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Objectives Cross-country (CC) skiing consists of two main techniques: classic and skating. Hip motion during the skating technique is similar to that in ice skating and is considered a risk factor for femoroacetabular impingement (FAI) in ice hockey players. We aimed to compare the presence of CAM-type FAI in a cohort of elite junior CC (EJCC) skiers with a control group of non-athlete (NA) high school students. Methods Observational cohort study: EJCC skiers and NAs were recruited from a sports school and a regular high school, respectively. Baseline demographics and training history were obtained via a questionnaire. Bilateral hip MRI was performed and the alpha angle was measured in three planes. CAM deformity was defined as an alpha angle>55° on at least two MRI planes per hip. Results A total of 20 EJCC skiers and 10 NAs participated. All participants were male, aged 16–19 years. Average training volume was 528.10±68.34 hours per year for the EJCC skiers compared with 153.50±57.09 for the NAs (p<0.001). The prevalence of CAM deformity in at least one hip on MRI was 50% in both groups (10 CC skiers and 5 NAs). The average alpha angles were 52.4±6.1° in the EJCC group and 52.5±4.9° in the NA group (p=0.94). Conclusion Radiographic evidence of CAM-type FAI was not more common in the CC skiers compared with NAs. The type, rather than volume or intensity of training, maybe a more important risk factor for the development of CAM-type FAI in young athletes.

Background:The expression of the receptor tyrosine kinase (RTK) Axl on cancer cells has been associated with poor prognosis and implicated in disease progression. Inhibition of Axl‐RTK with TP‐0903, a high affinity Axl‐RTK inhibitor induces robust apoptosis of several tumors, including chronic lymphocytic leukemia (CLL). Axl‐RTK inhibition has also been found to induce nonspecific immunomodulatory effects in syngeneic tumor models.Aims:We aimed to investigate the impact and downstream effects of Axl‐RTK inhibition on naïve T cells and chimeric antigen receptor T cells (CART), using CD19 directed CART cells (CART19) as a model.Methods:We utilized either PMA/Ionomycin or the CD19+ mantle cell lymphoma cell line, JeKo as a stimulant for naïve T cells and CART19, respectively. Cells were analyzed for cytokine profile, T cell phenotype, and kinetics after the stimulation in the presence or the absence of the Axl‐RTK inhibitor TP‐0903. Regarding in vivo experiment, a relapse JeKo xenograft model was used. Mice were treated with vehicle alone, TP‐0903 alone, CART19 alone, or TP‐0903 + CART19. Three weeks after the treatment, mice were re‐challenged with JeKo as a CART19 relapse model.Results:Stimulation of naïve T cells in the presence of the Axl‐RTK inhibitor TP‐0903 resulted in a significant reduction of Th2 cytokines and downregulation of inhibitory receptors. The differential expansion of either effector T cells or Tregs in the presence of TP‐0903 resulted in a preferential reduction of Tregs (Fig 1A). Axl‐RTK inhibition of CART19 led to Th1 polarization upon stimulation with the JeKo, as evident by the selective reduction of Th2 cytokine. Additionally, this resulted in a reduction of myeloid attracting cytokines, such as CXCL1, IL‐8, IL‐6, and IL‐10, cytokines implicated in the development cytokine release syndrome and neurotoxicity after CART cell therapy and in adaptive resistance to immunotherapy (Fig 1B). TP‐0903 also significantly downregulated inhibitory receptors on activated CARTs (Fig 1C). In our relapsed in vivo model, mice treated with CART19 + TP‐0903 rejected the JeKo challenge while mice received CART19 alone redeveloped disease, suggesting that Axl‐RTK inhibition enhanced CART cell persistence. Peripheral blood analysis of mice after the rechallenge showed a higher number of circulating T cells and lower level of MCP‐1. Western blotting was performed to investigate the downstream effect of Axl‐RTK inhibition on CART19 and it revealed a relatively selective inhibition of LCK on stimulated CART19. Transcriptome analysis of activated CARTs treated with TP‐0903 revealed >100 genes that were differentially expressed compared to untreated cells. Among these, Th cell and Treg polarization genes were significantly altered in activated CARTs treated with TP‐0903.imageFinally, we validated our findings in phase I clinical trial of TP‐0903 (NCT02729298). T cells isolated from 3 cancer patients showed a significant reduction of Tregs and Th1 polarization. This will be further investigated in a planned phase I clinical trial of TP‐0903 in relapsed/refractory CLL (NCT03572634).Summary/Conclusion:We showed for the first time that Axl‐RTK inhibition polarizes T cells into a Th1 functional phenotype, downregulates inhibitory receptors, and reduces myeloid associated cytokine production by CART19. The combination therapy yielded synergistic cytotoxicity against JeKo in vitro and in a CART19 relapse model. These findings encourage further study of Axl‐RTK inhibition with TP‐0903 as an enhancer of T cell immunotherapies.

This paper reports temporal changes in physiological measurements of exercise performance in a young man transitioning from alpine skiing until he became a world junior champion time trial cyclist after only 3 yr of bike-specific training. At the time he became World Champion he also achieved among the highest reported maximal oxygen uptake (V̇o2max) value, 96.7 ml·min−1·kg−1, or 7,397 ml/min in absolute terms at 76.5 kg, which had increased by 29.6% from 74.6 ml·min−1·kg−1 pre-bike-specific training. After 15 mo with almost no structured exercise training, V̇o2max returned to 77.0 mL·min−1·kg−1 and was similar to the value reported before specific bike training, albeit with absolute term (6,205 ml/min) still being 11.3% higher. Part of the explanation for his athletic achievements is likely also related to the up to 20.9% improvement in Power@4 mmol/l (W). Although genetic profiles of endurance athletes have not generated data suggesting a shared genetic signature associated with elite endurance performance, this case study highlights the importance of intrinsic biological factors in elite endurance performance. NEW & NOTEWORTHY This study shows that very high V̇o2max values (>70 ml·min−1·kg−1) can be found in individuals not previously specializing in aerobic training and that values of >90 ml·min−1·kg−1, as well as a cycling world junior champion title, can be achieved in such individuals with just 3 yr of dedicated exercise training.

Purpose To evaluate for appearance-based discrimination in the selection of radiology residents. Method A deception study simulating the resident selection process examined the impact of attractiveness and obesity on resident selection. Seventy-four core faculty from 5 academic radiology departments reviewed mock residency applications in September and October 2017. Each application included demographic information and a photograph, representing a prespecified distribution of facial attractiveness and obesity, combined with randomized academic and supporting variables. Reviewers independently scored applications for interview desirability. Reviewer scores and application variables were compared using linear mixed fixed- and random-effects models. Results Reviewers evaluated 5,447 applications (mean: 74 applications per reviewer). United States Medical Licensing Examination Step 1 scores were the strongest predictor of reviewer rating (B = 0.35 [standard error (SE) = 0.029]). Applicant facial attractiveness strongly predicted rating (attractive vs unattractive, B = 0.30 [SE = 0.056]; neutral vs unattractive, B = 0.13 [SE = 0.028]). Less influential but still significant predictors included race/ethnicity (B = 0.25 [SE = 0.059]), preclinical class rank (B = 0.25 [SE = 0.040]), clinical clerkship grades (B = 0.23 [SE = 0.034]), Alpha Omega Alpha membership (B = 0.21 [SE = 0.032]), and obesity (vs not obese) (B = −0.14 [SE = 0.024]). Conclusions Findings provide preliminary evidence of discrimination against facially unattractive and obese applicants in radiology resident selection. Obesity and attractiveness were as influential in applicant selection for interview as traditional medical school performance metrics. Selection committees should invoke strategies to detect and manage appearance-based bias.

Aim: Compare the effect of Latarjet and Trillat procedures on glenohumeral stability and range of motion. Background: Little is known about the impact of the location of the sling effect on joint stability and range of motion. Methods: 12 cadaveric shoulders were cleaned of soft tissue except for the subscapularis, conjoined tendon, and anterior capsule. A custom-made apparatus generating anterior humeral translation and joint compression was used. The machine applied compression load in the medial direction. The subscapularis and conjoint tendon were loaded. Internal/external range of motion and joint stability were assessed at 0°, 30° and 60° glenohumeral abduction. Range of motion was assessed by rotating the humeral shaft. Joint stability was assessed at maximum external rotation, translating the humerus. Specimen were tested in five conditions: 1) intact shoulder, 2) 6-mm bony glenoid defect (20% defect) 3) Trillat procedure, 4) Latarjet procedure with subscapularis split at the junction between its superior 2/3rds and inferior 1/3 rd, 5) Latarjet procedure with subscapularis split at the superior 1/3rds and inferior 2/3rds. Means were compared with a full factorial-repeated measures ANOVA with pairwise post hoc comparisons. Results: Peak translation force and stability ratio were significantly lower with the glenoid defect when compared to the intact and all the repaired conditions at all levels of glenohumeral abduction. The level of the subscapularis split had no significant influence on these values and no significant difference could be found between Trillat and Latarjet procedures. Range of motion in internal and external rotation were not significantly different between the different conditions. Conclusions: Joint stability and range of motion after a Latarjet are not impacted by the location of the subscapularis muscle split. Trillat and Latarjet techniques provide comparable stabilization of the joint, even in the presence of a critical bony defect of the glenoid.

Background: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDGs) with defective N-glycosylation. Methods: We studied 29 patients with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)–deficiency CDG and PMM2 (phosphomannomutase 2)–deficiency CDG, and 23 first- and second-degree relatives with a heterozygous mutation and measured plasma cholesterol levels. Low-density lipoprotein (LDL) metabolism was studied in 3 cell models—gene silencing in HepG2 cells, patient fibroblasts, and patient hepatocyte-like cells derived from induced pluripotent stem cells—by measuring apolipoprotein B production and secretion, LDL receptor expression and membrane abundance, and LDL particle uptake. Furthermore, SREBP2 (sterol regulatory element-binding protein 2) protein expression and activation and endoplasmic reticulum stress markers were studied. Results: We report hypobetalipoproteinemia (LDL cholesterol [LDL-C] and apolipoprotein B below the fifth percentile) in a large cohort of patients with type I CDG (mean age, 9 years), together with reduced LDL-C and apolipoprotein B in clinically unaffected heterozygous relatives (mean age, 46 years), compared with 2 separate sets of age- and sex-matched control subjects. ALG6 and PMM2 deficiency led to markedly increased LDL uptake as a result of increased cell surface LDL receptor abundance. Mechanistically, this outcome was driven by increased SREBP2 protein expression accompanied by amplified target gene expression, resulting in higher LDL receptor protein levels. Endoplasmic reticulum stress was not found to be a major mediator. Conclusions: Our study establishes N-glycosylation as an important regulator of LDL metabolism. Given that LDL-C was also reduced in a group of clinically unaffected heterozygotes, we propose that increasing LDL receptor–mediated cholesterol clearance by targeting N-glycosylation in the LDL pathway may represent a novel therapeutic strategy to reduce LDL-C and cardiovascular disease.

BackgroundThe optimal anticoagulation strategy for patients with atrial fibrillation (AF) and bioprosthetic valve (BPV) replacement or native valve repair remains uncertain.HypothesisWe evaluated the safety and efficacy of apixaban vs warfarin in patients with AF and a history of BPV replacement or native valve repair.MethodsUsing data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (n = 18 201), a randomized trial comparing apixaban with warfarin in patients with AF, we analyzed the subgroup of patients (n = 251) with prior valve surgery. We contacted sites by telephone to obtain additional data about prior valve surgery. Full data were available for 156 patients. The primary efficacy endpoint was stroke/systemic embolism. The primary safety endpoint was major bleeding. Treatment groups were compared using a Cox regression model.ResultsIn ARISTOTLE, 104 (0.6%) patients had a history of BPV replacement (n = 73 [aortic], n = 26 [mitral], n = 5 [mitral and aortic]) and 52 (0.3%) had a history of valve repair (n = 50 [mitral], n = 2 [aortic]). Among patients with BPVs, 55 were randomized to apixaban and 49 to warfarin. Among those with a history of native valve repair, 32 were randomized to apixaban and 20 to warfarin. Overall clinical event rates were low, with no significant differences between apixaban and warfarin for any outcomes.ConclusionsIn patients with AF and a history of BPV replacement or repair, the safety and efficacy of apixaban compared with warfarin was consistent with results from ARISTOTLE. These data suggest that apixaban may be reasonable for patients with BPVs or prior valve repair, though future larger randomized trials are needed.ClinicalTrials.govNCT00412984.

Objectives Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF). Methods The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2 months of study treatment. Results In patients not on VKA treatment at randomisation, F1+2 and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p<0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2 and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p<0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2 months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2 months. Conclusions Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk. Trial registration number NCT00412984.