Merkel cell polyomavirus-specific CD8 T cells in Merkel cell carcinoma: T cell receptor diversity & novel immune therapies

Thesis (Ph.D.)--University of Washington, 2016-06

Participation in the RACS sentinel node biopsy versus axillary clearance trial

Background: The Royal Australasian College of Surgeons (RACS) SNAC trial is a randomized controlled trial of sentinel node biopsy (SNB) versus axillary clearance (AC). It opened in May 2001 and is recruiting rapidly with good acceptance by consumers. Methods: A study of eligibility and treatment choices was conducted between November 2001 and September 2002 for women presenting with early breast cancer to 10 centres participating in the trial. Results: More than half of the 622 women (54%) were ineligible for trial entry because they had large (> 3 cm) or multicentric cancers. Participation was offered to 92% of eligible women and was taken up by 63%. The commonest reason for not participating was the desire to choose treatment rather than have it randomly allocated. Despite this there is a great acceptance of clinical trials because very few women (4% of those eligible) gave 'lack of interest in clinical trials' as the reason for non-participation. Few women who declined trial participation chose to have SNB alone (4.5% of those eligible). Conclusion: Sentinel node biopsy may become the standard of care for managing small breast cancers, but a significant number of patients will still require or choose axillary dissection. Results from large randomized trials are needed to determine the relative benefits and harms of SNB compared with AC. Surgeons must carefully discuss options for management with their patients.

Photodynamic therapy with verteporfin for juxtafoveal choroidal neovascularisation secondary to pathological myopia

The treatment of choroidal neovascularisation (CNV) secondary to pathological myopia has presented a number of problems to ophthalmologists over the years, but the advent of photodynamic therapy (PDT) with verteporfin has changed how we manage these patients. Until PDT became available, the use of laser photocoagulation for extra and juxtafoveal lesions had been shown to be effective in the short term in preventing loss of vision, although the risk of regrowth of CNV and undertreatment were well recognised. However, even in apparent successful cases of photocoagulation, laser scar enlargement and creepage into the fovea in the mid-to-long term often occurred with resulting loss of central vision.1 Other options for treatment were very limited with little evidence that other modalities such as transpupillary thermotherapy or submacular surgery and macular transplantation surgery would be successful in highly myopic eyes. The evidence for the role of PDT and verteporfin CNV secondary to pathological myopia comes from the verteporfin in photodynamic therapy (VIP) study that has shown how effective this treatment is in eyes with subfoveal CNV.2, 3 Now in this publication, Lam et al4 from Hong Kong have shown that PDT is also effective in juxtafoveal CNV, with high myopia. They performed a small prospective study of 11 patients of mean age 44.8 years, with 12 months of follow-up. They found that there was a mean improvement of 1.8 lines of LogMAR best-corrected visual acuity (BCVA) at 12 months, with a mean number of 2.3 PDT treatments. The most rapid improvement occurred within the first 3 months of treatment and by 12 months none of the patients had suffered a deterioration in BCVA from baseline. There were no cases of adverse effects from the infusion or laser treatment. For ophthalmologists dealing with patients with CNV secondary to causes other than AMD, this is further evidence of the effectiveness of PDT with verteporfin in maintaining vision. These patients are likely to be younger than those with AMD and are likely to be in active employment and supporting families, and clearly the preservation of best vision possible is imperative in this group. It is therefore encouraging for ophthalmologists in the United Kingdom that the verteporfin in PDT Cohort Study (VPDT Study) includes the ability to treat patients with subfoveal CNV secondary to high myopia if they fulfill National Institute of Clinical Excellence guidelines, and will allow representations to be made on an individual basis for treatment of juxtafoveal lesions.5 For those ophthalmologists used to juggling increased patient expectations with scarce NHS resources, this is promising news and will allow us to offer a better standard of care to our patients.

Cardiovascular risk factors in Turkish immigrants with type 2 diabetes living in the Netherlands

The cross sectional study investigated the association of tobacco smoke, vitamin D status, anthropometric parameters, and kidney function in Turkish immigrants with type 2 diabetes (T2D) living in the Netherlands. Study sample included a total of 110 participants aged 30 years and older (males= 46; females= 64). Serum cotinine, a biomarker for smoke exposure, was measured with a solid-phase competitive chemiluminescent immunoassay. Serum 25-hydroxyvitamin D [25(OH)D] was determined by electrochemiluminescence immunoassay (ECLIA). Measures of obesity including: body weight, body mass index (BMI), waist circumference (WC), and hip circumference (HC) were measured. Waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were calculated. Urine albumin was measured by immunoturbidimetric assay. Urine creatinine was determined using the Jaffe method. All statistical analyses were performed using SPSS, version 19.0 (SPSS Inc., Chicago, IL, USA). Independent samples t-test, chi-squared tests, multiple linear regression and logistic regression analysis were used. Cotinine levels were positively associated with cholesterol to HDL ratio and atherosclerosis-index. Serum 25(OH)D levels were negatively associated with diastolic blood pressure. Gender-specific associations between anthropometric measures and high sensitivity C-reactive protein (hs-CRP) levels were observed. Hs-CRP was positively associated with WC and WHR in males and WHtR in females. Microalbuminuria (MAU), as determined by albumin-to-creatinine ratio, was present in 21% of the Turkish immigrants with T2D. Participants with hypertension were 6.58 times more likely (adjusted odds ratio) to have positive MAU as compared to normotensive participants. Our findings indicate that serum cotinine, 25(OH)D, hs-CRP, and MAU may be assessed as a standard of care for T2D management in the Turkish immigrant population. Further research should be conducted following cohorts to determine the effects of these biomarkers on CVD morbidity and mortality.

Medical advice and diabetes self-management reported by Mexican-American, Black- and White-non-Hispanic adults across the United States

Background Diabetes has reached epidemic proportions in the United States, particularly among minorities, and if improperly managed can lead to medical complications and death. Healthcare providers play vital roles in communicating standards of care, which include guidance on diabetes self-management. The background of the client may play a role in the patient-provider communication process. The aim of this study was to determine the association between medical advice and diabetes self care management behaviors for a nationally representative sample of adults with diabetes. Moreover, we sought to establish whether or not race/ethnicity was a modifier for reported medical advice received and diabetes self-management behaviors. Methods We analyzed data from 654 adults aged 21 years and over with diagnosed diabetes [130 Mexican-Americans; 224 Black non-Hispanics; and, 300 White non-Hispanics] and an additional 161 with 'undiagnosed diabetes' [N = 815(171 MA, 281 BNH and 364 WNH)] who participated in the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Logistic regression models were used to evaluate whether medical advice to engage in particular self-management behaviors (reduce fat or calories, increase physical activity or exercise, and control or lose weight) predicted actually engaging in the particular behavior and whether the impact of medical advice on engaging in the behavior differed by race/ethnicity. Additional analyses examined whether these relationships were maintained when other factors potentially related to engaging in diabetes self management such as participants' diabetes education, sociodemographics and physical characteristics were controlled. Sample weights were used to account for the complex sample design. Results Although medical advice to the patient is considered a standard of care for diabetes, approximately one-third of the sample reported not receiving dietary, weight management, or physical activity self-management advice. Participants who reported being given medical advice for each specific diabetes self-management behaviors were 4-8 times more likely to report performing the corresponding behaviors, independent of race. These results supported the ecological model with certain caveats. Conclusions Providing standard medical advice appears to lead to diabetes self-management behaviors as reported by adults across the United States. Moreover, it does not appear that race/ethnicity influenced reporting performance of the standard diabetes self-management behavior. Longitudinal studies evaluating patient-provider communication, medical advice and diabetes self-management behaviors are needed to clarify our findings.

Medical Advice and Diabetes Self-Management Reported by Mexican-American, Black- and White-Non-Hispanic Adults Across the United States

Background: Diabetes has reached epidemic proportions in the United States, particularly among minorities, and if improperly managed can lead to medical complications and death. Healthcare providers play vital roles in communicating standards of care, which include guidance on diabetes self-management. The background of the client may play a role in the patient-provider communication process. The aim of this study was to determine the association between medical advice and diabetes self care management behaviors for a nationally representative sample of adults with diabetes. Moreover, we sought to establish whether or not race/ethnicity was a modifier for reported medical advice received and diabetes self-management behaviors. Methods: We analyzed data from 654 adults aged 21 years and over with diagnosed diabetes [130 MexicanAmericans; 224 Black non-Hispanics; and, 300 White non-Hispanics] and an additional 161 with ‘undiagnosed diabetes’ [N = 815(171 MA, 281 BNH and 364 WNH)] who participated in the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Logistic regression models were used to evaluate whether medical advice to engage in particular self-management behaviors (reduce fat or calories, increase physical activity or exercise, and control or lose weight) predicted actually engaging in the particular behavior and whether the impact of medical advice on engaging in the behavior differed by race/ethnicity. Additional analyses examined whether these relationships were maintained when other factors potentially related to engaging in diabetes self management such as participants’ diabetes education, sociodemographics and physical characteristics were controlled. Sample weights were used to account for the complex sample design. Results: Although medical advice to the patient is considered a standard of care for diabetes, approximately onethird of the sample reported not receiving dietary, weight management, or physical activity self-management advice. Participants who reported being given medical advice for each specific diabetes self-management behaviors were 4-8 times more likely to report performing the corresponding behaviors, independent of race. These results supported the ecological model with certain caveats. Conclusions: Providing standard medical advice appears to lead to diabetes self-management behaviors as reported by adults across the United States. Moreover, it does not appear that race/ethnicity influenced reporting performance of the standard diabetes self-management behavior. Longitudinal studies evaluating patient-provider communication, medical advice and diabetes self-management behaviors are needed to clarify our findings.

Obesity and Serum High Sensitivity C-Reactive Protein Levels Among Elderly Turkish Immigrants in the Netherlands with Type 2 Diabetes

The study examined the associations of anthropometric measures of obesity with high sensitivity C-reactive protein (hs-CRP) levels in Turkish immigrants with type 2 diabetes (T2D) living in the Netherlands. A total of 110 participants, physician-diagnosed with T2D, aged 30 years and older were recruited from multiple sources from The Hague, Netherlands. Serum hs-CRP levels were measured with immunoturbidimetric assay. Glycated hemoglobin (A1C) was determined by high-pressure liquid chromatography. Measures of obesity: body weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were determined. Statistical analysis included descriptive statistics, Pearson’s correlations and multiple linear regressions (MLR) stratified by gender. Hs-CRP was log transformed to achieve normality. Subjects with hs-CRP levels >10 mg/L (n = 17) were excluded from the analysis. Females had a higher BMI (p = 0.007), HC (p < 0.001), and WHtR (p = 0.011) as compared to males. Conversely, males had a higher weight (p = 0.007), and WHR (p < 0.001) than females. MLR showed that after controlling for covariates, log hs-CRP was positively associated with BMI (B = 0.039, SE = 0.019, β = 0.287, p < 0.05), WC (B = 0.025, SE = 0.011, β = 0.332, p < 0.05) and WHtR (B = 4.015, SE = 1.464, β = 0.376, p < 0.01) in females only. Gender-specific associations between obesity measures and hs-CRP level need to be further investigated in the Turkish immigrant population. Hs-CRP assessment may be added as a standard of care for T2D treatment within this population.

Construção e validação do instrumento de investigação do conhecimento de gestantes sobre sua saúde bucal e a do seu bebê: perspectiva do cuidado em saúde

INTRODUCTION: Humanized and quality prenatal and post-partum care is critical to maternal and newborn health, as well as oral health care. Currently, the National Oral Health Policy is aiming at expanding dental care for pregnant women. Thus, the promotion of oral health and attention to prenatal care policies should be integrated; however, there is still limited participation of pregnant women. Thus, it is necessary to verify the knowledge of pregnant women related to oral health, seeking to estimate the quality of dental care provided during prenatal care, being essential for the Family Health strategy to organize personnel, plan costs and to ensure the quality standard of care. OBJECTIVE: To develop and validate a research instrument on the knowledge of pregnant women about their oral health and of their baby. METHOD: This is a construction and validation study with 93 pregnant women in Family Health Units and specialized private clinics in Obstetrics, in the city of Natal / RN. It was authorized by the Onofre Lopes University Hospital Ethics Committee of the Universidade Federal do Rio Grande do Norte (UFRN) under the registration number 421.163/13. The construction of the instrument followed steps so that it was valid, reliable and sensitive: creation and reduction of the items (drafting of the instrument), content validity and testing of the instrument, and hypotheses validation. Once constructed, the instrument was evaluated by experts who suggested modifications. There was consultation with the target population about the new version of the created instrument, which had the instrument validation verified by internal consistency through intra and inter-calibration and test-retest. Next, the hypotheses were validated. A database was built in the Statistical Package for Social Sciences (SPSS), version 22.0. After creating the hypotheses, an association was found for validating the criteria between each of the specific issues for each established criteria, considering a 5% significance level. Data analysis was carried out by describing the absolute and relative frequencies of the variables pertaining to issues relating to their pregnancy knowledge about their oral health and their baby. The Kappa coefficient was used for the calibration process (Inter and Intra-examiner calibration) and Cronbach's alpha coefficient was used to analyze instrument reproducibility (test-retest). In addition, the chi-square test was used to cross the dependent variable with the (dichotomized) independent variables. RESULTS: The intra and inter agreement analysis presented a Kappa coefficient between 0.400 and 1.000. Internal consistency through the analysis showed that 90% of the instrument's questions showed great reliability in the answers (Cronbach α ˃ 0.7). In the investigation of the relationship between the dependent variable (knowledge about oral health) and the independent variables (trimester of pregnancy, education, income and multiparous), it was found that none of these independent variables were significantly associated. All hypotheses had their Ho confirmed. CONCLUSION: The constructed instrument was validated, considering that it showed to be sensitive with good reliability and good accuracy, and therefore can be used to assess pregnant women’s knowledge about their oral health and the oral health of their baby.

Construção e validação do instrumento de investigação do conhecimento de gestantes sobre sua saúde bucal e a do seu bebê: perspectiva do cuidado em saúde

INTRODUCTION: Humanized and quality prenatal and post-partum care is critical to maternal and newborn health, as well as oral health care. Currently, the National Oral Health Policy is aiming at expanding dental care for pregnant women. Thus, the promotion of oral health and attention to prenatal care policies should be integrated; however, there is still limited participation of pregnant women. Thus, it is necessary to verify the knowledge of pregnant women related to oral health, seeking to estimate the quality of dental care provided during prenatal care, being essential for the Family Health strategy to organize personnel, plan costs and to ensure the quality standard of care. OBJECTIVE: To develop and validate a research instrument on the knowledge of pregnant women about their oral health and of their baby. METHOD: This is a construction and validation study with 93 pregnant women in Family Health Units and specialized private clinics in Obstetrics, in the city of Natal / RN. It was authorized by the Onofre Lopes University Hospital Ethics Committee of the Universidade Federal do Rio Grande do Norte (UFRN) under the registration number 421.163/13. The construction of the instrument followed steps so that it was valid, reliable and sensitive: creation and reduction of the items (drafting of the instrument), content validity and testing of the instrument, and hypotheses validation. Once constructed, the instrument was evaluated by experts who suggested modifications. There was consultation with the target population about the new version of the created instrument, which had the instrument validation verified by internal consistency through intra and inter-calibration and test-retest. Next, the hypotheses were validated. A database was built in the Statistical Package for Social Sciences (SPSS), version 22.0. After creating the hypotheses, an association was found for validating the criteria between each of the specific issues for each established criteria, considering a 5% significance level. Data analysis was carried out by describing the absolute and relative frequencies of the variables pertaining to issues relating to their pregnancy knowledge about their oral health and their baby. The Kappa coefficient was used for the calibration process (Inter and Intra-examiner calibration) and Cronbach's alpha coefficient was used to analyze instrument reproducibility (test-retest). In addition, the chi-square test was used to cross the dependent variable with the (dichotomized) independent variables. RESULTS: The intra and inter agreement analysis presented a Kappa coefficient between 0.400 and 1.000. Internal consistency through the analysis showed that 90% of the instrument's questions showed great reliability in the answers (Cronbach α ˃ 0.7). In the investigation of the relationship between the dependent variable (knowledge about oral health) and the independent variables (trimester of pregnancy, education, income and multiparous), it was found that none of these independent variables were significantly associated. All hypotheses had their Ho confirmed. CONCLUSION: The constructed instrument was validated, considering that it showed to be sensitive with good reliability and good accuracy, and therefore can be used to assess pregnant women’s knowledge about their oral health and the oral health of their baby.

Bioengineered Approaches to Prevent Hypertrophic Scar Contraction

Burn injuries in the United States account for over one million hospital admissions per year, with treatment estimated at four billion dollars. Of severe burn patients, 30-90% will develop hypertrophic scars (HSc). Current burn therapies rely upon the use of bioengineered skin equivalents (BSEs), which assist in wound healing but do not prevent HSc. HSc contraction occurs of 6-18 months and results in the formation of a fixed, inelastic skin deformity, with 60% of cases occurring across a joint. HSc contraction is characterized by abnormally high presence of contractile myofibroblasts which normally apoptose at the completion of the proliferative phase of wound healing. Additionally, clinical observation suggests that the likelihood of HSc is increased in injuries with a prolonged immune response. Given the pathogenesis of HSc, we hypothesize that BSEs should be designed with two key anti-scarring characterizes: (1) 3D architecture and surface chemistry to mitigate the inflammatory microenvironment and decrease myofibroblast transition; and (2) using materials which persist in the wound bed throughout the remodeling phase of repair. We employed electrospinning and 3D printing to generate scaffolds with well-controlled degradation rate, surface coatings, and 3D architecture to explore our hypothesis through four aims.

In the first aim, we evaluate the impact of elastomeric, randomly-oriented biostable polyurethane (PU) scaffold on HSc-related outcomes. In unwounded skin, native collagen is arranged randomly, elastin fibers are abundant, and myofibroblasts are absent. Conversely, in scar contractures, collagen is arranged in linear arrays and elastin fibers are few, while myofibroblast density is high. Randomly oriented collagen fibers native to the uninjured dermis encourage random cell alignment through contact guidance and do not transmit as much force as aligned collagen fibers. However, the linear ECM serves as a system for mechanotransduction between cells in a feed-forward mechanism, which perpetuates ECM remodeling and myofibroblast contraction. The electrospinning process allowed us to create scaffolds with randomly-oriented fibers that promote random collagen deposition and decrease myofibroblast formation. Compared to an in vitro HSc contraction model, fibroblast-seeded PU scaffolds significantly decreased matrix and myofibroblast formation. In a murine HSc model, collagen coated PU (ccPU) scaffolds significantly reduced HSc contraction as compared to untreated control wounds and wounds treated with the clinical standard of care. The data from this study suggest that electrospun ccPU scaffolds meet the requirements to mitigate HSc contraction including: reduction of in vitro HSc related outcomes, diminished scar stiffness, and reduced scar contraction. While clinical dogma suggests treating severe burn patients with rapidly biodegrading skin equivalents, these data suggest that a more long-term scaffold may possess merit in reducing HSc.

In the second aim, we further investigate the impact of scaffold longevity on HSc contraction by studying a degradable, elastomeric, randomly oriented, electrospun micro-fibrous scaffold fabricated from the copolymer poly(l-lactide-co-ε-caprolactone) (PLCL). PLCL scaffolds displayed appropriate elastomeric and tensile characteristics for implantation beneath a human skin graft. In vitro analysis using normal human dermal fibroblasts (NHDF) demonstrated that PLCL scaffolds decreased myofibroblast formation as compared to an in vitro HSc contraction model. Using our murine HSc contraction model, we found that HSc contraction was significantly greater in animals treated with standard of care, Integra, as compared to those treated with collagen coated-PLCL (ccPLCL) scaffolds at d 56 following implantation. Finally, wounds treated with ccPLCL were significantly less stiff than control wounds at d 56 in vivo. Together, these data further solidify our hypothesis that scaffolds which persist throughout the remodeling phase of repair represent a clinically translatable method to prevent HSc contraction.

In the third aim, we attempt to optimize cell-scaffold interactions by employing an anti-inflammatory coating on electrospun PLCL scaffolds. The anti-inflammatory sub-epidermal glycosaminoglycan, hyaluronic acid (HA) was used as a coating material for PLCL scaffolds to encourage a regenerative healing phenotype. To minimize local inflammation, an anti-TNFα monoclonal antibody (mAB) was conjugated to the HA backbone prior to PLCL coating. ELISA analysis confirmed mAB activity following conjugation to HA (HA+mAB), and following adsorption of HA+mAB to the PLCL backbone [(HA+mAB)PLCL]. Alican blue staining demonstrated thorough HA coating of PLCL scaffolds using pressure-driven adsorption. In vitro studies demonstrated that treatment with (HA+mAB)PLCL prevented downstream inflammatory events in mouse macrophages treated with soluble TNFα. In vivo studies using our murine HSc contraction model suggested positive impact of HA coating, which was partiall impeded by the inclusion of the TNFα mAB. Further characterization of the inflammatory microenvironment of our murine model is required prior to conclusions regarding the potential for anti-TNFα therapeutics for HSc. Together, our data demonstrate the development of a complex anti-inflammatory coating for PLCL scaffolds, and the potential impact of altering the ECM coating material on HSc contraction.

In the fourth aim, we investigate how scaffold design, specifically pore dimensions, can influence myofibroblast interactions and subsequent formation of OB-cadherin positive adherens junctions in vitro. We collaborated with Wake Forest University to produce 3D printed (3DP) scaffolds with well-controlled pore sizes we hypothesized that decreasing pore size would mitigate intra-cellular communication via OB-cadherin-positive adherens junctions. PU was 3D printed via pressure extrusion in basket-weave design with feature diameter of ~70 µm and pore sizes of 50, 100, or 150 µm. Tensile elastic moduli of 3DP scaffolds were similar to Integra; however, flexural moduli of 3DP were significantly greater than Integra. 3DP scaffolds demonstrated ~50% porosity. 24 h and 5 d western blot data demonstrated significant increases in OB-cadherin expression in 100 µm pores relative to 50 µm pores, suggesting that pore size may play a role in regulating cell-cell communication. To analyze the impact of pore size in these scaffolds on scarring in vivo, scaffolds were implanted beneath skin graft in a murine HSc model. While flexural stiffness resulted in graft necrosis by d 14, cellular and blood vessel integration into scaffolds was evident, suggesting potential for this design if employed in a less stiff material. In this study, we demonstrate for the first time that pore size alone impacts OB-cadherin protein expression in vitro, suggesting that pore size may play a role on adherens junction formation affiliated with the fibroblast-to-myofibroblast transition. Overall, this work introduces a new bioengineered scaffold design to both study the mechanism behind HSc and prevent the clinical burden of this contractile disease.

Together, these studies inform the field of critical design parameters in scaffold design for the prevention of HSc contraction. We propose that scaffold 3D architectural design, surface chemistry, and longevity can be employed as key design parameters during the development of next generation, low-cost scaffolds to mitigate post-burn hypertrophic scar contraction. The lessening of post-burn scarring and scar contraction would improve clinical practice by reducing medical expenditures, increasing patient survival, and dramatically improving quality of life for millions of patients worldwide.

"It's just not cricket". Or is it?

Considers the Wolverhampton County Court decision in Bartlett v English Cricket Board Association of Cricket Officials on whether cricket umpires at an amateur match were liable for injuries to a player based on their inspection of the condition of the cricket ground after heavy rain and their decision to allow play to proceed. Comments on the approach to the umpires' standard of care.

MODERN SPORT COACHING AND THE LAW: IMPLICATIONS FOR COACH EDUCATION

Introduction
The intersection between the law of negligence and sport coaching in the UK is a developing area (Partington, 2014; Kevan, 2005). Crucially, since the law of negligence may be regarded as generally similar everywhere (Magnus, 2006), with the predominance of volunteer coaches in the UK reflective of the majority of countries in the world (Duffy et al., 2011), a detailed scrutiny of this relationship from the perspective of the coach uncovers important implications for coach education beyond this jurisdiction.  
Argumentation
Fulfilment of the legal duty of discharging reasonable care may be regarded as consistent with the ethical obligation not to expose athletes to unreasonable risks of injury (Mitten, 2013). More specifically, any ‘profession’ requiring ‘special skill or competence’ (Bolam v Friern Hospital Management Committee [1957] 1 WLR 582), including the coaching of sport (e.g., Davenport v Farrow [2010] EWHC 550), requires a higher standard of care to be displayed than would be expected of the ordinary reasonable person (Lunney & Oliphant, 2013; Jones & Dugdale, 2010). For instance, volunteer coaches with no formal qualifications (e.g., Fowles v Bedfordshire County Council [1996] ELR 51) would be judged by this benchmark of professional liability (Powell & Stewart, 2012). Further, as the principles of coaching are constantly assessed and revised (Cassidy et al., 2009; Taylor & Garratt, 2010), so too is the legal standard of care required of coaches (Powell & Stewart, 2012). Problematically, ethical concerns may include coaches being unwilling to increase knowledge, abusive treatment of players and incompetence/inexperience (Haney et al., 1998). These factors accentuate coaches’ exposure to civil liability.
Implications
It is imperative that coaches have an awareness of this emerging intersection and develop a ‘proactive risk assessment lens’ (Hartley, 2010). In addition to supporting the professionalisation of sport coaching, coach education/CPD focused on the legal and ethical aspects of coaching (Duffy et al., 2011; Telfer, 2010; Haney et al., 1998) would enhance the safety and welfare of performers, safeguard coaches from litigation risk, and potentially improve all levels of coaching (Partington, 2014). Interestingly, there is evidence to suggest a demand from coaches for more training on health and safety issues, including risk management and (ir)responsible coaching (Stirling et al., 2012). Accordingly, critical examination of the issue of negligent coaching would inform coach education by: enabling the modelling and sharing of best practice; unpacking important ethical concerns; and, further informing the classification of coaching as a ‘profession’.

Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

Aferição das dificuldades/competências na área da Endodontia percepcionadas pelos alunos do 4º e 5º anos da FCS-UFP

Introdução: Com uma consciencialização cada vez maior das populações para a preservação dos dentes naturais, a Endodontia tem assumido uma importância crescente, tendo por objectivo principal a manutenção de dentes funcionais, sem prejudicar a saúde dos pacientes. Estes devem beneficiar de um tratamento segundo o “standard of care”, proporcionado por profissionais competentes. Vários estudos demonstram que a Endodontia é considerada uma área difícil e stressante para os estudantes, exibindo um sentimento de menor confiança na prática clínica, sobretudo no que diz respeito a procedimentos mais complexos, nomeadamente, no tratamento de dentes posteriores. Em 2010, na tentativa de homogeneizar as competências adquiridas pelos Médicos Dentistas (MD), a Associação para a Educação Dentária Europeia (AEDE) definiu critérios para a sua formação pré-graduada, indicando que o MD recém-graduado deve ter adquirido competências e capacidades técnicas que lhe permita começar a sua prática clínica de forma independente. Objectivos: Analisar os conhecimentos adquiridos e as dificuldades sentidas na área da Endodontia pelos alunos do 4º e 5º anos do Mestrado Integrado em Medicina Dentária da Faculdade de Ciências de Saúde (FCS) da Universidade Fernando Pessoa (UFP), fazendo, igualmente, uma abordagem ao ensino ministrado na área da Endodontia face aos resultados obtidos. Materiais e Métodos: Este trabalho está dividido em duas partes: revisão bibliográfica e investigação científica. A revisão bibliográfica do tema engloba o ensino graduado em Medicina Dentária, o uso de isolamento absoluto (IA) na prática clínica de Endodontia, a instrumentação manual versus rotatória, a influência no sucesso do tratamento endodôntico (TE) da sua execução por estudantes do 4º e 5º ano, as Guidelines para o TE e o ensino de Endodontia na UFP. A pesquisa bibliográfica foi efectuada através da base de dados PubMed, tendo sido utilizadas, em diferentes combinações, as seguintes palavras-chave: ”Endodontics”, “teaching”; “pre-clinical”; “undergraduate”; “Clinical”; “treatment” e “Europe”. O trabalho de investigação consistiu na elaboração, aprovação pela Comissão de Ética da UFP e posterior aplicação de um questionário destinado aos alunos do 4º e 5º ano do Mestrado Integrado em Medicina Dentária da FCS-UFP. A população estimada de alunos do 4º ano foi de 190 alunos e a de 5º ano de 150 alunos, o que perfaz um total de 340 alunos. Dos inquéritos respondidos, apenas foram considerados 338, uma vez que dois foram anulados pois continham respostas inválidas. Resultados: A “condição socioeconómica do paciente” foi considerada a causa menos relevante para avaliar um caso endodôntico, tendo sido apontada por 34,3% dos alunos. Assinala-se que 92% dos alunos de 4º ano e 93,3% dos alunos de 5º ano consideram que os molares superiores são os dentes mais difíceis de tratar, sendo a visibilidade uma das principais razões para esta opinião. O grau de dificuldade para a colocação do IA é definido como “Elevado” para a maioria dos alunos de 4º ano. A maior parte dos alunos de 5º ano considera que o grau de dificuldade para a “Determinação do tipo de reconstrução/prótese fixa mais indicada” é “Elevado”. O passo do TE onde os alunos do 4º ano se sentem mais confiantes é no “Diagnóstico de cárie”, sendo que os alunos do 5º ano se sentem mais confiantes ao realizar o “TE em dentes com 1 ou 2 canais”. O “Conteúdo leccionado nas aulas teóricas” foi considerado o principal aspecto positivo do ensino endodôntico. Por outro lado, o “Número de actos clínicos realizados” foi considerado o principal aspecto negativo, tanto para alunos de 4º como de 5º ano. Em ambos os anos, os principais pontos que os alunos acham que devem ser melhorados são o “Número de pacientes nas aulas clínicas” e a “Aprendizagem da técnica de instrumentação mecanizada/obturação termoplástica”. As principais preocupações referidas, tanto por alunos de 4º como de 5º anos, foram a “Insegurança na prática clínica” e a “Dificuldade em encontrar ofertas profissionais”. Relativamente à qualidade dos seus TE existe um número significativo de alunos do 5º ano que já se auto-avaliam como “Bons” (33,6%), por comparação com os do 4º ano (21,2%), sendo a auto-avaliação de “Razoável” dominante em ambos os anos de formação. Conclusões: Conclui-se que na disciplina de Endodontia na FCS-UFP, são seguidas as Guidelines da European Society of Endodontology (ESE), sendo que estas indicam o protocolo mais correcto a seguir durante o Tratamento Endodôntico Não-Cirúrgico (TENC). Contudo, o reduzido número de actos clínicos e a consequente falta de prática faz com que os alunos se sintam pouco confiantes ao iniciar a sua actividade profissional.

Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations. PATIENTS AND METHODS: Specialist centres collaborated to report prognostic factors and outcome for 113 patients. RESULTS: Median age was 30 years (range: 11-80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1-34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3-28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03-10.96) and 20 (95% CI: 12.63-27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P=0.046; hazard ratio (HR)=0.482 95% CI: 0.213-0.996) and death (P=0.004; HR=0.445 95% CI: 0.256-0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P=0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P<0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3 years (95% CI: 0-4.25). CONCLUSIONS: Prognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease.