Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Exploring the existence, strength, and independence of relative age and maturation selection biases: a case study in Gaelic football talent development programmes.

BACKGROUND: Biological maturity and relative age player selection biases are well documented in youth sports. However, there has been limited examination of the relationship between these biases. AIM: This study investigated the presence, strength, and independence of relative age and biological maturity selection biases in Gaelic football. SUBJECTS AND METHODS: A total of 247 male players from U14 to U16, from two talent academies were assessed for relative age (decimal age (DA)) and biological maturity (discrepancy between biological and chronological age (BA-CA)). RESULTS: Relative age effects (RAE) were observed in the U14 (DA = 0.62, d = 0.40) and U15 squads (DA = 0.57. d = 0.26) only. A bias towards advanced maturity status was present at U14 (BA-CA = 0.60, d = 0.83), U15 (BA-CA = 0.78, d = 0.89), and U16 (BA-CA, d = 1.01). There was a trivial (U14, r(83) = -0.210; U15, r(88) = 0.060) and low (U16, r(76) = 0.352) correlation between relative age and maturity status. CONCLUSION: Substantial maturity selection biases and, to a lesser degree, relative age biases are evident in youth Gaelic football. Critically, these biases are independent constructs. Coaches and policy makers should be educated on the distinct influences of relative age and maturation, and on strategies to address these biases.

Optimising Radium 223 Therapy for Metastatic Castration-Resistant Prostate Cancer -5-year Real-World Outcome: Focusing on Treatment Sequence and Quality of Life.

AIMS: Real-world evidence of radium 223 (Ra-223) for the treatment of men with metastatic castration-resistant prostate cancer is emerging. In this prospective single-centre service evaluation, we report for the first time in the UK, real-world quality of life (QoL) and survival outcomes, including the sequencing impact, in 228 treated patients. We aim to share our 5-year experience on how to optimise Ra-223 treatment. MATERIALS AND METHODS: Patients who received Ra-223 therapy between 2014 and 2018 at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK were included in this evaluation. Demographics, clinical characteristics, blood parameters, treatment sequencing and QoL data using abbreviated Functional Assessment of Cancer Therapy-Prostate questionnaires were prospectively collected and analysed. RESULTS: In total, 228 patients were included; median age 72 years (51-87). The medium overall survival was 11.1 months. Overall survival in post-chemotherapy and chemotherapy-naïve patients was 8.1 and 12.3 months, respectively (P = 0.02, hazard ratio 1.52, 95% confidence interval 1.06-2.17); in pre-enzalutamide and post-enzalutamide patients was 11.3 and 10.4 months, respectively (P = 0.65, hazard ratio 0.92, 95% confidence interval 0.63-1.33); in pre-abiraterone and prednisolone and post-abiraterone and prednisolone patients was 11.8 and 10.5 months, respectively (P = 0.08, hazard ratio 0.74, 95% confidence interval 0.51-1.06); in this latter group, the fracture rate was 24% (15/63). QoL post Ra-223 (n = 101 evaluated) showed that pain scores improved in 54%, there was no change in 17% and pain scores worsened in 30% of treated patients. Overall QoL scores showed a similar trend. QoL was not significantly associated with overall survival. CONCLUSIONS: Ra-223 palliates pain and improves disease-related QoL in most patients in the real-world setting. Our survival outcome is comparable with other real-world studies. Chemotherapy-naïve patients seemed to have better survival than those who received prior chemotherapy. No significant survival differences were observed between pre- and post-abiraterone and prednisolone or enzalutamide patients. The fracture rate in the post-abiraterone and prednisolone group seemed to be high. Bone health evaluation and protection should be incorporated as standard of care.

Growing pains: Maturity associated variation in injury risk in academy football.

Reducing injuries to youth players is of primary importance to academies, as injuries can result in a significant loss in both training and match time, as well as, negatively affecting player development. In total, 76 talented young football players were analysed over two full competitive seasons. The injury incidence and burden for all non-contact and overuse injuries were recorded. Exposure was calculated as the total number of competitive matches hours played. Somatic maturation was estimated by expressing the current height of each player as a percentage of their predicted adult height [Roche, A. F., Tyleshevski, F., & Rogers, E. (1983). Non-invasive measurements of physical maturity in children. Research Quarterly for Exercise and Sport, 54(4), 364-371.]. The period of circa-peak height velocity (PHV) (24.5 injuries per 1000 h) was associated with a significantly higher injury incidence rate and burden compared to pre-PHV (11.5 injuries per 1000 h; RR:2.15, 95%CI:1.37-3.38, P < .001). No significant differences in injury risk between maturity timing groups were observed. The interaction effect between maturity status and maturity timing confirmed there is a risk period circa-PHV, but this was not dependent on maturity timing. The main practical application of this study is that football academies should regularly assess the maturity status of young footballers to identify those players with increased susceptibility to injury. Moreover, academies should individualise training and injury prevention strategies based on maturation.

Projecting boreal bird responses to climate change: the signal exceeds the noise.

For climate change projections to be useful, the magnitude of change must be understood relative to the magnitude of uncertainty in model predictions. We quantified the signal-to-noise ratio in projected distributional responses of boreal birds to climate change, and compared sources of uncertainty. Boosted regression tree models of abundance were generated for 80 boreal-breeding bird species using a comprehensive data set of standardized avian point counts (349,629 surveys at 122,202 unique locations) and 4-km climate, land use, and topographic data. For projected changes in abundance, we calculated signal-to-noise ratios and examined variance components related to choice of global climate model (GCM) and two sources of species distribution model (SDM) uncertainty: sampling error and variable selection. We also evaluated spatial, temporal, and interspecific variation in these sources of uncertainty. The mean signal-to-noise ratio across species increased over time to 2.87 by the end of the 21st century, with the signal greater than the noise for 88% of species. Across species, climate change represented the largest component (0.44) of variance in projected abundance change. Among sources of uncertainty evaluated, choice of GCM (mean variance component = 0.17) was most important for 66% of species, sampling error (mean= 0.12) for 29% of species, and variable selection (mean =0.05) for 5% of species. Increasing the number of GCMs from four to 19 had minor effects on these results. The range of projected changes and uncertainty characteristics across species differed markedly, reinforcing the individuality of species' responses to climate change and the challenges of one-size-fits-all approaches to climate change adaptation. We discuss the usefulness of different conservation approaches depending on the strength of the climate change signal relative to the noise, as well as the dominant source of prediction uncertainty.

Associations between breakfast frequency and adiposity indicators in children from 12 countries.

OBJECTIVES: Reports of inverse associations between breakfast frequency and indices of obesity are predominantly based on samples of children from high-income countries with limited socioeconomic diversity. Using data from the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE), the present study examined associations between breakfast frequency and adiposity in a sample of 9-11-year-old children from 12 countries representing a wide range of geographic and socio-cultural variability. METHODS: Multilevel statistical models were used to examine associations between breakfast frequency (independent variable) and adiposity indicators (dependent variables: body mass index (BMI) z-score and body fat percentage (BF%)), adjusting for age, sex, and parental education in 6941 children from 12 ISCOLE study sites. Associations were also adjusted for moderate-to-vigorous physical activity, healthy and unhealthy dietary patterns and sleep time in a sub-sample (n=5710). Where interactions with site were significant, results were stratified by site. RESULTS: Adjusted mean BMI z-score and BF% for frequent breakfast consumers were 0.45 and 20.5%, respectively. Frequent breakfast consumption was associated with lower BMI z-scores compared with occasional (P<0.0001, 95% confidence intervals (CI): 0.10-0.29) and rare (P<0.0001, 95% CI: 0.18-0.46) consumption, as well as lower BF% compared with occasional (P<0.0001, 95% CI: 0.86-1.99) and rare (P<0.0001, 95% CI: 1.07-2.76). Associations with BMI z-score varied by site (breakfast by site interaction; P=0.033): associations were non-significant in three sites (Australia, Finland and Kenya), and occasional (not rare) consumption was associated with higher BMI z-scores compared with frequent consumption in three sites (Canada, Portugal and South Africa). Sub-sample analyses adjusting for additional covariates showed similar associations between breakfast and adiposity indicators, but lacked site interactions. CONCLUSIONS: In a multinational sample of children, more frequent breakfast consumption was associated with lower BMI z-scores and BF% compared with occasional and rare consumption. Associations were not consistent across all 12 countries. Further research is required to understand global differences in the observed associations.

Reproducibility of peak power output during a 10-s cycling maximal effort using different sampling rates.

The study was aimed to investigate the reproducibility of performance parameters obtained from 10-s maximal cycling effort against different braking forces in young adult athletes. The sample (n = 48) included male athletes aged 18.9-29.9 years (175.5 ± 6.9 cm, 76.2 ± 10.1 kg). The exercise protocol was performed in a cycle-ergometer against a random braking force (4% to 11% of body mass). Intra-individual variation was examined from repeated tests within one week. Descriptive statistics were computed and differences between sessions were tested using paired t-test. The coefficient of correlation between repeated measures, technical error of measurement (TEM), coefficient of variation and ICC were calculated. Agreement between trials was examined using the Bland-Altman procedure. Mean values of peak power were relatively stable when obtained from sampling rates of 50 Hz and ranged between 1068 watt and 1082 watt (t(47) = 1.149, p = 0.256, ES-r = 0.165) or while corresponding to a sampling rate of 1 Hz (t(47) = 0.742, p = 0.462, ES-r = 0.107). Correlations between repeated measures were high (+0.907, 95% CI: +0.839 to +0.947) and TEM about 59.3 watt (%CV = 5.52%; ICC = 0.951, 95% CI: 0.912 to 0.972). The present study suggests that reproducibility of peak power in male adult athletes tended to be acceptable and within individual error appeared unrelated to braking force.

Concurrent and prospective associations among biological maturation, and physical activity at 11 and 13 years of age.

This study examined concurrent and prospective associations between objective measures of biological maturation, body composition and physical activity (PA) in adolescent males (n = 671) and females (n = 680). Participants born to women recruited to the Avon Longitudinal Study of Parents and Children birth cohort study were assessed at 11 and 13 years. Percentage of predicted adult stature was used as an estimate of biological maturation. PA and time sedentary was assessed over 7 consecutive days using Actigraph accelerometers. Body composition was assessed using whole-body DXA scans. At 11 and 13 years, maturity in males was inversely associated with accelerometer counts-per-minute (CPM) and time engaged in light PA, and positively associated with time sedentary. In females, maturity was inversely associated with accelerometer (CPM) at 11 but not 13 years. Adjusting for accelerometer wear times and corresponding activity levels at 11 years, maturity and percentage fat mass at 11 years did not predict any indices of PA or sedentary behavior in males or females at 13 years. Whereas advanced maturation in males is associated with less PA and more sedentary behavior at 11 and 13 years, maturity at 11 does not predict PA or sedentary behavior at 13 years in either sex.

Starting treatment according to guidelines evaluation: a multicentre audit of HIV patients in the UK.

The aim of this audit was to assess whether HIV patients are being started on antiretroviral therapy (ART) according to British and European guidelines. Data were collected from the Survey of Prevalent HIV Infections Diagnosed (SOPHID) return for 2010 at five major HIV management centres in the UK. Data from this 3873 patient cohort revealed 52 patients who should have been receiving ART according to the guidelines but were not. Of these, 23 patients elected not to start ART despite clinical advice to the contrary. Information required to assist in the decision for earlier ART initiation (CD4 count 350­500 cells/mL) was missing for some patients. Clinicians must pay attention to the regular assessment of patients with a CD4 count of 351­500 cells/mL so that all those who may benefit from earlier treatment are identified. Future research should investigate patient barriers to initiating therapy following recommendation by a clinician.

Concurrent validation of estimated activity energy expenditure using a 3-day diary and accelerometry in adolescents.

Estimates of daily energy expenditure are important to studies of physical activity and energy balance. Objective measures are not always feasible and further research is needed to validate survey instruments and diaries. The study validates estimated activity energy expenditure (AEE) based on a 3-day diary protocol relative to AEE derived from uniaxial accelerometry in adolescents, 265 girls and 227 boys (12.5-16.4 years). Participants completed the diary and wore a GT1M Actigraph accelerometer on the same days. Height and weight were measured. Correlations between protocols were significant (P<0.001) but moderate, r=0.65 in males and r=0.69 in females. The highest correlation occurred among males on Friday, r=0.74 (P<0.01). Controlling for body mass, partial correlations between protocols decreased to 0.44 and 0.35 in males and females, respectively. About 97% of the cases fell within the limits of agreement in a Bland-Altman plot. The criterion of inclusion for the accelerometer excluded 18% of the initial sample. In summary, the 3-day diary was completed without any major problems and provided a reasonably valid alternative for assessing AEE. Concordance between methods was slightly lower for individuals with higher values of AEE.

Effects of strength and aerobic-based training on functional fitness, mood and the relationship between fatness and mood in older adults.

AIM: Physical independence and positive mood states contribute to successful aging. The aim of this study was to analyze the effects of aerobic and strength-based training programs on functional fitness and mood in older adults, and to assess the relationship between adiposity and mood states. METHODS: Seventy eight participants (age 65 to 95 year old) were randomly assigned to a control group, aerobic training (AT), or strength training group (ST). Functional fitness was assessed using dimensions of the Senior Fitness Test battery relating to lower and upper body strength and flexibility, velocity, agility and dynamic balance, and aerobic endurance. Mood states (depression, tension, fatigue, vigour, anger, and confusion) were determined using the POMS-SF questionnaire. Participants were evaluated at the baseline and at the end of a 16-week exercise programme. RESULTS: Both the ST and AT groups improved their functional fitness following the 16 week training. Body Mass Index (BMI) was positively associated with tension (r=0.30; P<0.01), fatigue (r=0.31; P<0.01) and confusion (r=0.24; P<0.05). At 16-week evaluation, control group reported increased levels of confusion, and the ST group reported increases in vigour (P<0.05). CONCLUSION: Results support the idea that strength-based training can be as effective as aerobic-based training in improving physical skills that contribute to functional mobility in later years. Positive associations between increased BMI and mood disturbance were also found. Physical training also contributed to some improvements in mood.

Discrimination of u-14 soccer players by level and position.

Adolescence is often viewed as a critical period for selection in youth soccer. The present study compared the characteristics of regionally selected and non-selected under-14 players (U-14) as a group and by position. Players were classified as local (n=69) and regional (n=45). Weight, height, skinfolds, functional capacities, soccer skills and goal orientation were measured and skeletal age was assessed with the Fels method. Factorial ANOVA was used to test the effect of selection, position and respective interaction terms, while discriminant analysis was used to identify the variables that contributed to selection. Selected players had an advanced maturity status (F=24.97, p<0.01), were heavier (F=30.67, p<0.01) and taller (F=35.07, p<0.01); performed better in explosive power (F=21.25, p<0.01), repeated sprints (F=20.04, p<0.01) and ball control (F=3.69, p<0.05); and were more ego oriented (F=13.29, p<0.01). The 2 competitive groups did not differ in agility, aerobic endurance, dribbling, shooting, passing, and task orientation. Position-related variation was negligible. The percentage of players who were correctly classified in the original groups was slightly lower when the analysis was performed for the total sample (86%) than by position (86-90%). Future research on talent identification and selection should adopt a multidimensional approach including variables related to the physiological, perceptual, cognitive and tactical demands.

The RNA stability regulator HuR regulates L1 protein expression in vivo in differentiating cervical epithelial cells.

Human papillomavirus (HPV) L1 and L2 capsid protein expression is restricted to the granular layer of infected, stratified epithelia and is regulated at least partly at post-transcriptional levels. For HPV16, a 79 nt late regulatory element (LRE) is involved in this control. Using W12 cells as a model for HPV16-infected differentiating cervical epithelial cells we show that HuR, a key cellular protein that controls mRNA stability, binds the LRE most efficiently in nuclear and cytoplasmic extracts of differentiated cells. Further, HuR binds the 3' U-rich portion of the LRE directly in vitro. Overexpression of HuR in undifferentiated W12 cells results in an increase in L1 mRNA and protein levels while siRNA knock-down of HuR in differentiated W12 cells depletes L1 expression. In differentiated cervical epithelial cells HuR may bind and stabilise L1 mRNAs aiding translation of L1 protein.

The relationship between cognitive function and clinical and functional outcomes in major depressive disorder.

BACKGROUND: Although cognitive variables have been shown to be useful in predicting outcomes in late-life depression, there has not yet been a comprehensive study in younger persons with depression. METHOD: The clinical symptoms and cognitive performance of participants were evaluated at admission to one of two university teaching hospitals and again at 3 months after remission and discharge. A total of 52 participants with a DSM-IV diagnosis of major depressive disorder, aged between 20 and 60 years and with a Hamilton Depression Rating Scale score 17 > or = entered the study. The sample for this paper comprises the 48 subjects (mean age 37.9 years, s.d.=10.7) who received admission and follow-up assessments; an attrition rate of 7.7%. RESULTS: More perseverative errors on the shortened Wisconsin Card Sorting Test at admission predicted a worse clinical outcome at follow-up. Poor event-based prospective memory and more perseverative errors on the shortened Wisconsin Card Sorting Test at admission predicted worse social and occupational outcome at follow-up. CONCLUSIONS: These results suggest that a brief cognitive screen at hospital admission, focusing on executive function, would have a useful prognostic value in depression. Determining early predictors of individuals at risk of poorer outcomes is important for identifying those who may need altered or additional treatment approaches.

Biotic and abiotic regulation of lightning fire initiation in the mixedwood boreal forest.

Lightning fire is the dominant natural disturbance of the western mixedwood boreal forest of North America. We quantified the independent effects of weather and forest composition on lightning fire initiation (a detected and recorded fire start) patterns in Alberta, Canada, to demonstrate how these biotic and abiotic components contribute to ecosystem dynamics in the mixedwood boreal forest. We used logistic regression to describe variation in annual initiation occurrence among 10,000-ha landscape units (voxels) covering a 9 million-ha study region over 11 years. At a voxel scale, forest composition explained more variation in annual initiation than did weather indices. Initiations occurred more frequently in landscapes with more conifer fuels (Picea spp.), and less in aspen-dominated (Populus spp.) ones. Initiations were less frequent in landscapes that had recently burned. Variation in initiation was also influenced by joint weather-lightning indices, but to a lesser degree. For each voxel, these indices quantified the number of days in the fire season when moisture levels were low and lightning was detected. Regional indices of fire weather severity explained substantial interannual variation of initiation, and the effect of forest composition was stronger in years with more severe fire weather. Our study is a conclusive demonstration of biotic and abiotic regulation of lightning fire initiation in the mixedwood boreal forest. The independent effects of forest composition emphasize that vegetation feedbacks strongly regulate disturbance dynamics in the region.

Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia.

Alpha(1)-antitrypsin functions as a "mousetrap" to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu(342)-->Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and beta-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha(1)-antitrypsin homozygote to emphysema. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and alpha(1)-antichymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.

C-type natriuretic peptide expression in olfactory regions of rat brain is modulated by acute water deprivation, salt loading and central angiotensin II.

To elucidate the central role of c-type natriuretic peptide (CNP), levels of CNP mRNA in control rat brain were compared with levels following acute water deprivation, salt loading and central administration of angiotensin II (AII), using Northern blot and in situ hybridisation. Rats with water deprivation (WD) had no access to water for 48 h, rats with salt loading (SL) had access to 2% saline for 48 h, and control rats had free access to water. Both WD and SL significantly raised plasma sodium (Na). Levels of CNP mRNA in olfactory regions were significantly decreased in WD and increased in SL. In the medulla, WD and SL both increased CNP mRNA, but levels of CNP mRNA elsewhere in the brain were not significantly altered. Intracerebroventricular AII (500 ng) increased water intake, and induced a significant increase in CNP expression at 4 h in olfactory regions, but not in other brain sites. In summary, CNP expression is regulated in olfactory regions of the rat brain in response to acute challenges to water and salt balance and by central AII.

The relationship between inflated personal responsibility and exaggerated danger expectancies in obsessive-compulsive concerns.

The association between responsibility for a negative outcome, perceived severity of the outcome and perceived likelihood of the outcome was examined in a sample of 70 undergraduate students. Participants were asked to rate the likelihood and severity of 10 negative outcomes, five related to contamination and five related to checking. Thirty-eight participants completed a version of the questionnaire that presented the subject as responsible for the action that may lead to a negative outcome ('personally responsible' group). The remaining 32 completed a version of the questionnaire that presented someone else performing the actions that may lead to a negative outcome ('other responsible' group). Significant differences emerged between the personally responsible and other responsible groups for severity of outcome ratings but not for likelihood of outcome ratings. Specifically, for both washing and checking concerns, participants in the personally responsible group rated the severity of the potential negative outcome as greater than did those in the other responsible group. The results support the claimed general tendency for individuals to regard an outcome as more aversive if they are personally responsible for that outcome, rather than someone else being responsible. The results suggest that, in general, increasing perceptions of personal responsibility will increase cost or severity estimates in subjective danger calculations, and that responsibility may influence OCD phenomena in this way. Finally, the results suggest that attempts to manipulate responsibility in the laboratory may be confounded by necessarily impacting on cost estimates, and therefore on danger expectancies.