effects of mild vs severe rejection episodes., Methods: Between 1988 and 2003, 489 1-year survivors of heart transplantation underwent 1,435 angiograms. These patients were classified as having no CAV (0% stenosis), mild/moderate CAV (<70%) or severe CAV (>70%). Acute rejection was considered either mild (Grades 1A, 1B and 2 untreated) or moderate/severe (Grade 2 treated on a clinical basis and Grades 3A, 3B and 4). We used multi-state Markov models to examine risk factors for the onset of CAV., Results: Expressed as relative risk, the onset of CAV was significantly increased by donor age (1.26 per 10 years, 95% confidence interval [CI] 1.12 to 1.42), male recipient (1.72, 95% CI 1.01 to 2.94), pre-transplant recipient ischemic disease (1.53, 95% CI 1.14 to 2.06) and cumulative number of moderate/severe rejections (1.10 per episode, 95% CI 1.03 to 1.18). Human leukocyte antigen (HLA) and cytomegalovirus (CMV) matching, donor gender, recipient age, smoking, cumulative CMV infections and mild rejections were not significant risk factors. Estimated annual onset rate of CAV was 11.3% for patients with no moderate/severe rejection, rising to 13.6% for those with two and 18.0% for those with five such rejections., Conclusions: Acute moderate/severe cellular rejection has a cumulative impact on CAV onset, whereas mild, untreated rejection is not associated with CAV.

The use of low levels of oxidants as antifouling agents in coastal and estuarine power station cooling water circuits can give rise to concerns over the likely production of chlorination byproducts (CBPs) including organohalogens, of largely cryptic identity, loading and impact. In order to review the current understanding of the degree of impact involved this paper describes a recent collaborative programme of work on CBPs within the wider context of a number of allied studies on power station cooling water entrainment and discharge effects. Bromoform was the single most important CBP found in coastal power station effluents. Although bromoform was found to accumulate in the liver of the sea bass Dicentrarchus labrax (L.) continuously exposed to a chlorinated effluent stream, no otherwise untoward impact on continuously exposed individuals was discerned. Populations of the common blue mussel Mytilus edulis L., likewise exposed, exhibited two responses: a high degree of genoplasticity and the evolution of stress proteins--although both may have been due to thermal rather than toxic stress. Experiments on plankton that simulated the conditions of entrainment within cooling water systems isolated the influence of oxidant usage, with mortality varying between taxa and life stage. The results suggest a very limited impact of oxidant use and the associated CBPs on receiving waters both in terms of plume toxicity or any more widespread ecotoxicological influence. Instead, it is in combination with applied temperature (DeltaT), pressure and the other stressors involved in entrainment within the power station cooling water circuits themselves that an impact is most marked.

Background: Human embryonic stem (hES) cells are a promising source for transplantation to replace diseased or damaged tissue, but their differentiated progeny express human leucocyte antigens (HLAs) that will probably cause graft rejection. The creation of a bank of HLA-typed hES cells, from which a best match could be selected, would help reduce the likelihood of graft rejection. We investigated how many hES cell lines would be needed to make matching possible in most cases., Methods: The number of hES cell lines needed to achieve varying degrees of HLA match was estimated by use of, as a surrogate for hES-cell donor embryos, blood group and HLA types on a series of 10,000 consecutive UK cadaveric organ donors. The degree of blood group compatibility and HLA matching for a recipient population consisting of 6577 patients registered on the UK kidney transplant waiting list was determined, assuming all donor hES cell lines could provide a transplant for an unlimited number of recipients., Findings: A bank of 150 consecutive donors provided a full match at HLA-A, HLA-B, and HLA-DR for a minority of recipients (<20%); a beneficial match (defined as one HLA-A or one HLA-B mismatch only) or better for 37.9% (range 27.9-47.5); and an HLA-DR match or better for 84.9% (77.5-90.0). Extending the number of donors beyond 150 conferred only a very gradual incremental benefit with respect to HLA matching. A panel of only ten donors homozygous for common HLA types selected from 10,000 donors provided a complete HLA-A, HLA-B and HLA-DR match for 37.7% of recipients, and a beneficial match for 67.4%., Interpretation: Approximately 150 consecutive blood group compatible donors, 100 consecutive blood group O donors, or ten highly selected homozygous donors could provide the maximum practical benefit for HLA matching. The findings from these simulations have practical, political, and ethical implications for the establishment of hES-cell banks.

Alemtuzumab is a powerful lymphocyte depleting antibody currently being evaluated in solid organ transplantation. This paper describes 5-year results of a single center study of alemtuzumab as induction in renal transplantation. Thirty-three renal transplant recipients received 20 mg alemtuzumab on day 0 and 1, followed by half-dose cyclosporin monotherapy (trough concentration 75-125 ng/mL) from day 3. They were compared in a retrospective contemporaneous-controlled manner with 66 kidney transplant recipients transplanted in the same period and center who received conventional immunosuppression with cyclosporin, azathioprine and prednisolone. In the alemtuzumab group 12% of recipients died compared to 17% in the control group (p = 0.48); likewise graft loss was similar in both groups (21% vs. 26%, respectively, p = 0.58). Incidence of acute rejection was also comparable at 5 years (31.5% vs. 33.6%), although the pattern of rejection was different with 14% patients in the alemtuzumab group experiencing rejection over 1 year post-transplant compared to none in the control group. There was no significant difference between groups in terms of infection or serious adverse events. While acknowledging the limitations of a relatively small single-center study, results suggest that alemtuzumab induction allowed satisfactory long-term patient and graft survival equivalent to that seen with standard triple immunosuppression, while avoiding steroid therapy.

The development of a whole-cell fluorescence-based biosensor for nitrate is reported. The sensor is Escherichia coli transformed with a plasmid (pPNARGFP) in which the promoter and regulatory regions of the membrane-bound nitrate reductase narGHJI operon (Pnar) are fused to a gfp gene encoding green fluorescent protein (GFP). Pnar-gfp activity was measured at a range of nitrate concentrations using whole-cell GFP fluorescence. The bioassay conditions have been optimized so that the fluorescence intensity is proportional to the extracellular nitrate concentration. The developed bioassay has established that E. coli (pPNARGFP) can be used for the quantitative determination of nitrate in environmental waters without interference from other electron acceptors, e.g., nitrite, dimethyl sulfoxide, trimethylamine-N-oxide and fumerate, and azide, an inhibitor of redox-active proteins.

Graft-versus-host disease (GVHD) after orthotopic liver transplantation (OLT) is a serious complication with mortality rates over 80%. Two patients with established GVHD after OLT were treated with Basiliximab, a chimeric murine human monoclonal antibody which binds to the alpha-chain of interleukin-2 receptor (IL-2R). Two males, aged 45 and 56 years, presented after OLT with a clinical picture consistent with GVHD. Quantitative measurements of recipient peripheral blood donor lymphocyte chimerism were carried out by flow cytometric analysis, and showed peak chimerism levels of 5% and 8%, respectively. Treatment comprised 3 doses of 1 g methyl prednisolone followed by 2 doses of 20 mg of Basiliximab. In both, treatment resulted in complete disappearance of macro-chimerism in blood. There was resolution of skin rash by day 7; however, diarrhea persisted. White cell scan showed increased uptake in the terminal ileum and small-bowel resection was performed in both patients. One patient is alive and well 36 months after OLT. The other patient had resolution of GVHD, but died of recurrent hepatitis C 1 year after OLT. The combination of immunological and surgical treatment for GVHD following solid organ transplantation has not previously been described.

Background: A number of studies have suggested that the non-antimicrobial actions of macrolide antibiotics may be valuable in treating patients with cystic fibrosis. The use of long-term macrolide antibiotics for the management of CF patients colonised by Pseudomonas aeruginosa and progressive pulmonary disease was introduced into our clinic in 1997. A retrospective study was undertaken to assess of the impact of this therapy., Methods: Twenty patients with progressive pulmonary disease (>10% fall in FEV(1) over 12 months despite optimising conventional therapy) were commenced on Azithromycin, 250 mg daily during a 21-month period. At the time of assessment they had remained on therapy for a mean of 0.9 years. Changes in lung function, weight, body mass index (BMI) and frequency of pulmonary exacerbations were assessed. A group of 20 patients with stable lung function and matched as far as possible for age and sex was identified for comparison., Results: Pulmonary function increased significantly in the Azithromycin group with FEV1% predicted increasing from a mean of 50.2-59.1% (P=0.001) while FVC% predicted increase from 64.5 to 76.1% (P=0.002). There was small but non-significant fall in lung function in the comparison group. Body mass index increased by a mean of 1.1 in the Azithromycin group but remained unchanged in the comparison group. The number of pulmonary exacerbations requiring intravenous antibiotics declined by 48.3% in macrolide treated subjects compared to the pre-treatment period (P<0.025); frequency of exacerbations in the control group was unchanged., Conclusion: Long-term Azithromycin treatment in patients with progressive deterioration in lung function appears to have led to an improvement in pulmonary function, increased body mass index and decreased the frequency of pulmonary exacerbations requiring intravenous antibiotics.

Background: A pilot evaluation to assess the safety and possible benefits of TLC C-53, (prostaglandin E(1) associated with egg phosphatidylcholine liposomes) in acute respiratory exacerbations in children with cystic fibrosis (CF)., Methods: Randomised, double-blind, placebo-controlled study in 20 P. aeruginosa colonised patients. All received intravenous antibiotics. Subjects were given a rising dose of TLC C-53 (0.15-1.8 microg/kg) by 4 x 1-h infusions. Primary outcome measures were sputum IL-6, IL-8 and sputum neutrophil elastase. The rate of decline in lung function was determined at 6 weeks post-therapy as was the interval until the next respiratory exacerbation requiring intravenous antibiotic therapy., Results: Analysis of primary and secondary outcome measures failed to show any significant differences between the two groups, although trends favoured the treated group. Decline in lung function over 6 weeks favoured the TLC C-53 group (FEV(1) mean difference 4.3%, 95% CI=-6.8, 15.4%). Time to next exacerbation also favoured the TLC C-53 group with a mean time to exacerbation for TLC C-53 of 26.0 weeks against 11.9 weeks., Conclusions: A larger multi-centre trial of TLC C-53 as an adjunct to antibiotic therapy in respiratory exacerbations in CF would appear warranted.

We have previously shown that IgG HLA specific antibodies in the sera of highly sensitised patients awaiting renal transplantation can cross-react with swine leukocyte antigens (SLA). In this study we determined the frequency of patient serum IgG HLA specific antibody binding to a porcine lymphocyte panel and the likelihood of locating a cross-match negative pig donor for sensitised patients. Serum samples (n = 82) were obtained from 35 sensitised [current IgG panel reactive antibodies (PRA) > 10%] and seven nonsensitised patients awaiting renal transplantation at Addenbrooke's Hospital, Cambridge, UK. Fifty sera had IgG HLA specific PRA of 11-84%, 20 had IgG PRA of >84% and 12 had 0% PRA (negative controls). Sera were absorbed with porcine erythrocytes to remove xenoreactive natural antibodies and tested for cross-reactive IgG HLA specific antibody binding by flow cytometry against a panel of porcine lymphocytes obtained from 23 human decay accelerating factor (hDAF) transgenic pigs. A total of 1,884 cross-match combinations were tested and 369 (20%) gave a positive porcine lymphocyte cross-match. For sera from sensitised patients with IgG PRA (11-64%), only 6 of 805 (0.75%) cross-match tests were positive. In contrast, for sera from patients with high IgG PRA (>64%), 363 of 805 (45%) cross-match tests were positive (p < 0.0001). There was no difference in the frequency of positive cross-matches between patient sera with IgG PRA 65-84% and highly sensitised patient sera with IgG PRA 85-100% [156/345 (45%) vs. 207/460 (45%)]. This study demonstrates that only patient sera with broadly reactive IgG HLA specific PRA (>64%) cross-react with porcine lymphocytes. If future clinical trials of xenotransplantation are undertaken, it may be of value to select a cross-match-negative pig organ donor for such patients.

Chronic rejection is a leading cause of graft loss in thoracic transplant recipients. Studies on the pathogenesis of chronic rejection have suggested a contributory role for certain cytokines and growth factors. The activity of these mediators is subject to genetic variation if a polymorphism alters expression, or function, of the ligand or its receptor. Here we have asked if certain cytokine and growth factor gene polymorphisms correlate with chronic rejection in recipients of thoracic allografts. In a retrospective analysis of 179 recipients of thoracic organ transplants (128 heart; 36 heart-lung; and 15 lung), polymorphisms in 8 genes that influence the inflammatory process, namely IL1B, IL1R1, IL1RN, IL6, IL10, TNFA, TGFB1 and FCGRIIA, were examined. Genotypic data from recipients who had either died or been re-transplanted as a result of chronic rejection (n = 96) were then compared to those of recipients who had a functioning graft for more than 11 years (n=83). In the heart graft recipients, only those polymorphisms that influenced expression of the IL1 receptor antagonist gene had a significant correlation with graft survival, with homozygosity for the IL1RN*1 allele being associated with rejection. The alternative, less frequent IL1RN alleles emerged as genomic predictors of long-term allograft survival. This association was especially strong when IL1 region haplotypes were considered, particularly when analysis was confined to heart transplant recipients who had had multiple acute rejection episodes (OR>20). This case-control study indicates that gene polymorphisms which influence IL1 bioactivity also influence the progression of chronic rejection in heart grafts.

Background/aims: The tumour necrosis factor (TNF)-2 promoter allele, which elicits elevated expression of TNF-alpha, is in linkage disequilibrium with the extended haplotype HLA-A1-B8-DR3-DQ2. TNF-2 and HLA-DR3 have been implicated in renal and cardiac graft rejection and loss. Cytomegalovirus (CMV) infection has been associated with chronic allograft rejection. We examined the relationship between HLA-DR3, promoter allele TNF-2 and cytomegalovirus in relation to chronic rejection following liver transplantation., Methods: (i) Retrospective analysis of HLA-DR3 was performed in 307 liver transplant recipients and 283 donors. (ii) Prospective analysis of TNF-alpha promoter allele status, HLA-DR3 status and cytomegalovirus infection was assessed in 123 recipients., Results: (i) Retrospective analysis. Recipient HLA-DR3 (relative risk 1.9; 95% C.I. 1.01-3.58) was a risk factor for chronic rejection. (ii) Prospective analysis. Recipient HLA-DR3 was a risk factor for chronic rejection (relative risk 3.41; 95% C.I. 1.66-7.03) which was elevated further by superimposed CMV infection (relative risk 5.01; 95% C.I. 2-12.55). Recipient TNF-2 was associated with chronic rejection (relative risk 2.29; 95% C.I. 0.9-5.83) through linkage to HLA-DR3., Conclusions: Recipient HLA-DR3, TNF-2 status and CMV infection were inter-related risk factors for chronic rejection of liver grafts.

This paper presents a series of 3D statistical models of the cortical sulci. They are built from points located automatically over the sulcal fissures, and corresponded automatically using variants on the iterative closest point algorithm. The models are progressively improved by adding in more and more structural and configural information, and the final results are consistent with findings from other anatomical studies. The models can be used to locate and label anatomical features automatically in 3D MR images of the head, for analysis, visualisation, classification, and normalisation.

A peptide specific antibody (AH1OW1) was raised against an epitope, AH10 (aa 449-463), of the alpha1(IV) chain adjacent to a cleavage site for matrix metalloproteinases (MMP)-2 and -9 within the triple helix of type IV collagen. The antibody only reacted with denatured and reduced preparations of type IV collagen, or with pepsin isolated type IV collagen digested with MMP-2 and MMP-9. The specificity of this antibody for the denatured triple helix was demonstrated by the lack of staining with pre-immune antibody and by pre-incubation of AH1OW1 antibody with excess AH10 peptide epitope. The AH1OWI antibody was used to detect whether proteolysis of type IV collagen occurs in ulcerative colitis, an inflammatory bowel condition often characterised by a large influx of granulocytes and macrophages and an associated tissue destruction. However, no evidence of in situ proteolysis of the basement membrane type IV collagen was observed. Only in the most actively inflamed mucosa was staining with AH1OW1 antibody observed in the mucosal connective tissue. Digestion of frozen sections of bowel with MMP-1, MMP-2, MMP-3 and MMP-9 did not result in the exposure of the AH10 epitope. These data demonstrate the stability of intact type IV collagen and indicate that susceptibility of alpha1(IV) chain to digestion with MMP-2 and MMP-9 may require other proteolytic/denaturing events in the molecule.

Computer-aided mammographic prompting systems require the reliable detection of a variety of signs of cancer. In this paper we concentrate on the detection of spiculated lesions in mammograms. A spiculated lesion is typically characterized by an abnormal pattern of linear structures and a central mass. Statistical models have been developed to describe and detect both these aspects of spiculated lesions. We describe a generic method of representing patterns of linear structures, which relies on the use of factor analysis to separate the systematic and random aspects of a class of patterns. We model the appearance of central masses using local scale-orientation signatures based on recursive median filtering, approximated using principal-component analysis. For lesions of 16 mm and larger the pattern detection technique results in a sensitivity of 80% at 0.014 false positives per image, whilst the mass detection approach results in a sensitivity 80% at 0.23 false positives per image. Simple combination techniques result in an improved sensitivity and specificity close to that required to improve the performance of a radiologist in a prompting environment.

A new approach to the problem of automatic construction of eigenshape models is presented. Eigenshape models have proved to be successful in a variety of medical image analysis problems. However, automatic construction of eigenshape models has proved to be a difficult problem, and in many applications the models are built by hand-a painstaking process. We show that the fundamental problem is a choice of the correct pose and parametrization of each shape in the training set. Eigenshape models are not invariant under reparametrizations and pose transformations of the training shapes. Since there is no a priori correct choice for the pose and parametrization of each shape, their value should be chosen so as to produce a model that is compact and specific. This problem can be solved by finding an objective function that measures these properties and varying the pose and parametrization of each shape to optimize this function. We show that the appropriate objective function is the determinant of the covariance matrix. We go on to show how this objective function can be optimized by a genetic algorithm (GA) and thus give a practical method for building eigenshape models. The models produced are often better than hand-built ones. The advantages of a GA over other choices of optimization method are that no assumptions about the nature of the shapes being modelled is required and that the global minimum of the objective function can, in principle, be found.

The O antigen of the lipopolysaccharide of Burkholderia cepacia serotype E (O2) was shown by a combination of methylation analysis, partial hydrolysis, NMR, and mass spectrometric methods to be a high molecular weight polysaccharide composed of two different trisaccharide repeating units in the ratio 2:1. The major trisaccharide component is composed of two alpha-D-mannopyranosyl and one beta-D-galactopyranosyl residues with the structure, [-->2)-alpha-D-Man p-(1-->2)-alpha-D-Man p-(1-->4)-beta-D-Gal p-(1-->]n The minor trisaccharide component is a D-mannan composed of two alpha- and one beta-D-mannopyranosyl residues with the structure, [-->2)-alpha-D-Man p-(1-->2)-alpha-D-Man p-(1-->3)-beta-D-Man p-(1-->]n