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Background: Amifostine is a pharmaceutical agent that is used clinically to counteract the side-effects of chemotherapy and radiotherapy. It acts as a free radical scavenger that protects against harmful DNA cross-linking. The purpose of this study was to determine the effect of amifostine on the development of skin cancer in xeroderma pigmentosum (XP) mice exposed to ultraviolet B radiation (UVB). Methods: Twenty-five XP mice were equally divided into five groups. Group 1 (control) received no amifostine and no UVB exposure. Group 2 also received no amifostine, but was exposed to UVB at a dose of 200 mJ/cm2 every other day. The remaining groups were subjected to the same irradiation, but were given amifostine at a dose of 50 mg/kg (group 3), 100 mg/kg (group 4), or 200 mg/kg (group 5) immediately prior to each exposure. Results: No tumours were seen in the control group. The animals in group 2 (no amifostine) developed squamous cell carcinoma (SCC) at 3.5-4.5 months (mean 3.9 months). Groups 3 and 4 (low- and medium-dose amifostine) developed SCC at 4.0-7.0 months (mean 5.3 months), representing a statistically significant delay in tumour presentation (p = 0.04). An even greater delay was seen in group 5 (highdose amifostine), which developed SCC at 7.0-9.0 months (mean 8.5 months, p < 0.001 versus groups 3 and 4). Ocular keratitis developed in all animals except the unexposed controls and the high-dose treatment group. Conclusion: Treatment with amifostine significantly delays the onset of skin cancer and prevents ocular keratitis in UVB-exposed XP mice. [ABSTRACT FROM AUTHOR]

Importance: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown., Objective: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity., Design, Setting, and Participants: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled., Exposures: Amount and intensity of physical activity., Main Outcomes and Measures: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category., Results: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority., Conclusions and Relevance: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Objective: To determine whether abnormal blood pressure response (ABPR), with or without left ventricular outflow tract obstruction (LVOTO), is associated with adverse heart failure and arrhythmia outcomes in hypertrophic cardiomyopathy (HCM)., Methods: A retrospective, single-center analysis was performed for adult HCM patients who underwent exercise stress testing., Results: Of 589 patients included in the study, 192 (33%) demonstrated ABPR. A similar proportion of patients with ABPR had LVOTO compared to those without ABPR (56% vs 63%, p = 0.11). Patients with ABPR demonstrated lower percent predicted VO2 and METs achieved than those with LVOTO (16.9 ± 6.8 vs 21.6 ± 7.9, p = 0.002 and 5.3 ± 2.4 vs 7.4 ± 3.1, p < 0.001). In a subgroup of 17 patients with LVOTO and ABPR who subsequently underwent successful myectomy, 5 (30%) demonstrated persistent ABPR. 23 patients (3.8%) experienced sudden cardiac death or ventricular arrhythmias, which were not associated with ABPR, regardless of age group. In multivariable analysis, syncope (p = 0.04), left ventricular hypertrophy (p = 0.02) and left atrial diameter (p = 0.006) were significantly associated with the composite outcome of sudden death or severe ventricular arrhythmia, whereas ABPR was not (p = 0.38). In contrast, ABPR was associated with subsequent heart failure hospitalization (p = 0.002), regardless of presence or absence of LVOTO (p = 0.04, p = 0.02)., Conclusions: ABPR is associated with reduced functional capacity in HCM regardless of the presence of LVOTO but is not associated with adverse arrhythmia outcomes. Patients with ABPR have a higher incidence of subsequent heart failure hospitalization., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges. These bridges fail to decatenate, and at mitotic exit form micronuclei that are indicative of genome instability. We also describe the cell cycle-dependent behaviour for two major isoforms of USP15, which differ by a short serine-rich insertion that is retained in isoform-1 but not in isoform-2. Although USP15 is predominantly cytoplasmic in interphase, we show that both isoforms move into the nucleus at prophase, but that isoform-1 is phosphorylated on its unique S229 residue at mitotic entry. The micronuclei phenotype we observe on USP15 depletion can be rescued by either USP15 isoform and requires USP15 catalytic activity. Importantly, however, an S229D phospho-mimetic mutant of USP15 isoform-1 cannot rescue either the micronuclei phenotype, or accumulation of TOP2A. Thus, S229 phosphorylation selectively abrogates this role of USP15 in maintaining genome integrity in an isoform-specific manner. Finally, we show that USP15 isoform-1 is preferentially upregulated in a panel of non-small cell lung cancer cell lines, and propose that isoform imbalance may contribute to genome instability in cancer. Our data provide the first example of isoform-specific deubiquitylase phospho-regulation and reveal a novel role for USP15 in guarding genome integrity.

PurposeHypertrophic cardiomyopathy (HCM) is considered a hereditary autosomal dominant condition, but genetic testing is positive in only half of patients. In patients with negative genetic tests, the inheritance pattern and utility of family screening are unclear.MethodsSubjects with HCM were prospectively enrolled in a registry. A survey at a median follow-up of 4 years determined the yield of family screening.ResultsThe outcome of cardiac screening on 267 family members was reported by 120 survey respondents. Subjects with positive genetic test or family history (n=74, 62%) reported an HCM diagnosis in 34 of 203 first-degree relatives who were screened (17%). Affected family members were diagnosed at a mean age of 30-39 years, and 22 of 34 experienced HCM-related adverse events (65%). Gene test-negative subjects with no prior family history of HCM (n=46, 38%) reported an HCM diagnosis in only 2 of 64 first-degree relatives who were screened (3%, p<0.001). These two individuals were diagnosed at age >40 years without HCM-related adverse events.ConclusionHypertrophic cardiomyopathy is a heterogeneous disorder, only half of which tracks with a Mendelian inheritance pattern. Negative genetic testing and family history indicates a more complex genetic basis corresponding to low risk for family members.

Objective: To investigate the clinical effectiveness of silver nitrate (95%) for the treatment of verruca pedis comparing professional and self-application treatments., Methods: A single-centre, two-armed randomized evaluation was conducted at a University podiatry clinic. A total of 113 participants (101 analysed) with verruca pedis were included. Participants were randomized to either a clinical group, where silver nitrate was applied by a healthcare professional or a home group, where silver nitrate was self-applied. The main outcome measure was post-treatment pain, controlling for pre-treatment pain, and resolution of the verruca. Secondary outcome measures were participant satisfaction, partial reduction in the verruca and ease of use of the product., Key Findings: The study showed no significant difference between home treatment and clinically applied treatment for the treatment of verruca pedis in either primary outcome; however, a substantive difference in resolution between groups was recorded, with 34.0% full resolution and 26.4% partial resolution in the clinical treatment group, and 18.8% full resolution and 37.5% partial resolution in the home treatment group. Participants widely reported general ease of use of the product. All participants reported a reduction in pain as a result of the intervention., Conclusion: Silver nitrate has been shown to be a safe and effective treatment for verruca pedis, with equal success rates when compared between home and clinical applications., (© 2017 Royal Pharmaceutical Society.)

Introduction: Chronic wounds remain a major clinical challenge. Human cryopreserved viable amniotic membrane (hCVAM) is among the most successful therapies, but the mechanisms of action remain loosely defined. Because proper regulation of macrophage behavior is critical for wound healing with biomaterial therapies, we hypothesized that hCVAM would positively regulate macrophage behavior in vitro , and that soluble factors released from the hCVAM would be important for this effect., Materials and Methods: Primary human pro-inflammatory (M1) macrophages were seeded directly onto intact hCVAM or cultured in separation via transwell inserts (Soluble Factors) in the presence of pro-inflammatory stimuli (interferon- γ and lipopolysaccharide) to simulate the chronic wound environment. Macrophages were characterized after 1 and 6 days using multiplex gene expression analysis of 37 macrophage phenotype- and angiogenesis-related genes via NanoString™, and protein content from conditioned media collected at days 1, 3 and 6 was analyzed via enzyme linked immunosorbent assays., Results and Discussion: Gene expression analysis showed that Soluble Factors promoted significant upregulation of pro-inflammatory marker IL1B on day 1 yet downregulation of TNF on day 6 compared to the M1 macrophage control. In contrast, intact hCVAM, which includes both extracellular matrix, viable cells, and soluble factors, promoted downregulation of pro-inflammatory markers TNF , CCL5 and CCR7 on day 1 and endothelial receptor TIE1 on day 6, and upregulation of the anti-inflammatory marker IL10 on day 6 compared to the M1 Control. Other genes related to inflammation and angiogenesis ( MMP9 , VEGF , SPP1 , TGFB1 , etc .) were differentially regulated between the Soluble Factors and intact hCVAM groups at both time points, though they were not expressed at significantly different levels compared to the M1 Control. Interestingly, Soluble Factors promoted increased secretion of the proinflammatory cytokine tumor necrosis factor- α (TNF- α ), while direct contact with hCVAM inhibited secretion of TNF, relative to the M1 Control. Both Soluble Factors and intact hCVAM inhibited secretion of MMP9 and VEGF, pro-inflammatory proteins that are critical for angiogenesis and remodeling, compared to the M1 Control, with intact hCVAM having a stronger effect., Conclusions: In a simulated pro-inflammatory environment, intact hCVAM has distinct anti-inflammatory effects on primary human macrophages, and direct macrophage contact with intact hCVAM is required for these effects. These findings are important for the design of next generation immunomodulatory biomaterials for wound repair and regenerative medicine that may include living cells, soluble factors, or a controlled drug delivery system., Competing Interests: CONFLICT OF INTEREST KLS discloses a potential conflict of interest: this study was funded in large part by Osiris Therapeutics, Inc. The study was designed by KLS and CEW, with some input from Osiris with respect to the potential impact of different experiments. Employees from Osiris had no part in interpretation of the study’s results. CEW, TY, MC, and WD declare that they have no conflicts of interest.

Importance: Formulating exercise recommendations for patients with hypertrophic cardiomyopathy is challenging because of concern about triggering ventricular arrhythmias and because a clinical benefit has not been previously established in this population., Objective: To determine whether moderate-intensity exercise training improves exercise capacity in adults with hypertrophic cardiomyopathy., Design, Setting, and Participants: A randomized clinical trial involving 136 patients with hypertrophic cardiomyopathy was conducted between April 2010 and October 2015 at 2 academic medical centers in the United States (University of Michigan Health System and Stanford University Medical Center). Date of last follow-up was November 2016., Interventions: Participants were randomly assigned to 16 weeks of moderate-intensity exercise training (n = 67) or usual activity (n = 69)., Main Outcomes and Measures: The primary outcome measure was change in peak oxygen consumption from baseline to 16 weeks., Results: Among the 136 randomized participants (mean age, 50.4 [SD, 13.3] years; 42% women), 113 (83%) completed the study. At 16 weeks, the change in mean peak oxygen consumption was +1.35 (95% CI, 0.50 to 2.21) mL/kg/min among participants in the exercise training group and +0.08 (95% CI, -0.62 to 0.79) mL/kg/min among participants in the usual-activity group (between-group difference, 1.27 [95% CI, 0.17 to 2.37]; P = .02). There were no occurrences of sustained ventricular arrhythmia, sudden cardiac arrest, appropriate defibrillator shock, or death in either group., Conclusions and Relevance: In this preliminary study involving patients with hypertrophic cardiomyopathy, moderate-intensity exercise compared with usual activity resulted in a statistically significant but small increase in exercise capacity at 16 weeks. Further research is needed to understand the clinical importance of this finding in patients with hypertrophic cardiomyopathy, as well as the long-term safety of exercise at moderate and higher levels of intensity., Trial Registration: clinicaltrials.gov Identifier: NCT01127061.

Phenotypic plasticity allows organisms to change their phenotype in response to shifts in the environment. While a central topic in current discussions of evolutionary potential, a comprehensive understanding of the genetic underpinnings of plasticity is lacking in systems undergoing adaptive diversification. Here, we investigate the genetic basis of phenotypic plasticity in a textbook adaptive radiation, Lake Malawi cichlid fishes. Specifically, we crossed two divergent species to generate an F 3 hybrid mapping population. At early juvenile stages, hybrid families were split and reared in alternate foraging environments that mimicked benthic/scraping or limnetic/sucking modes of feeding. These alternate treatments produced a variation in morphology that was broadly similar to the major axis of divergence among Malawi cichlids, providing support for the flexible stem theory of adaptive radiation. Next, we found that the genetic architecture of several morphological traits was highly sensitive to the environment. In particular, of 22 significant quantitative trait loci (QTL), only one was shared between the environments. In addition, we identified QTL acting across environments with alternate alleles being differentially sensitive to the environment. Thus, our data suggest that while plasticity is largely determined by loci specific to a given environment, it may also be influenced by loci operating across environments. Finally, our mapping data provide evidence for the evolution of plasticity via genetic assimilation at an important regulatory locus, ptch1. In all, our data address long-standing discussions about the genetic basis and evolution of plasticity. They also underscore the importance of the environment in affecting developmental outcomes, genetic architectures, morphological diversity and evolutionary potential., (© 2016 John Wiley & Sons Ltd.)

Background: Trials using inadequate levels of blinding may report larger effect sizes than blinded studies. It has been suggested that blinded outcome assessment in open trials may in some cases be undertaken by assessments of photographs. The aim of this paper is to explore the effect of using different methods to assess the primary outcome in the EVerT (Effective Verruca Treatments) trial. It also aims to give an overview of the experiences of using digital photographs within the trial., Methods: We undertook a secondary analysis to explore the effect of using three different methods to assess the primary outcome in the EVerT trial: assessment of digital photographs by blinded healthcare professionals; blinded healthcare professional assessment at the recruiting site and patient self-report. The verruca clearance rates were calculated using the three different methods of assessment. A Cohen's kappa measure of inter-rater agreement was used to assess the agreement between the methods. We also investigated the experiences of healthcare professionals using digital photographs within the trial., Results: Digital photographs for 189 out of 240 (79 %) patients in the trial were received for outcome assessment. Of the 189 photographs, 30 (16 %) were uninterpretable. The overall verruca clearance rates were 21 % (43/202,) using the unblinded patient self-reported outcome, 6 % (9/159,) using blinded assessment of digital photographs and 14 % (30/210,) using blinded outcome assessment at the site., Conclusions: Despite differences in the clearance rates found using different methods of outcome assessment, this did not change the original conclusion of the trial, that there is no evidence of a difference in effectiveness between cryotherapy and salicylic acid. Future trials using digital photographs should consider individual training needs at sites and have a backup method of assessment agreed a priori., Trial Registration: ISRCTN Registry ISRCTN18994246.

This study assesses the effect of salicylic acid plasters on the time to resolution of 324 corns experienced by 201 participants taking part in a randomized controlled trial. While the rate of corn resolution was substantively higher in the treatment group than in the control group, treatment was found to be not significantly related to time to corn recurrence when analyzed over the full 12-month follow-up period. Parametric survival analysis modeling of interval-censored data and incorporating patient-specific frailty terms was utilized, to model correlation of corns within patients (hazard ratio [HR], 1.189; 95% confidence interval [CI], 0.780-1.813; P = 0.422). Median resolution times were 10.0 months for corns in the treatment group and 13.4 months for corns in the control group. Controlling for treatment, corn type was found to be related to resolution time, with dorsal/interdigital (ID) corns showing better resolution than plantar corns (HR, 1.670; 95% CI, 1.061-2.630; P = 0.027). Median resolution times were 5.9 months for dorsal/ID corns and 14.9 months for plantar corns. Secondary measures relating to quality of life (QoL) and foot-related disability, using the EQ-5D questionnaire and the Manchester Foot Pain and Disability Index (MFPDI), were also assessed at the patient level in multivariate models. Treatment was not significantly related to any of these measures over the whole period of analysis. However, a trend analysis revealed a quadratic trend in QoL and MFPDI scores, arising from a substantive initial improvement between baseline and 3 months, followed by a gradual decrease between 3 and 12 months., (© 2015 Japanese Dermatological Association.)

Disconnection of a cell from its epithelial neighbours and the formation of a mesenchymal phenotype are associated with profound changes in the distribution of cellular components and the formation of new cellular polarity. We observed a dramatic redistribution of inositol trisphosphate receptors (IP3Rs) and stromal interaction molecule 1 (STIM1)-competent endoplasmic reticulum-plasma membrane junctions (ER-PM junctions) when pancreatic ductal adenocarcinoma (PDAC) cells disconnect from their neighbours and undergo individual migration. In cellular monolayers IP3Rs are juxtaposed with tight junctions. When individual cells migrate away from their neighbours IP3Rs preferentially accumulate at the leading edge where they surround focal adhesions. Uncaging of inositol trisphosphate (IP3) resulted in prominent accumulation of paxillin in focal adhesions, highlighting important functional implications of the observed novel structural relationships. ER-PM junctions and STIM1 proteins also migrate to the leading edge and position closely behind the IP3Rs, creating a stratified distribution of Ca(2+) signalling complexes in this region. Importantly, migration of PDAC cells was strongly suppressed by selective inhibition of IP3Rs and store-operated Ca(2+) entry (SOCE), indicating that these mechanisms are functionally required for migration., (© 2016 Authors.)

Immunization is the best way to prevent seasonal epidemics and pandemics of influenza. There are two kinds of influenza vaccines available in the United States: an inactivated vaccine (TIV) and an attenuated vaccine; however, only TIV is approved for immunization of the elderly population. While the aged population has the highest rate of influenza vaccination, the protective efficacy is low as evidenced by elderly individuals having the highest mortality associated with influenza. Recently, we reported that an adjuvant derived from the helminth parasite Onchocerca volvulus, named O. volvulus activation-associated secreted protein-1 (Ov-ASP-1), can significantly enhance the protective efficacy of an inactivated vaccine (TIV) in young adult mice. In the current study, we examined whether this recombinant Ov-ASP-1 (rOv-ASP-1) can enhance the efficacy of TIV in aged mice as well. While primary immunization with TIV alone produced only a low level of influenza-specific antibodies (total IgG, IgG1, and IgG2c) in aged mice, the antibody levels were significantly increased after immunization with TIV+rOv-ASP-1. More importantly, the level of the total IgG in aged mice administered TIV+rOv-ASP-1 was comparable to that of young adult mice immunized with TIV alone. Co-administration of rOv-ASP-1 induced a low level of cross-reactive antibody and enhanced the protective efficacy of TIV in aged mice, reflected by significantly increased survival after challenge with a heterologous influenza virus. rOv-ASP-1 was also superior to the conventional adjuvant alum in inducing specific IgG after TIV immunization in aged mice, and in conferring protection after challenge. These results demonstrate that rOv-ASP-1 may serve as a potential adjuvant for influenza vaccine to improve the efficacy of protection in the elderly., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Corns are a common foot problem affecting a large proportion of the population. This study describes the characteristics of corns experienced by 201 participants taking part in a randomised controlled trial to investigate associations between demographic and corn parameters on pain, foot related disability and quality of life (QoL)., Methods: Pain from the main (index) corn was measured using a visual analogue scale (VAS); foot related disability was assessed with the Foot Disability Questionnaire (now known as the Manchester Foot Pain and Disability Index) and quality of life was recorded with the EQ-5D questionnaire. The effect of demographic and corn parameters on the pain and quality of life outcomes was assessed with analysis of variance (ANOVA) methods. The effect of the same factors on a linear combination of the foot-related disability outcome measures was assessed using multivariate ANOVA methods. Pain was also tested for its mediating properties on the causal pathway between the independent variables and quality of life., Results: The mean pain score was 5.29 points on a 10 cm VAS, with females reporting substantively higher pain levels than males. Age affected foot-related disability, with lower levels on all domains of the MFPDI reported in older participants; each year of advancing age was associated with falls of: 0.009 points on the Concern about Appearance (CA) domain; 0.047 points on the Functional Limitation (FL) domain and 0.048 points on the Pain Intensity (PI) domain. Sex and corn type also affected disability, with higher scores reported by females and participants with plantar corns., Conclusions: The effect of pain was shown to mediate the relationship between sex and foot-related disability. The presence of plantar corns has a more detrimental effect on QoL than dorsal/inter-digital corns., Trial Registration: ISRCTN 13166839.

Sleep apnea affects more than half of patients with acute ischemic stroke and is associated with poor stroke outcome. This pilot study assessed the feasibility of a randomized, sham-controlled continuous positive airway pressure (CPAP) trial in subjects with acute ischemic stroke. Subjects identified with sleep apnea based on an apnea-hypopnea index≥5 on overnight polysomnography or portable respiratory monitoring within 7 days of onset of stroke symptoms were randomized to receive active or sham CPAP for a 3-month period. Objective usage was ascertained by compliance data cards. Subjects, treating physicians, and outcome assessors were masked to intervention allocation. Among 87 subjects who provided consent, 74 were able to complete sleep apnea screening, 54 (73%) of whom had sleep apnea. Thirty-two subjects agreed to randomization. Of the 15 subjects who commenced active titration, 11 (73%) took the device home, and 8 (53%) completed the 3-month follow-up. Of the 17 subjects who commenced sham titration, 11 (65%) took the sham device home and completed the 3-month follow-up. The median cumulative usage hours over the 90 days were similar in the active group (53 hours; interquartile range, 22-173 hours) and the sham group (74 hours; interquartile range, 17-94 hours), and blinding to subject condition was successfully maintained. This first-ever randomized, sham-controlled trial of CPAP in patients with recent stroke and sleep apnea demonstrates that sham treatment can be an effective placebo., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Corns are a common foot problem and surveys have indicated that between 14-48% of people suffer from them. Many of these will seek podiatry treatment, however there is little evidence to indicate which current treatments provide long term resolution. This study compared 'usual' treatment (enucleation with a scalpel) with the application of 40% salicylic acid plasters to corns to investigate which is the most effective in terms of clinical, economic and patient-centred outcomes., Methods: A parallel-group randomised controlled trial was carried out in two centres where adults who presented with one or more corns and who met the inclusion criteria were allocated to either 'usual' scalpel debridement or corn plaster treatment. All participants had measurements of corn size, pain using a 100 mm visual analogue scale (VAS) and health-related quality of life (EQ-5D) measures by an independent podiatrist, blind to treatment allocation at baseline, 3, 6, 9 and 12 months., Results: 202 participants were randomised to receive scalpel debridement or corn plaster treatment (101 in each group). At 3 months 34% (32/95) of corns had completely resolved in the corn plaster group compared with 21% (20/94) in the scalpel group (p = 0.044), and 83% (79/95) had reduced in size in the corn plaster group compared with 56% (53/94) in the scalpel group (p < 0.001). At 12 months, time to corn recurrence was longer in the corn plaster group (p < 0.001). Pain from the corns was significantly lower in the corn plaster group at 3 months (p < 0.001) and EQ-5D scores changed (improved), from baseline, by 0.09 (SD ±0.31) and 0.01 (SD ±0.25) points in the corn plaster and scalpel groups respectively (p = 0.056). By month 12, EQ-5D scores had changed by 0.12 and -0.05 in the corn plaster and scalpel groups respectively (p = 0.005). The EQ-5D, VAS scores and the four domains of the Foot Disability Scale were similar in both groups at 3 and 12 months. The economic analysis indicated that corn plasters were a cost effective intervention., Conclusions: The use of corn plasters was associated with a higher proportion of resolved corns, a prolonged time to corn recurrence, less pain and reduced corn size over the first 6 months in comparison with 'usual' scalpel treatment and this intervention was cost effective. Used under supervision of a podiatrist on appropriate patients, corn plasters offer an effective alternative to scalpel debridement.

Background: Randomised controlled trials are widely accepted as the gold standard method to evaluate medical interventions, but they are still open to bias. One such bias is the effect of patient's preference on outcome measures. The aims of this study were to examine whether patients' treatment preference affected clearance of plantar warts and explore whether there were any associations between patients' treatment preference and baseline variables in the EverT trial., Methods: Two hundred and forty patients were recruited from University podiatry schools, NHS podiatry clinics and primary care. Patients were aged 12 years and over and had at least one plantar wart which was suitable for treatment with salicylic acid and cryotherapy. Patients were asked their treatment preference prior to randomisation. The Kruskal-Wallis test was performed to test the association between preference group and continuous baseline variables. The Fisher's exact test was performed to test the association between preference group and categorical baseline variables. A logistic regression analysis was undertaken with verruca clearance (yes or no) as the dependent variable and treatment, age, type of verruca, previous treatment, treatment preference as independent variables. Two analyses were undertaken, one using the health professional reported outcome and one using the patient's self reported outcomes. Data on whether the patient found it necessary to stop the treatment to which they had been allocated and whether they started another treatment were summarised by treatment group., Results: Pre-randomisation preferences were: 10% for salicylic acid; 42% for cryotherapy and 48% no treatment preference. There was no evidence of an association between treatment preference group and either patient (p=0.95) or healthcare professional (p=0.46) reported verruca clearance rates. There was no evidence of an association between preference group and any of the baseline variables except gender, with more females expressing a preference for salicylic acid (p=0.004). There was no evidence that the number of times salicylic acid was applied was different between the preference groups at one week (p=0.89) or at three weeks (p=0.24). Similarly, for the number of clinic visits for cryotherapy (p=0.71) CONCLUSIONS: This secondary analysis showed no evidence to suggest that patients' baseline preferences affected verruca clearance rates or adherence with the treatment., Trial Registration: Current Controlled Trials ISRCTN18994246 and National Research Register N0484189151.

This article is centred around the similarities and highlights some differences between a sports injury compared with any other injury profile. The authors use a musculoskeletal assessment, diagnosis and management of an injury based on a particular case study. The intention is to highlight how problems may be masqueraded in the history and perception of the injured athlete and how this perception may have complicated the injury and the rehabilitation process. This issue generates a renewed awareness for all primary care nurses and health practitioners who may be involved in treatment pathways for associated injuries related to sports medicine problems. The article gives an insight into peroneal dislocation/subluxation, but primarily focuses on peroneal tendonitis/tendonosis. The management of the injury briefly touches on the associated benefits (and risks) of barefoot running and its role in the prevention of sporting injuries. This article illustrates how the frustration of a chronic injury can lead to the athlete making ill-informed decisions and highlights the need for a thorough assessment and an evidence-based management plan that is negotiated with the athlete.

Using the case study of an 18-year-old track athlete with a chronic Achilles tendinopathy, this article identifies risk factors associated with training for major athletic events, such as the forthcoming Olympic Games, and presents evidence for adopting a multidisciplinary approach to the treatment and management of athletic injury, addressing the physical aspects of the injury, as well as the psychological needs of the athlete. The athlete's GP and practice nurse, as well as a podiatrist and sport psychologist, are all involved in providing an accurate clinical diagnosis, effective physical intervention, and psychological skills training to address emotional issues and encourage adherence to the rehabilitation programme. Nurses, in both secondary and primary care, can play a crucial role; in this case, the practice nurse recognised the adverse impact that the injury was having on the athlete's emotional wellbeing before making a referral to a trained sport psychologist.

Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the α2β1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the α2β1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the α2β1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express α2β1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.

Denervation of oropharyngeal muscles in obstructive sleep apnea (OSA) has been suggested by needle electromyography (EMG) and muscle biopsy, but little is known about oropharyngeal nerve conduction abnormalities in OSA. We sought to compare hypoglossal nerve conduction studies in patients with and without OSA. Unilateral hypoglossal nerve conduction studies were performed on 20 subjects with OSA and 20 age-matched controls using standard techniques. Median age was 48 years in OSA subjects and 47 years in controls. Hypoglossal compound muscle action potential (CMAP) amplitudes were significantly reduced (P = 0.01, Wilcoxon signed-rank test), but prolongation of latencies in OSA subjects did not reach significance in comparison to those of controls. Among a subgroup of subjects without polyneuropathy (15 pairs), reduced amplitudes in OSA subjects retained borderline significance (P = 0.05). Hypoglossal nerve conduction abnormalities may distinguish patients with OSA from controls. These abnormalities could potentially contribute to, or arise from, OSA.