Showing papers by "St Thomas' Hospital published in 2011"

Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report.

Abstract: Chronic spontaneous urticaria, formerly also known as chronic idiopathic urticaria and chronic urticaria (CU), is more common than previously thought. At any time, 0.5-1% of the population suffers from the disease (point prevalence). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1-5 years but is likely to be longer in more severe cases, cases with concurrent angioedema, in combination with physical urticaria or with a positive autologous serum skin test (autoreactivity). Chronic spontaneous urticaria has major detrimental effects on quality of life, with sleep deprivation and psychiatric comorbidity being frequent. It also has a large impact on society in terms of direct and indirect health care costs as well as reduced performance at work and in private life. In the majority of patients, an underlying cause cannot be identified making a causal and/or curative treatment difficult. Nonsedating H₁-antihistamines are the mainstay of symptomatic therapy, but treatment with licensed doses relieves symptoms effectively in < 50% of patients. Although guideline-recommended updosing up to fourfold increases symptom control in many patients, a substantial number of patients have only little benefit from H₁ -antihistamines. Consequently, there is a great need for new therapeutic strategies.

One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.

Abstract: Background—Transcatheter aortic valve implantation was developed to provide a therapeutic option for patients considered to be ineligible for, and to mitigate mortality and morbidity associated with, high-risk surgical aortic valve replacement. Methods and Results—The Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry was designed to assess initial post commercial clinical transcatheter aortic valve implantation results of the Edwards SAPIEN valve in consecutive patients in Europe. Cohort 1 consists of 1038 patients enrolled at 32 centers. One-year outcomes are presented. Patients with the transapical approach (n=575) suffered more comorbidities than transfemoral patients (n=463) with a significantly higher logistic EuroSCORE (29% versus 25.8%; P=0.007). These groups are different; therefore, outcomes cannot be directly compared. Total Kaplan Meier 1-year survival was 76.1% overall, 72.1% for transapical and 81.1% for transfemoral patients, and 73.5% of surviving patients were in New Y...

Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines

Abstract: Previously undiagnosed anaemia is common in elective orthopaedic surgical patients and is associated with increased likelihood of blood transfusion and increased perioperative morbidity and mortality. A standardized approach for the detection, evaluation, and management of anaemia in this setting has been identified as an unmet medical need. A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. A systematic literature review and critical evaluation of the evidence was performed, and recommendations were formulated according to the method proposed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. We recommend that elective orthopaedic surgical patients have a haemoglobin (Hb) level determination 28 days before the scheduled surgical procedure if possible (Grade 1C). We suggest that the patient's target Hb before elective surgery be within the normal range, according to the World Health Organization criteria (Grade 2C). We recommend further laboratory testing to evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C). We recommend that nutritional deficiencies be treated (Grade 1C). We suggest that erythropoiesis-stimulating agents be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A). Anaemia should be viewed as a serious and treatable medical condition, rather than simply an abnormal laboratory value. Implementation of anaemia management in the elective orthopaedic surgery setting will improve patient outcomes.

Genomic inflation factors under polygenic inheritance.

Abstract: Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133,000 individuals.

Genomic inflation factors under polygenic inheritance

Abstract: Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133,000 individuals.

European guidelines on managing adverse effects of medication for ADHD.

Abstract: The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.

Effect of body mass index on IVF treatment outcome: an updated systematic review and meta-analysis

Abstract: There is conflicting evidence regarding the effect of raised body mass index (BMI) on the outcome of assisted reproductive technology In particular, there is insufficient evidence to describe the effect of BMI on live birth rates We carried out a systematic review and meta-analysis of studies to evaluate the effect of raised BMI on treatment outcome following IVF/ICSI treatment Subgroup analysis on overweight and obese patients was performed Literature searches were conducted on MEDLINE, EMBASE and the Web of Science from 1966 to 2010 Thirty-three studies including 47,967 treatment cycles were included Results indicated that women who were overweight or obese (BMI ≥ 25) had significantly lower clinical pregnancy (RR=090, P<00001) and live birth rates (RR=084, P=00002) and significantly higher miscarriage rate (RR=131, P < 00001) compared to women with a BMI < 25 following treatment A subgroup analysis of overweight women (BMI ≥ 25-299) revealed lower clinical pregnancy (RR=091, P=00003) and live birth rates (RR=091, P=001) and higher miscarriage rate (RR=124, P < 000001) compared to women with normal weight (BMI < 25) In conclusion, raised BMI is associated with adverse pregnancy outcome in women undergoing IVF/ICSI treatment, including lower live birth rates This effect is present in overweight as well as obese women

Au(I) /Au(III) catalysis: an alternative approach for C-C oxidative coupling.

Abstract: When reacted in the presence of external oxidants, gold complexes are capable of catalyzing oxidative homo- and cross-coupling reactions involving the formation of new C-C bonds. Over the last few years, several cascade processes have been reported in which coupling is preceded by a gold-mediated aryl C-H functionalization or nucleophilic addition. These reactions combine the unique reactivity of gold with oxidative coupling, enabling the construction of C-C bonds between coupling partners that are not easily accessed using alternative catalysts. In this Concept paper, the development of gold-catalyzed oxidative coupling reactions is discussed focusing on C-C bond-forming reactions of broad synthetic appeal.

Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status.

Abstract: Germline mutations in the FH gene encoding the Krebs cycle enzyme fumarate hydratase predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. FH-deficient cells and tissues accumulate high levels of fumarate, which may act as an oncometabolite and contribute to tumourigenesis. A recently proposed role for fumarate in the covalent modification of cysteine residues to S-(2-succinyl) cysteine (2SC) (termed protein succination) prompted us to assess 2SC levels in our existing models of HLRCC. Herein, using a previously characterized antibody against 2SC, we show that genetic ablation of FH causes high levels of protein succination. We next hypothesized that immunohistochemistry for 2SC would serve as a metabolic biomarker for the in situ detection of FH-deficient tissues. Robust detection of 2SC was observed in Fh1 (murine FH)-deficient renal cysts and in a retrospective series of HLRCC tumours (n = 16) with established FH mutations. Importantly, 2SC was undetectable in normal tissues (n = 200) and tumour types not associated with HLRCC (n = 1342). In a prospective evaluation of cases referred for genetic testing for HLRCC, the presence of 2SC-modified proteins (2SCP) correctly predicted genetic alterations in FH in every case. In two series of unselected type II papillary renal cancer (PRCC), prospectively analysed by 2SCP staining followed by genetic analysis, the biomarker accurately identified previously unsuspected FH mutations (2/33 and 1/36). The investigation of whether metabolites in other tumour types produce protein modification signature(s) that can be assayed using similar strategies will be of interest in future studies of cancer.

A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus

Abstract: AIMS: A blind, randomised, prospective, bilateral study to investigate the efficacy of riboflavin/ultraviolet A corneal collagen cross-linkage to halt the progression of keratoconus. METHODS: 24 patients with early/moderate bilateral keratoconus with recent progression were recruited. One eye was randomly assigned to undergo collagen cross-linkage following epithelial removal with riboflavin 0.1% and ultraviolet A (370 nm at 3 mW/cm(2)). The other remained untreated as a control. The follow-up was 18 months in 22 patients. RESULTS: At 18 months, Orbscan II 3 mm, 5 mm keratometry and simulated astigmatism and cone apex power and wave-front measurements (Keraton Scout), including root mean square, coma and pentafoil showed significant reductions from baseline in treated compared with untreated eyes (p=0.04). In treated eyes at 18 months, the best spectacle-corrected acuity improved (p=0.01), and Orbscan II-simulated keratometry (p<0.001), 3 mm keratometry (p=0.008), simulated astigmatism (p=0.007), cone apex power (p=0.002), root mean square, coma, spherical aberration, secondary astigmatism and pentafoil (p=0.05) decreased from baseline. One treated eye experienced transient recurrent corneal erosions; otherwise there were no complications attributable to the treatment. CONCLUSIONS: Corneal collagen cross-linkage appears to be an effective and safe modality to halt the progression of keratoconus. Improvements in visual and topographic parameters are seen in some eyes.

Synthesis of 64CuII–Bis(dithiocarbamatebisphosphonate) and Its Conjugation with Superparamagnetic Iron Oxide Nanoparticles: In Vivo Evaluation as Dual‐Modality PET–MRI Agent

Abstract: The synergistic combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) is likely to become the next generation of dual-modality scanners in medical imaging. These instruments will provide us with accurate diagnoses thanks to the sensitive and quantifiable signal of PET and the high soft-tissue resolution of MRI. Furthermore, patients will receive less radiation dose and spend less time in the procedure relative to current dual-modality scanners (e.g. PET–computed tomography (CT)). As a consequence, there has been increasing interest recently in the development of dual-modality PET–MRI agents.[1]

Optical Coherence Tomography May Be Used to Predict Visual Acuity in Patients with Macular Edema

Abstract: Purpose. To determine whether the volume of retinal tissue passing between the inner and outer retina in macular edema could be used as an indicator of visual acuity. Methods. Diabetic and uveitic patients with cystoid macular edema (81 subjects, 129 eyes) were recruited. Best corrected logMAR visual acuity and spectral optical coherence tomography (OCT/SLO; OTI, Toronto, ONT, Canada) were performed in all patients. Coronal OCT scans obtained from a cross section of the retina between the plexiform layers were analyzed with a grid of five concentric radii (500, 1000, 1500, 2000, and 2500 μm centered on the fovea). The images were analyzed to determine the amount of retinal tissue present within each ring. A linear regression model was developed to determine the relationship between tissue integrity and logMAR visual acuity. Results. A linear relationship between tissue integrity and VA was demonstrated. The volume of retinal tissue between the plexiform layers in rings 1 and 2 (up to 1000 μm from the foveal center) predicted 80% of visual acuity. By contrast, central macular thickness within the central 1000 μm predicted only 14% of visual acuity. Conclusions. This study showed that the cross-sectional area of retinal tissue between the plexiform layers in cystoid macular edema, as imaged by OCT, is the best indicator of visual function at baseline. Further prospective treatment trials are needed to investigate this parameter as a predictor of visual outcome after intervention.

Slip at Fluid-Solid Interface

Abstract: The “no-slip” is a fundamental assumption and generally-accepted boundary condition in rheology, tribology, and fluid mechanics with strong experimental support. The violations of this condition, however, are widely recognized in many situations, especially in the flow of non-Newtonian fluids. Wall slip could lead to large errors and flow instabilities, such as sharkskin formation and spurt flow, and hence complicates the analysis of fluid systems and introduces serious practical difficulties. In this article, we discuss slip at fluid-solid interface in an attempt to highlight the main issues related to this diverse complex phenomenon and its implications.

Normative values and inter-observer agreement for liquid and solid bolus swallows in upright and supine positions as assessed by esophageal high-resolution manometry.

Abstract: Background High-resolution manometry (HRM) with spatiotemporal representation of pressure data is a recent advance in esophageal measurement. At present, normal values are available for 5 mL water swallows in the supine position. This study provides reference values for liquid and solid bolus swallows in the upright seated and supine positions. Methods A total of 23 asymptomatic volunteers (11M : 12F, age 20–56) underwent HRM (Manoscan 360; Sierra Scientific Instruments) with 5 mL water and 1 cm3 bread swallows in the upright and supine positions. Normal values for primary parameters associated with effective bolus transport [proximal transition zone length (PTZ, assesses peristaltic coordination], contraction front velocity (CFV), distal contractile index (DCI) and integrated relaxation pressure (IRP)] are presented. For each parameter, median values along with the 5–95th percentile range are reported. Inter-observer agreement between independent observers is reported using the intra-class correlation coefficient. Key Results A higher proportion of swallows were peristaltic for liquids than solids in both the upright and supine positions (both P < 0.05). As workload increases with solid bolus and on moving from the upright to the supine position the esophageal contractile response resulted in a shorter PTZ, a slower CFV, and a more vigorous DCI. Also IRP increased during solid bolus transit (all P < 0.01). There was significant agreement between independent observers for HRM parameters. Conclusions & Inferences Normative values for esophageal function for solids as well as liquids and in the ‘physiologic’, upright position will optimize the utility of HRM studies. The high level of inter-observer agreement indicates that these can be applied as reference values in clinical practice.

Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy.

Abstract: Aims Cardiac resynchronization therapy (CRT) has emerged as one of the few effective and safe treatments for heart failure. However, identifying patients that will benefit from CRT remains controversial. The dependence of CRT efficacy on organ and cellular scale mechanisms was investigated in a patient-specific computer model to identify novel patient selection criteria. Methods and results A biophysically based patient-specific coupled electromechanics heart model has been developed which links the cellular and sub-cellular mechanisms which regulate cardiac function to the whole organ function observed clinically before and after CRT. A sensitivity analysis of the model identified lack of length dependence of tension regulation within the sarcomere as a significant contributor to the efficacy of CRT. Further simulation analysis demonstrated that in the whole heart, length-dependent tension development is key not only for the beat-to-beat regulation of stroke volume (Frank–Starling mechanism), but also the homogenization of tension development and strain. Conclusions In individuals with effective Frank–Starling mechanism, the length dependence of tension facilitates the homogenization of stress and strain. This can result in synchronous contraction despite asynchronous electrical activation. In these individuals, synchronizing electrical activation through CRT may have minimal benefit.

Topical interventions for genital lichen sclerosus

Abstract: A B S T R A C T Background Lichen sclerosus is a chronic, inflammatory skin condition that most commonly occurs in adult women, although it may also be seen in men and children. It primarily affects the genital area and around the anus, where it causes persistent itching and soreness. Scarring after inflammation may lead to severe damage by fusion of the vulval lips (labia); narrowing of the vaginal opening; and burying of the clitoris in women and girls, as well as tightening of the foreskin in men and boys, if treatments are not started early. Affected people have an increased risk of genital cancers. Objectives To assess the effects of topical interventions for genital lichen sclerosus and adverse effects reported in included trials. Search methods We searched the following databases up to 16 September 2011: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), LILACS (from 1982), CINAHL(from1981), British Nursing Index andArchive(from1985), ScienceCitation Index Expanded(from1945), BIOSIS Previews (from 1926), Conference Papers Index (from 1982), and Conference Proceedings Citation Index - Science (from 1990). We also searched ongoing trial registries and scanned the bibliographies of included studies, published reviews, and papers that had cited the included studies.

Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis.

Abstract: Objective To compare rates and predictors of pregnancy complications in mothers with systemic lupus erythematosus (SLE) with and without previous nephritis (PN). Methods Retrospective analysis of 107 pregnancies in 83 women with SLE diagnosed prepregnancy. Results Mothers with PN had higher rates of preterm delivery ( 80 mmHg and proteinuria, and prepregnancy estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m2. In women with PN, midtrimester uterine-artery-Doppler notching had low negative predictive value (47%). After 39 months followup, eGFR was stable in women with or without PN. Conclusion In SLE, preterm deliveries are more frequent and preeclampsia occurs earlier in women with PN, but longterm eGFR is preserved.

Antibiotic dosing in critical illness

Abstract: Early and effective antibiotic therapy is essential in the management of infection in critical illness. The loading dose is probably the most important dose and is a function of the volume of distribution of the drug and the desired plasma concentration but independent of renal function. Antibiotics are classified in a number of ways that have implications for dosing. Doses of hydrophilic agents such as β-lactams should be increased in the early stages of sepsis as the extravascular space increases. For lipophilic agents such as macrolides, the inflammatory process is less important, although factors such as obesity will affect dosing. Classification can also be based on pharmacodynamic properties. Concentration-dependent antibiotics such as aminoglycosides should be administered by extended interval regimens, which maximize bactericidal effect, minimize nephrotoxicity and allow time between doses for the post-antibiotic effect. The critical factor for time-dependent agents, such as β-lactams, is time above the MIC. Ideally administration of these agents should be continuous, although vascular access availability can restrict infusion time to between 4 and 6 h, which is probably adequate. As well as antibiotic factors, patient factors such as hepatic and renal failure will affect dosing. Hepatic failure will affect antibiotic metabolism, although it is most important in end-stage failure. Renal failure and support will affect drug elimination. Knowledge of these factors is essential. Patient safety and prevention of unnecessary harm is a weighty consideration in critical illness. To ensure effective treatment and minimize adverse effects, therapy should be reviewed daily and adjusted in the light of changes in patient organ function and underlying pathology.

The pathogenesis, diagnosis, investigation and management of osteoporosis

Abstract: With an increasingly ageing population, osteoporosis and osteoporosis-related fractures is fast becoming an important public health problem placing a considerable economic burden on health service resources. This does not account for the substantial pain, disability and indeed mortality incurred after a fracture, particularly a hip fracture. Osteoporosis is a systemic skeletal disorder which results from an imbalance in bone remodeling. This leads to a reduction in bone strength and increased susceptibility to fracture. It affects up to 1 in 2 women and 1 in 5 men. In the past 2 decades, there have been significant advances in bone biology which have helped in the understanding of the pathogenesis of osteoporosis and have led to improved therapies. In developing strategies for fracture prevention, it is important to identify those individuals with the highest fracture risk who will require pharmacological intervention. Treatment is aimed at fracture prevention and includes modification of general lifestyle factors which have been linked to fractures in epidemiological studies and ensuring optimum calcium and vitamin D intake as adjunct to active anti-fracture therapy. A number of drugs are now approved for the treatment of osteoporosis. This review article will describe the pathogenesis of osteoporosis and focus on the methods currently in use for the identification of patients at high fracture risk and will highlight their usefulness and limitations. The existing anti-fracture pharmacotherapies and those in development will be reviewed. Assessment of their effectiveness including the use of biochemical markers of bone turnover in this clinical context will be reviewed.