Development of a core outcome set for venous leg ulceration (CoreVen) research evaluations (protocol)

BackgroundA venous leg ulcer is a chronic leg wound caused by poor venous blood circulation in the lower limbs. It is a recurring condition causing pain, malodour, reduced mobility, and depression. Randomised controlled trials evaluating treatments for venous leg ulcers provide important evidence to inform clinical decision-making. However, for findings to be useful, outcomes need to be clinically meaningful, consistently reported across trials, and fully reported. Research has identified the large number of outcomes reported in venous leg ulcer trials, impacting both synthesis of results, and clinical decision-making. To address this, a core outcome set will be developed. A core outcome set is an agreed standardised set of outcomes which should be, as a minimum, measured and reported in all trials which evaluate treatment effectiveness for a given indication. A core outcome set has the potential to reduce research waste, improve the utility of RCTs, reduce reporting bias, facilitate treatment comparisons across different sources of evidence and expedite the production of systematic reviews, meta-analyses and evidence-based clinical guidelines.AimThe aim of this project is to develop a core outcome set for research evaluating the effectiveness of interventions for treating venous leg ulceration.MethodsThrough a scoping review of the literature on venous leg ulceration, we will firstly identify a list of candidate outcome domains (broad categories in relation to what is being measured) from randomised controlled trials and qualitative research, and outcomes (specific methods in relation to what is being measured). In two further stages, we will use the resulting lists of outcome domains and outcomes to design two online surveys. A range of stakeholders will be invited to participate in the surveys and they will be asked to indicate which outcome domains and outcomes are most important and should be considered as core in future research reports.     

Systematic review of methods to diagnose infection in foot ulcers in diabetes.

AIM: To undertake a systematic review of the diagnostic performance of clinical examination, sample acquisition and sample analysis in infected foot ulcers in diabetes. METHODS: Nineteen electronic databases plus other sources were searched. To be included, studies had to fulfil the following criteria: (i) compare a method of clinical assessment, sample collection or sample analysis with a reference standard; (ii) recruit diabetic individuals with foot ulcers; (ii) present 2 x 2 diagnostic data. Studies were critically appraised using a 12-item checklist. RESULTS: Three eligible studies were identified, one each on clinical examination, sample collection and sample analysis. For all three, study groups were heterogeneous with respect to wound type and a small proportion of participants had foot ulcers due to diabetes. No studies identified an optimum reference standard. Other methodological problems included non-blind interpretation of tests and the time lag between index and reference tests. Individual signs or symptoms of infection did not prove to be useful tests when assessed against punch biopsy as the reference standard. The wound swab did not perform well when assessed against tissue biopsy. Semiquantitative analysis of wound swab might be a useful alternative to quantitative analysis. The limitations of these findings and their impact on recommendations from relevant clinical guidelines are discussed. CONCLUSION: Given the importance of this topic, it is surprising that only three eligible studies were identified. It was not possible to describe the optimal methods of diagnosing infection in diabetic patients with foot ulceration from the evidence identified in this systematic review.     

Load transfer characteristics of the wrist. Part II. Perilunate instability

An experimental model with a static positioning frame, pressure-sensitive film (Fuji), and a microcomputer-based video digitizing system, previously developed by the two senior authors, was used in this study to examine the effects of increasing perilunate instability on the load transfer characteristics of the wrist. These effects included a significant dorsal ulnar shift of the scaphoid centroid with increasing perilunate instability together with a less dramatic palmar ulnar shift of the lunate centroid. Overall, the scaphoid contact area was found to decrease as the stage of perilunate instability increased, even in ulnar deviation and/or extension, which in the normal wrist was found to be the positions that had the greatest scaphoid contact area. Average pressures in the high pressure zones were found to significantly increase in wrists with a stage III instability compared with normal wrists. An increase in the intercentroid (scaphoid/lunate) distance was most evident with the wrist in 20 degrees extension, neutral radioulnar deviation, and 90 degrees supination.     

Acute interstitial nephritis: clinical features and response to corticosteroid therapy.

BACKGROUND: Acute interstitial nephritis (AIN) is a recognized cause of reversible acute renal failure characterized by the presence of an interstitial inflammatory cell infiltrate. METHODS: In order to evaluate the clinical characteristics and management of this disorder, we performed a retrospective study of all cases of AIN found by reviewing 2598 native renal biopsies received at our institution over a 12 year period. Presenting clinical, laboratory and histological features were identified, as was clinical outcome with specific regard to corticosteroid therapy response. RESULTS: AIN was found in 2.6% of native biopsies, and 10.3% of all biopsies performed in the setting of acute renal failure during the period analysed (n = 60). The incidence of AIN increased progressively over the period observed from 1 to 4% per annum. AIN was drug related in 92% of cases and appeared to be idiopathic in the remainder. The presenting symptoms included oliguria (51%), arthralgia (45%), fever (30%), rash (21%) and loin pain (21%). Median serum creatinine at presentation was 670 micromol/l [interquartile range (IQR) 431-1031] and 58% of cases required acute renal replacement therapy. Corticosteroid therapy was administered in 60% of cases. Serum creatinine at baseline was similar in the corticosteroid-treated and conservatively managed groups; 700 micromol/l (IQR 449-1031) vs 545 micromol/l (IQR 339-1110) P = 0.4. In this, the largest retrospective series to date, we did not detect a statistically significant difference in outcome, as determined by serum creatinine, between those patients who received corticosteroid therapy and those who did not, at 1, 6 and 12 months following presentation. CONCLUSION: The results of this study do not support the routine administration of corticosteroid therapy in the management of AIN.     

Calciphylaxis – a topical overview

'Calciphylaxis', a calcification syndrome associated with ischaemic cutaneous necrosis, is acquired naturally in humans in disease states. It is a life and limb-threatening complication, usually observed in patients with renal disease and secondary hyperparathyroidism, but known to occur in the absence of renal or parathyroid disease. The reported mortality rate, which ranges from 60-80%, relates to wound infection, sepsis and organ failure. It is a small-vessel vasculopathy, which is estimated to occur in about 4% of haemodialysis patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and eschar may be evident, particularly in the extremities. In addition to the clinical picture, a raised calcium phosphorous product, an elevated parathyroid hormone level, radiographic evidence of vessel and soft-tissue calcification and the finding of mural calcification affecting small arteries and arterioles on histopathology help to confirm the diagnosis of this entity which generally has a poor prognosis. A high index of suspicion and an active multidisciplinary management approach, with rigorous attention to wound care and prevention of sepsis, are vital in the management of these patients. In this overview, we discuss the pathophysiology, clinical features and associations, risk factors, diagnosis and management issues relating to calciphylaxis.     

A new approach to the management of Broviac catheter infection.

Infection continues to be a major complication of the use of indwelling venous catheters. In an attempt to avoid removal of the catheter and to minimize the systemic side-effects of antibiotics, the potential value of in-situ treatment of confirmed Broviac catheter infection was assessed in carefully selected patients attending an oncology unit. Fourteen episodes from 11 children were included in the study. A variety of organisms were encountered. Infective episodes were divided into two categories: (a) those occurring in patients with negative peripheral blood cultures and neutrophil count greater than 1.5 x 10(9) l-1 which were treated only by local instillation of heparinized antibiotic 8-hourly for 7-14 days (N = 8); (b) those occurring simultaneously with positive peripheral blood culture (or peripheral blood culture not performed) regardless of neutrophil count, or infection restricted to Broviac catheter but with a neutrophil count of less than 1.5 x 10(9) l-1; these were treated, with one exception, as above with the addition of systemic antibiotics (N = 6). Treatment was successful in 100% of infective episodes with negative cultures achieved between 5 and 12 days. Catheters remained in use a mean of 118 days following treatment of infection. This approach has obvious advantages but requires careful patient selection and monitoring. It prolongs the catheter life, obviates the need for systemic antibiotics for a local infection, and with appropriate instruction to parents and family practitioner, treatment may be administered on an outpatient basis.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Inhaled latex allergen (Hev b 1)

BACKGROUND: IgE-mediated responses to natural rubber latex allergens have become a major health problem among recognized risk groups. OBJECTIVE: The purpose of this investigation was to measure the amounts of Hevea brasiliensis latex allergen (Hev b 1) inhaled and deposited on surfaces when latex or vinyl gloves were worn and compare the results with the conventional measures (breathing zone samplers) of occupational exposure. METHODS: Hev b 1 exposure was measured by nasal sampling and breathing zone sampling. Latex allergen exposure was generated by having each subject don a pair of powdered latex examination gloves and continuing his or her normal daily activity for 30 minutes. By means of adhesive tape, surface dust samples were collected from the surfaces of gloves, the subject's hands, and work areas. Sampling was performed with subjects wearing no gloves, subjects wearing powdered vinyl gloves, subjects wearing powdered latex gloves, and nearby colleagues wearing latex gloves. All samples were assayed through use of the HALOgen assay (Inhalix, Sydney, Australia) with a Hev b 1-specific mAb. Particles transporting latex allergen were identified by a surrounding immunostain halo, and these were quantified and reported as total numbers of particles inhaled, airborne, or found on surface areas evaluated. RESULTS: Study subjects inhaled 26 times more allergen when powdered latex gloves were worn than under the "no glove" and powdered vinyl glove conditions. During the same period, Hev b 1 particle levels measured in the ambient air through use of the breathing zone sampler increased by 24-fold. The median numbers of particles carrying Hev b 1 allergen per square centimeter on the surface of the hands after the wearing of latex and vinyl gloves were 1964 and 5, respectively. Latex allergen was physically associated both with cornstarch granules and with larger dust particles having a darker, more irregular appearance. CONCLUSION: In a laboratory where gloves are worn for protection, the use of latex gloves resulted in a 26-fold increase in inhaled latex allergen over background levels measured while vinyl gloves were worn as controls. Low levels of latex exposure also occurred when vinyl gloves or no gloves were worn; the reasons for this are under investigation.     

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.