Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).

BACKGROUND: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations. METHODS: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity. RESULTS: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related). CONCLUSIONS: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib. CLINICAL TRIAL REGISTRATION: NCT02780687.

Reliability of Measures of Lower-Body Strength and Speed in Academy Male Adolescent Soccer Players.

ABSTRACT: Ferguson, J, Gibson, NV, Weston, M, and McCunn, R. Reliability of measures of lower body strength and speed in academy male adolescent soccer players. J Strength Cond Res 38(3): e96-e103, 2024-The Nordbord and ForceFrame represent a practical and time efficient means of assessing eccentric hamstring and isometric adductor strength in the large number of squads and players associated with youth soccer academies, yet measurement reliability in this population is unexamined. Therefore, over a period of 4 days, with no less than 24 hours and no more than 48 hours between trials, 37 players (age: 14.7 ± 0.8 years, stature: 168.7 ± 7.8 cm, mass: 57.7 ± 9.1 kg, and maturity offset: 0.8 ± 0.9 years) were assessed for eccentric hamstring strength (force, torque), isometric adductor strength (long and short lever positions), and 30-m sprint (5, 10, and 20-m splits), using the Nordbord, ForceFrame, and electronic timing gates, respectively, on 3 separate occasions. Relative reliability (intraclass correlation coefficient) was rated as good for all Nordbord (range: 0.86-0.89) and ForceFrame (0.78-0.85) measures and ranged from moderate (0.53) to excellent (0.93) for the speed measures, improving with increased distance. Absolute reliability (standard error of the measurement [%SEM]) ranged from 7 to 8% (Nordbord), 3 to 11% (ForceFrame), and 1 to 4% (sprints). Our data provide the first Nordbord and ForceFrame reliability estimates in adolescent soccer academy players. To interpret test sensitivity, practitioners are encouraged to interpret our estimates of absolute reliability against meaningful change values derived from personal experience and evidence-based knowledge and not against absolute or standardized thresholds.

Recommendations from Diabetes UK's 2022 diabetes and physical activity workshop.

AIMS: To describe the process and outputs of a workshop convened to identify key priorities for future research in the area of diabetes and physical activity and provide recommendations to researchers and research funders on how best to address them. METHODS: A 1-day research workshop was conducted, bringing together researchers, people living with diabetes, healthcare professionals, and members of staff from Diabetes UK to identify and prioritise recommendations for future research into physical activity and diabetes. RESULTS: Workshop attendees prioritised four key themes for further research: (i) better understanding of the physiology of exercise in all groups of people: in particular, what patient metabolic characteristics influence or predict the physiological response to physical activity, and the potential role of physical activity in beta cell preservation; (ii) designing physical activity interventions for maximum impact; (iii) promoting sustained physical activity across the life course; (iv) designing physical activity studies for groups with multiple long-term conditions. CONCLUSIONS: This paper outlines recommendations to address the current gaps in knowledge related to diabetes and physical activity and calls on the research community to develop applications in these areas and funders to consider how to stimulate research in these areas.

Injury incidence and burden differ between season phases in male academy football (soccer) players.

Adolescent elite-level footballers are exposed to unique physical and psychological stressors which may increase injury risk, with fluctuating injury prevalence and burden. This study investigates the patterns of injury incidence and burden from 2017 to 2020 within combined pre-, start-of-, mid- and end-of-season and school-holiday phases in U13-U18 Australian male academy players. Injury incidence rate and burden were calculated for medical attention (MA), full and partial time-loss (TL) and non-time-loss (non-TL) injuries. Injury rate ratios (IRR) for injury incidences were assessed using Generalised Linear Mixed Models, and 99% confidence intervals for injury burden differences between phases. MA and non-TL injury incidence rates were higher during pre-season (IRR 1.65, p = 0.01; IRR 2.08, p = 0.02, respectively), and mid-season showed a higher non-TL incidence rate (IRR 2.15, p = 0.02) and burden (69 days with injury/1000 hrs, CI 47-103) compared to end-of-season (25 days with injury/1000 hrs, CI 15-45). MA injury rates and partial TL injury burden were higher during school compared to holiday periods (IRR 0.6, p = 0.04; 61 partial days lost/1000 hrs, CI 35-104; 13 partial days lost/1000 hrs, CI 8-23). Season phase and return-to-school may increase injury risks for elite academy footballers, and considering these phases may assist in developing injury prevention systems.

Comprehensive analysis of the ErbB receptor family in pediatric nervous system tumors and rhabdomyosarcoma.

BACKGROUND: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. PROCEDURE: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. RESULTS: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in ∼20%-30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. CONCLUSIONS: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs.

Overnight sleeping heart rate variability of Army recruits during a 12-week basic military training course.

PURPOSE: This study aimed to quantify sleeping heart rate (HR) and HR variability (HRV) alongside circulating tumor necrosis factor alpha (TNFα) concentrations during 12-week Basic Military Training (BMT). We hypothesised that, despite a high allostatic load, BMT would increase cardiorespiratory fitness and HRV, while lowering both sleeping HR and TNFα in young healthy recruits. METHODS: Sixty-three recruits (18-43 years) undertook ≥ 2 overnight cardiac frequency recordings in weeks 1, 8 and 12 of BMT with 4 h of beat-to-beat HR collected between 00:00 and 06:00 h on each night. Beat-to-beat data were used to derive HR and HRV metrics which were analysed as weekly averages (totalling 8 h). A fasted morning blood sample was collected in the equivalent weeks for the measurement of circulating TNFα concentrations and predicted VO2max was assessed in weeks 2 and 8. RESULTS: Predicted VO2max was significantly increased at week 8 (+ 3.3 ± 2.6 mL kg-1 min-1; p < 0.001). Sleeping HR (wk1, 63 ± 7 b min-1) was progressively reduced throughout BMT (wk8, 58 ± 6; wk12, 55 ± 6 b min-1; p < 0.01). Sleeping HRV reflected by the root mean square of successive differences (RMSSD; wk1, 86 ± 50 ms) was progressively increased (wk8, 98 ± 50; wk12, 106 ± 52 ms; p < 0.01). Fasted circulating TNFα (wk1, 9.1 ± 2.8 pg/mL) remained unchanged at wk8 (8.9 ± 2.5 pg/mL; p = 0.79) but were significantly reduced at wk12 (8.0 ± 2.4 pg/mL; p < 0.01). CONCLUSION: Increased predicted VO2max, HRV and reduced HR during overnight sleep are reflective of typical cardiorespiratory endurance training responses. These results indicate that recruits are achieving cardiovascular health benefits despite the high allostatic load associated with the 12-week BMT.

Reliability and Validity of a 6-Minute Yo-Yo Intermittent Endurance Test Level 2 in Subelite Part Time Male Soccer Players.

ABSTRACT: Gibson, N, Easton, C, Williams, M, McCunn, R, Gibson, NV. Reliability and validity of a 6-minute Yo-Yo Intermittent Endurance Test Level 2 in subelite part time male soccer players. J Strength Cond Res 36(4): 1011-1018, 2022-The aim of this study was to assess the reliability and relationship to maximal intermittent running performance of the 6-minute Yo-Yo Intermittent Endurance Test Level 2 (YYIET2), among subelite part time soccer players. Twenty male soccer players (15-22 years) completed three 6-minute YYIET2 trials with heart rate (HR), PlayerLoad, and rating of perceived exertion assessed during the protocol and HR and blood lactate assessed during 5 minutes of recovery. Subjects also completed a maximal version of the YYIET2 and the maximal Yo-Yo Intermittent Recovery Test Level 1 (YYIRT1) and 2 (YYIRT2). Heart rate at 4 and 6 minutes, PlayerLoad at 4 minutes, and HR recovery at 2, 3, 4, and 5 minutes during recovery from the 6-minute YYIET2 demonstrated little variance between tests. Correlations between variables measured during and after the 6-minute YYIET2 and distance covered in maximal tests ranged from r = 0.02 to -0.72. The 6-minute YYIET2 provides practitioners with a method of reliably assessing HR responses within subelite part time soccer players, although large correlations with maximal assessments suggest it can be used as a proxy measure for maximal intermittent running performance. Given its ease of administration and low time cost, the 6-minute YYIET2 offers practitioners a useful means of tracking training status and movement efficiency in players longitudinally.

Initial fitness, maturity status, and total training explain small and inconsistent proportions of the variance in physical development of adolescent footballers across one season.

To investigate how initial fitness, maturity status, and training time explain changes in physical performance across one season. Eighty-eight adolescent male footballers, representing four age categories (Under 15 [n = 12], Under 14 [n = 21], Under 13 [n = 25], Under 12 [n = 30]), were tested using physical performance tests (20 m sprint, change of direction, squat jump and yo-yo intermittent recovery test level 1 [YYIRTL1]) and maturity offset at the season start (Test 1) and end (Test 2). Multiple regression determined the proportion of variance in test score changes, explained by three predictor variables: initial fitness (i.e., Test 1), maturity offset change, and training time. With combined categories, predictor variables explained 0.051 to 0.297 of the variance in physical performance score changes. Analysing age categories separately, predictor variables explained 0.047 to 0.407 (20 m sprint), 0.202 to 0.626 (change of direction), 0.336 to 0.502 (squat jump), and 0.196 to 0.777 (YYIRTL1) of variance in test score changes. Of the limited differences in relative predictor contribution, Test 1 was the strongest predictor of test score change. Initial fitness, maturity status change, and training time explain small and inconsistent proportions of variance in adolescent footballers' physical development across one season.

Activation of the Gluteus Maximus During Performance of the Back Squat, Split Squat, and Barbell Hip Thrust and the Relationship With Maximal Sprinting.

ABSTRACT: Williams, MJ, Gibson, N, Sorbie, GG, Ugbolue, UC, Brouner, J, and Easton, C. Activation of the gluteus maximus during performance of the back squat, split squat, and barbell hip thrust and the relationship with maximal sprinting. J Strength Cond Res 35(1): 16-24, 2021-The purpose of this research was to compare muscle activation of the gluteus maximus and ground reaction force between the barbell hip thrust, back squat, and split squat and to determine the relationship between these outcomes and vertical and horizontal forces during maximal sprinting. Twelve, male, team sport athletes (age, 25.0 ± 4.0 years; stature, 184.1 ± 6.0 cm; body mass, 82.2 ± 7.9 kg) performed separate movements of the 3 strength exercises at a load equivalent to their individual 3 repetition maximum. The ground reaction force was measured using force plates and the electromyography (EMG) activity of the upper and lower gluteus maximus and was recorded in each leg and expressed as percentage of the maximum voluntary isometric contraction (MVIC). Subjects then completed a single sprint on a nonmotorized treadmill for the assessment of maximal velocity and horizontal and vertical forces. Although ground reaction force was lower, peak EMG activity in the gluteus maximus was higher in the hip thrust than in the back squat (p = 0.024; 95% confidence interval [CI] = 4-56% MVIC) and split squat (p = 0.016; 95% CI = 6-58% MVIC). Peak sprint velocity correlated with both anterior-posterior horizontal force (r = 0.72) and peak ground reaction force during the barbell hip thrust (r = 0.69) but no other variables. The increased activation of gluteus maximus during the barbell hip thrust and the relationship with maximal running speed suggests that this movement may be optimal for training this muscle group in comparison to the back squat and split squat.

Quantitative biokinetics over a 28 day period of freshly generated, pristine, 20 nm silver nanoparticle aerosols in healthy adult rats after a single 1½-hour inhalation exposure.

BACKGROUND: There is a steadily increasing quantity of silver nanoparticles (AgNP) produced for numerous industrial, medicinal and private purposes, leading to an increased risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose exposure. RESULTS: To study the fate of inhaled AgNP, healthy adult rats were exposed to 1½-hour intra-tracheal inhalations of pristine 105Ag-radiolabeled, 20 nm AgNP aerosols (with mean doses across all rats of each exposure group of deposited NP-mass and NP-number being 13.5 ± 3.6 µg, 7.9 ± 3.2•1011, respectively). At five time-points (0.75 h, 4 h, 24 h, 7d, 28d) post-exposure (p.e.), a complete balance of the [105Ag]AgNP fate and its degradation products were quantified in organs, tissues, carcass, lavage and body fluids, including excretions. Rapid dissolution of [105Ag]Ag-ions from the [105Ag]AgNP surface was apparent together with both fast particulate airway clearance and long-term particulate clearance from the alveolar region to the larynx. The results are compatible with evidence from the literature that the released [105Ag]Ag-ions precipitate rapidly to low-solubility [105Ag]Ag-salts in the ion-rich epithelial lining lung fluid (ELF) and blood. Based on the existing literature, the degradation products rapidly translocate across the air-blood-barrier (ABB) into the blood and are eliminated via the liver and gall-bladder into the small intestine for fecal excretion. The pathway of [105Ag]Ag-salt precipitates was compatible with auxiliary biokinetics studies at 24 h and 7 days after either intravenous injection or intratracheal or oral instillation of [110mAg]AgNO3 solutions in sentinel groups of rats. However, dissolution of [105Ag]Ag-ions appeared not to be complete after a few hours or days but continued over two weeks p.e. This was due to the additional formation of salt layers on the [105Ag]AgNP surface that mediate and prolonge the dissolution process. The concurrent clearance of persistent cores of [105Ag]AgNP and [105Ag]Ag-salt precipitates results in the elimination of a fraction > 0.8 (per ILD) after one week, each particulate Ag-species accounting for about half of this. After 28 days p.e. the cleared fraction rises marginally to 0.94 while 2/3 of the remaining [105Ag]AgNP are retained in the lungs and 1/3 in secondary organs and tissues with an unknown partition of the Ag species involved. However, making use of our previous biokinetics studies of poorly soluble [195Au]AuNP of the same size and under identical experimental and exposure conditions (Kreyling et al., ACS Nano 2018), the kinetics of the ABB-translocation of [105Ag]Ag-salt precipitates was estimated to reach a fractional maximum of 0.12 at day 3 p.e. and became undetectable 16 days p.e. Hence, persistent cores of [105Ag]AgNP were cleared throughout the study period. Urinary [105Ag]Ag excretion is minimal, finally accumulating to 0.016. CONCLUSION: The biokinetics of inhaled [105Ag]AgNP is relatively complex since the dissolving [105Ag]Ag-ions (a) form salt layers on the [105Ag]AgNP surface which retard dissolution and (b) the [105Ag]Ag-ions released from the [105Ag]AgNP surface form poorly-soluble precipitates of [105Ag]Ag-salts in ELF. Therefore, hardly any [105Ag]Ag-ion clearance occurs from the lungs but instead [105Ag]AgNP and nano-sized precipitated [105Ag]Ag-salt are cleared via the larynx into GIT and, in addition, via blood, liver, gall bladder into GIT with one common excretional pathway via feces out of the body.

Quantitative biokinetics over a 28 day period of freshly generated, pristine, 20 nm titanium dioxide nanoparticle aerosols in healthy adult rats after a single two-hour inhalation exposure.

BACKGROUND: Industrially produced quantities of TiO2 nanoparticles are steadily rising, leading to an increasing risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose exposure. RESULTS: To study the fate of inhaled TiO2-NP, adult rats were exposed to 2-h intra-tracheal inhalations of 48V-radiolabeled, 20 nm TiO2-NP aerosols (deposited NP-mass 1.4 ± 0.5 µg). At five time points (1 h, 4 h, 24 h, 7d, 28d) post-exposure, a complete balance of the [48V]TiO2-NP fate was quantified in organs, tissues, carcass, lavage and body fluids, including excretions. After fast mucociliary airway clearance (fractional range 0.16-0.31), long-term macrophage-mediated clearance (LT-MC) from the alveolar region is 2.6-fold higher after 28d (integral fraction 0.40 ± 0.04) than translocation across the air-blood-barrier (integral fraction 0.15 ± 0.01). A high NP fraction remains in the alveoli (0.44 ± 0.05 after 28d), half of these on the alveolar epithelium and half in interstitial spaces. There is clearance from both retention sites at fractional rates (0.02-0.03 d- 1) by LT-MC. Prior to LT-MC, [48V]TiO2-NP are re-entrained to the epithelium as reported earlier for 20 nm inhaled gold-NP (AuNP) and iridium-NP (IrNP). CONCLUSION: Comparing the 28-day biokinetics patterns of three different inhaled NP materials TiO2-NP, AuNP and IrNP, the long-term kinetics of interstitial relocation and subsequent re-entrainment onto the lung-epithelium is similar for AuNP and Ir-NP but slower than for TiO2-NP. We discuss mechanisms and pathways of NP relocation and re-entrainment versus translocation. Additionally, after 28 days the integral translocated fractions of TiO2-NP and IrNP across the air-blood-barrier (ABB) are similar and become 0.15 while the translocated AuNP fraction is only 0.04. While NP dissolution proved negligible, translocated TiO2-NP and IrNP are predominantly excreted in urine (~ 0.1) while the urinary AuNP excretion amounts to a fraction of only 0.01. Urinary AuNP excretion is below 0.0001 during the first week but rises tenfold thereafter suggesting delayed disagglomeration. Of note, all three NP dissolve minimally, since no ionic radio-label release was detectable. These biokinetics data of inhaled, same-sized NP suggest significant time-dependent differences of the ABB translocation and subsequent fate in the organism.

Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial.

BACKGROUND: miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes. METHODS: In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49. FINDINGS: Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4·42 (IQR 3·23-5·00) and 5·07 (4·19-5·35) log10 IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5' UTR of the HCV genome. INTERPRETATION: This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks. FUNDING: Regulus Therapeutics, Inc.

The Effect of Maturation on Performance During Repeated Sprints With Self-Selected Versus Standardized Recovery Intervals in Youth Footballers.

PURPOSE: The purpose of this experiment was to assess performance during repeated sprints utilizing self-selected recovery intervals in youth football (soccer) players at different stages of maturation. METHODS: Quota sampling method was used to recruit 14 prepeak height velocity (PHV) and 14 post-PHV participants for the study (N = 28; age = 13 [0.9] y, stature = 162.5 [10.8] cm, mass = 50.2 [12.7] kg). Players performed repeated sprints comprising 10 × 30 m efforts under 2 experimental conditions: using 30-second and self-selected recovery intervals. Magnitude of effects for within- and between-group differences were reported using effect size (ES) statistics ± 90% confidence intervals and percentage differences. RESULTS: The decline in sprint performance was likely lower in the pre-PHV compared with the post-PHV group during the standardized recovery trial (between-group difference = 37%; ES = 0.41 ± 0.51), and likely lower in the post-PHV group during the self-selected recovery trial (between-group difference = 50%; ES = 0.45 ± 0.54). Mean recovery duration was likely shorter in the pre-PHV compared with the post-PHV group during the self-selected recovery trial (between-group difference = 26.1%; ES = 0.47 ± 0.45). CONCLUSION: This is the first study to show that during repeated sprints with self-selected recovery, pre-PHV children have an impaired ability to accurately interpret physical capabilities in the context of the task compared with post-PHV adolescents.

Point of care ultrasound training for internal medicine: a Canadian multi-centre learner needs assessment study.

BACKGROUND: Significant gaps currently exist in the Canadian internal medicine point-of-care ultrasound (POCUS) curriculum. From a learner's perspective, it remains unknown what key POCUS skills should be prioritized. This needs assessment study seeks to establish educational priorities for POCUS for internal medicine residents at five Canadian residency training programs. METHODS: All internal medicine trainees [postgraduate year (PGY) 1-5] from five internal medicine residency training programs in Canada (n = 598) were invited to complete an online survey on 15 diagnostic POCUS applications, 9 bedside procedures, and 18 POCUS knowledge items. For POCUS applications and procedures, participants were asked how applicable they are to patient care in internal medicine and the participants' reported skills in those domains. Self-reported knowledge and skills were rated on a 5-point Likert scale, where 1 = very poor and 5 = very good. Applicability was rated, where 1 = not at all applicable and 5 = very applicable. RESULTS: A total of 253 of 598 residents (42%) participated in our study. Data from one centre (n = 15) was removed because of low response rate (15%) and significant baseline differences between those trainees and the remaining participants. Of the remaining analyzable data from four training programs (n = 238), participants reported highest applicability to internal medicine for the following applications and procedures: identifying ascites/free fluid [mean applicability score of 4.9 ± standard deviation (SD) 0.4]; gross left ventricular function (mean 4.8 ± SD 0.5) and pericardial effusion (mean 4.7 ± SD 0.5); thoracentesis (mean score 4.9 ± SD 0.3), central line insertion (mean 4.9 ± SD 0.3), and paracentesis (mean 4.9 ± SD 0.3), respectively. Overall reported knowledge/skills was low, with skill gaps being the highest for identifying deep vein thrombosis (mean gap 2.7 ± SD 1.1), right ventricular strain (mean 2.7 ± SD 1.1), and gross left ventricular function (mean 2.7 ± SD 1.0). CONCLUSIONS: Many POCUS applications and procedures were felt to be applicable to the practice of internal medicine. Significant skill gaps exist in the four Canadian training programs included in the study. POCUS curriculum development efforts should target training based on these perceived skill gaps.

Match Demands of Senior and Junior Players During International Rugby League.

Dempsey, GM, Gibson, NV, Sykes, D, Pryjmachuk, BC, and Turner, AP. Match demands of senior and junior players during International Rugby League. J Strength Cond Res 32(6): 1678-1684, 2018-This study aims to quantify and compare the positional game demands of international junior and senior rugby league competition for the first time. Global positioning system (GPS) and video analysis were used to track 118 elite male rugby league players (57 seniors aged 28.7 ± 4.4 years; 61 juniors aged 17.2 ± 0.5 years) over 10 international matches (6 senior; 4 junior) characterized as either forwards (n = 67) or backs (n = 51). There were significant increases in the offensive carries (0.18 cf. 0.09 n·min; r = 0.56) and defensive tackles (0.36 cf. 0.23 n·min; r = 0.3) between senior and junior players, and forwards and backs (0.16 cf. 0.09; r = 0.34 and 0.41 cf. 0.14; r = 0.52), respectively. Running demands were significantly greater in backs than forwards (independent of playing level) for total distance (6,962 ± 1,263 m cf. 4,879 ± 1,824 m; r = 0.55), individualized high-speed distances (310 ± 158 m cf. 250 ± 171 m; r = 0.2), high-intensity accelerations (28.7 ± 12.1 m·s cf. 21.9 ± 11.7 m·s; r = 0.27), and decelerations (57.2 ± 18.3 m·s cf. 43.0 ± 17.8 m·s; r = 0.38). Positional differences were eliminated when reported relative to minutes played. From a practical perspective, although running demands relative to time on the pitch may prepare junior players for senior competition, it is not representative of the increased body mass and contact frequency within the senior game. Coaches should therefore reflect these differences within their physical preparation programs to prepare junior athletes accordingly for progression to the senior level.

EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6.

BACKGROUND: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). METHODS: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. RESULTS: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA- (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. CONCLUSIONS: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.

Physiological, Perceptual and Performance Responses Associated With Self-Selected Versus Standardized Recovery Periods During a Repeated Sprint Protocol in Elite Youth Football Players: A Preliminary Study.

PURPOSE: To examine the physiological and perceptual responses of youth footballers to a repeated sprint protocol employing standardized and self-selected recovery. METHODS: Eleven male participants (13.7 ± 1.1 years) performed a repeated sprint assessment comprising 10 × 30 m efforts. Employing a randomized cross-over design, repeated sprints were performed using 30 s and self-selected recovery periods. Heart rate was monitored continuously with ratings of perceived exertion (RPE) and lower body muscle power measured 2 min after the final sprint. The concentration of blood lactate was measured at 2, 5 and 7 min post sprinting. Magnitude of effects were reported using effect size (ES) statistics ± 90% confidence interval and percentage differences. Differences between trials were examined using paired student t tests (p < .05). RESULTS: Self-selected recovery resulted in most likely shorter recovery times (57.7%; ES 1.55 ± 0.5; p < .01), a most likely increase in percentage decrement (65%; ES 0.36 ± 0.21; p = .12), very likely lower heart rate recovery (-58.9%; ES -1.10 ± 0.72; p = .05), and likely higher blood lactate concentration (p = .08-0.02). Differences in lower body power and RPE were unclear (p > .05). CONCLUSION: Self-selected recovery periods compromise repeated sprint performance.

Influence of Physical Maturity Status on Sprinting Speed Among Youth Soccer Players.

McCunn, R, Weston, M, Hill, JKA, Johnston, RD, and Gibson, NV. Influence of physical maturity status on sprinting speed among youth soccer players. J Strength Cond Res 31(7): 1795-1801, 2017-The relative age effect is well documented with the maturation-selection hypothesis the most common explanation; however, conflicting evidence exists. We observed the birth date distribution within an elite junior soccer academy. The influence of physical maturity status on anthropometric variables and sprinting ability was also investigated. Annual fitness testing was conducted over an 8-year period with a total of 306 players (age: 12.5 ± 1.7 years [range: 9.7-16.6 years]; stature: 156.9 ± 12.9 cm; mass: 46.5 ± 12.5 kg) drawn from 6 age categories (under-11s to under-17s) who attended the same Scottish Premiership club academy. Measurements included mass, stature, maturity offset and 0-15 m sprint. Odds ratios revealed a clear bias toward recruitment of players born in quartile 1 compared with quartile 4. The overall effect (all squads combined) of birth quartile was very likely small for maturity offset (0.85 years; 90% confidence interval [CI], 0.44-1.26 years) and stature (6.2 cm; 90% CI, 2.8-9.6 cm), and likely small for mass (5.1 kg; 90% CI, 1.7-8.4 kg). The magnitude of the relationship between maturity offset and 15-m sprinting speed ranged from trivial for under-11s (r = 0.01; 90% CI, -0.14 to 0.16) to very likely large for under-15s (r = -0.62; -0.71 to -0.51). Making decisions about which players to retain and release should not be based on sprinting ability around the under-14 and under-15 age categories because any interindividual differences may be confounded by transient inequalities in maturity offset.