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Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer.Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III - V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%).Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC.Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer.

This is the first study to document the training and tapering practices of elite CrossFit athletes. Seventy-two CrossFit athletes (39 females, 33 males) (mean ±SD; 26.5 ± 3.6 y, 167.1 ± 9.5 cm, 74.5 ± 12.7 kg, 12.8 ± 6.5 y general training, 5.4 ± 1.7 y CrossFit training) who competed at the “Regionals” level or higher in the 2018 CrossFit Games season completed a self-reported 5-page online survey. Almost all athletes (98.6%) tapered before important competitions. Taper length was 5.4 ± 2.7 days, with the step and linear tapering styles being most commonly utilised. Strength training volume peaked 5.1 ± 4.6 weeks before competition, whereas conditioning training volume peaked 4.0 ± 4.4 weeks before competition. Strength training intensity peaked 3.1 ± 2.4 weeks before competition, whereas conditioning training intensity peaked 2.8 ± 2.2 weeks before competition. Almost all athletes (90.0%) reduced training duration during tapering, but changes to frequency and intensity were mixed. Training volume decreased by 41.2 ± 15.5% during the taper, all training ceased 2.0 ± 1.1 days before competition. Tapering was performed to achieve peak performance, recover (physically and psychologically), and reduce feelings of fatigue. Poor results from tapering were experienced when athletes tapered for too long or insufficiently. This observational data may be valuable for coaches and athletes engaged in CrossFit as well as other sports with concurrent training and competition demands.

Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on ASCL1lo and ASCL1hi GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in ASCL1lo GSCs. In contrast, in ASCL1hi GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in ASCL1lo GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype-restricted cancer stem cells.

High efficiency lunate-tail swimming with high-aspect-ratio lifting surfaces has evolved in many vertebrate lineages, from fish to cetaceans. Baleen whales (Mysticeti) are the largest swimming animals that exhibit this locomotor strategy, and present an ideal study system to examine how morphology and the kinematics of swimming scale to the largest body sizes. We used data from whale-borne inertial sensors coupled with morphometric measurements from aerial drones to calculate the hydrodynamic performance of oscillatory swimming in six baleen whale species ranging in body length from 5 to 25 m (fin whale, Balaenoptera physalus; Bryde's whale, Balaenoptera edeni; sei whale, Balaenoptera borealis; Antarctic minke whale, Balaenoptera bonaerensis; humpback whale, Megaptera novaeangliae; and blue whale, Balaenoptera musculus). We found that mass-specific thrust increased with both swimming speed and body size. Froude efficiency, defined as the ratio of useful power output to the rate of energy input ( Sloop, 1978), generally increased with swimming speed but decreased on average with increasing body size. This finding is contrary to previous results in smaller animals, where Froude efficiency increased with body size. Although our empirically parameterized estimates for swimming baleen whale drag were higher than those of a simple gliding model, oscillatory locomotion at this scale exhibits generally high Froude efficiency as in other adept swimmers. Our results quantify the fine-scale kinematics and estimate the hydrodynamics of routine and energetically expensive swimming modes at the largest scale., Summary: Tags attached to baleen whales demonstrate how thrust power output, drag coefficient and Froude efficiency scale with swimming speed and body length.

Winwood, PW, Pritchard, HJ, Wilson, D, Dudson, M, and Keogh, JWL. The competition-day preparation strategies of strongman athletes. J Strength Cond Res 33(9): 2308-2320, 2019-This study provides the first empirical evidence of the competition-day preparation strategies used by strongman athletes. Strongman athletes (n = 132) (mean ± SD: 33.7 ± 8.1 years, 178.2 ± 11.1 cm, 107.0 ± 28.6 kg, 12.8 ± 8.0 years general resistance training, 5.9 ± 4.8 years strongman implement training) completed a self-reported 4-page internet survey on their usual competition-day preparation strategies. Analysis of the overall group and by sex, age, body mass, and competitive standard was conducted. Ninety-four percent of strongman athletes used warm-ups in competition, which were generally self-directed. The typical warm-up length was 16.0 ± 8.9 minutes, and 8.5 ± 4.3 minutes was the perceived optimal rest time before the start of an event. The main reasons for warming up were injury prevention, to increase activation, and increase blood flow/circulation, temperature, and heart rate. Athletes generally stated that competition warm-ups were practiced in training. Dynamic stretching, foam rolling, and myofascial release work were performed during warm-ups. Warm-up intensity was monitored using the rate of perceived exertion, perceived speed of movement, and training load (as a percentage of 1 repetition maximum). Cognitive strategies were used to improve competition performance, and psychological arousal levels needed to increase or be maintained in competition. Electrolyte drinks, caffeine, and preworkout supplements were the commonly used supplements. These data will provide strongman athletes and coaches some insight into common competition-day preparation strategies, which may enhance competition performances. Future research could compare different competition-day preparation strategies in an attempt to further improve strongman competition performance and injury prevention.

Background DriveSafe DriveAware (DSDA) has been validated as an off-road screening tool for predicting on-road driving performance in clinical populations, but its utility in people with Huntington's disease (HD) is unknown. Objective Our aim was to evaluate the utility of DSDA in people with HD by demonstrating sensitivity of DSDA scores to HD progression and exploring associations between DSDA performance and cognitive functions that are essential to driving and impaired in people with HD. Methods We administered the iPad application version of DSDA to 26 pre-symptomatic and symptomatic participants with HD. Disease progression was assessed via measures of motor impairment, disease burden and functional capacity. Standardised neuropsychological tests were used to assess cognitive function across several domains including attention, processing speed, planning, and visuoperception. Results Results underscore the sensitivity of DSDA to HD progression and cognitive impairment; that is, poorer DSDA performance was associated with greater HD severity and poorer cognitive ability across the domains of attention, processing speed, and planning. Nevertheless, we identified a proportion of participants with HD who were predicted to pass on-road testing based on DSDA, but scored in the impaired range on multiple cognitive tests. These participants tended to score closer to the cut-off score used by DSDA to categorise pass/fail outcomes. Conclusions Our findings demonstrate potential for use of DSDA in the HD population, however, significant variability in cognitive performance among those predicted to 'pass' on-road driving assessment suggests the screening tool requires further development for use with HD drivers.

Background: Breast cancer, is increasing in prevalence amongst South East (SE) Asian women, highlighting the need for high quality, early diagnoses. This study investigated radiologists’ detection efficacy in a developing (DC) and developed (DDC) SE Asian country, as compared to Australian radiologists. Methods: Using a test-set of 60 mammographic cases, 20 containing cancer, JAFROC figures of merit (FOM) and ROC area under the curves (AUC) were calculated as well as location sensitivity, sensitivity and specificity. The test set was examined by 35, 15, and 53 radiologists from DC, a DDC and Australia, respectively. Results: DC radiologists, compared to both groups of counterparts, demonstrated significantly lower JAFROC FOM, ROC AUC and specificity scores. DC radiologists had a significantly lower location sensitivity than Australian radiologists. DC radiologists also demonstrated significantly lower values for age, hours of reading per week, and years of mammography experience when compared with other radiologists. Conclusion: Significant differences in breast cancer detection parameters can be attributed to the experience of DC radiologists. The development of inexpensive, innovative, interactive training programs are discussed. This nonuniform level of breast cancer detection between countries must be addressed to achieve the World Health Organisation goal of health equity.

We applied continuous flash suppression (CFS) during an interocular transfer paradigm to evaluate the importance of awareness and the contribution of early versus late visual structures in size recognition. Specifically, we tested if size judgements of a visible target could be influenced by a congruent or incongruent prime presented to the same or different eye. Without CFS, participants categorised a target as “small” or “large” more quickly when it was preceded by a congruent prime – regardless of whether the prime and target were presented to the same or different eye. Interocular transfer enabled us to infer that the observed priming was mediated by late visual areas. In contrast, there was no priming under CFS, which underscores the importance of awareness. We conclude that awareness and late visual structures are important for size perception and that any subconscious processing of the stimulus has minimal effect on size recognition.

Pritchard, HJ, Barnes, MJ, Stewart, RJC, Keogh, JWL, and McGuigan, MR. Short-term training cessation as a method of tapering to improve maximal strength. J Strength Cond Res 32(2): 458-465, 2018-The aim of this study was to determine the effects of 2 different durations of training cessation on upper- and lower-body maximal strength performance and to investigate the mechanisms underlying performance changes following short-term training cessation. Eight resistance trained males (23.8 ± 5.4 years, 79.6 ± 10.2 kg, 1.80 ± 0.06 m, relative deadlift 1 repetition maximum of 1.90 ± 0.30 times bodyweight [BW]) each completed two 4-week strength training periods followed by either 3.5 days (3.68 ± 0.12 days) or 5.5 days (5.71 ± 0.13 days) of training cessation. Testing occurred pretraining (T1), on the final day of training (T2), and after each respective period of training cessation (T3). Participants were tested for salivary testosterone and cortisol, plasma creatine kinase, psychological profiles, and performance tests (countermovement jump [CMJ], isometric midthigh pull, and isometric bench press [IBP]) on a force plate. Participants' BW increased significantly over time (p = 0.022). The CMJ height and IBP peak force showed significant increases over time (p = 0.013, 0.048, and 0.004, respectively). Post hoc testing showed a significant increase between T1 and T3 for both CMJ height and IBP peak force (p = 0.022 and 0.008 with effect sizes of 0.30 and 0.21, respectively). No other significant differences were seen for any other measures. These results suggest that a short period of strength training cessation can have positive effects on maximal strength expression, perhaps because of decreases in neuromuscular fatigue.

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

IntroductionFollowing the treatment of patients with soft tissue sarcomas (STS) that are not metastatic at presentation, the high risk for local and systemic disease recurrence necessitates post-treatment surveillance. Systemic recurrence is most often detected in the lungs. The most appropriate surveillance frequency and modality remain unknown and, as such, clinical practice is highly varied. We plan to assess the feasibility of conducting a multi-centre randomised controlled trial (RCT) that will evaluate the effect on overall 5-year survival of two different surveillance frequencies and imaging modalities in patients with STS who undergo surgical excision with curative intent.Methods and analysisThe Surveillance After Extremity Tumor Surgery trial will be a multi-centre 2×2 factorial RCT. Patients with non-metastatic primary Grade II or III STS treated with excision will be allocated to one of four treatment arms1: chest radiograph (CXR) every 3 months for 2 years2; CXR every 6 months for 2 years3; chest CT every 3 months for 2 years or4 chest CT every 6 months for 2 years. The primary outcome of the pilot study is the feasibility of a definitive RCT based on a combination of feasibility endpoints. Secondary outcomes for the pilot study include the primary outcome of the definitive trial (overall survival), patient-reported outcomes on anxiety, satisfaction and quality of life, local recurrence-free survival, metastasis-free survival, treatment-related complications and net healthcare costs related to surveillance.Ethics and disseminationThis trial received provisional ethics approval from the McMaster/Hamilton Health Sciences Research Ethics Board on 7 August 2019 (Project number 7562). Final ethics approval will be obtained prior to commencing patient recruitment. Once feasibility has been established and the definitive protocol is finalised, the study will transition to the definitive study.Trial registrationNCT03944798; Pre-results.

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.

Much of the previous research on the emergence of team-level constructs has overlooked their inherently dynamic nature by relying on static, cross-sectional approaches. Yet theoretical arguments regarding emergent states have underscored the importance of considering time in understanding these states. Unfortunately, minimal work has been dedicated towards examining the dynamics of team emergent states. In the present research, we address this limitation by investigating the dynamic nature of group potency, a crucial emergent state, over time. Theory around the ‘better-than-average’ effect (i.e., an individual’s tendency to think he/she is better than the average person) suggests that individuals may have elevated expectations of their group’s potency early on, but may decrease over time as team members interact and members gain a more realistic perspective on their group’s potential abilities. In addition, as members gain experience with each other, they develop a shared understanding of team attributes. To investigate this, the current study used both latent growth and consensus emergence modeling to examine how group potency changed over time, and its relation with team effectiveness. Further, in accordance with the input-process-output framework, we investigated how the change in group potency mediated the relation between the team-level compositions of conscientiousness and extraversion personality traits and team effectiveness. We collected data from 337 first-year engineering students that comprised 77 project teams. Data were collected at three time points throughout an engineering design course. First, the results of the latent growth model suggested that group potency decreased, on average, following a linear trend over time. Second, we found that group consensus regarding group potency increased over time. Third, we found that teams’ initial group potency was a significant predictor of team effectiveness, but that change in potency was not significantly related to team effectiveness. Finally, we found that teams with higher mean-level conscientiousness – but not extraversion – had higher initial group potency. The indirect effect linking conscientiousness to team effectiveness, through initial potency, was also supported. Overall, the current study offers a unique understanding of the emergence of group potency.

The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction.Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the brain responds as if there were low levels of leptin, leading to increased appetite and suppressed fertility. Here we show that leptin resistant infertility is caused in part by the leptin signaling molecule SOCS3. Deletion of SOCS3 from brain neurons delays the onset of diet-induced infertility.

Objectives: Nerve block administration in concert with general anesthesia can help manage post-operative pain and provide favorable muscle relaxation of the operative leg in hip surgery. However, the optimal nerve blockade_if any_for arthroscopic surgery of the hip remains undefined. Considerations specific to hip arthroscopy include control of intra-operative pain, adequate muscle relaxation to allow for distraction for work in the central compartment, and post-operative pain control. Dold et al. recently reported in AJSM that a pre-operative femoral nerve block administered in concert with general anesthesia led to decreased patient-reported pain scores at the 60 minute mark post-operatively. Given this demonstrated benefit of the pre-operative femoral nerve block, we hypothesized that a regional block that anesthetized the femoral nerve and the lateral femoral cutaneous nerve (as the fascia iliaca block does), or one that anesthetized the obturator nerve in addition to the femoral and lateral femoral cutaneous nerves (i.e. the lumbar plexus block), would provide additional benefit. The purpose of this study is to examine the effects of pre-operative fascia iliaca and lumbar plexus nerve blocks on post-operative pain and secondary post-operative variables following arthroscopic surgery of the hip. Methods: A retrospective chart analysis was conducted on 145 patients undergoing arthroscopic surgery of the hip in 3 groups. Group 1 (n=55) received general anesthesia only, Group 2 (n=30) received general anesthesia and a fascia iliaca nerve block, and Group 3 (n=60) received general anesthesia and a lumbar plexus nerve block. Post-operative measures were recorded, examined and compared. The primary outcome measure was patient reported pain scores (0-10) at 0, 30, 60, 90 and 120 minutes in the post-anesthesia care unit (PACU). Secondary variables examined included time spent in the PACU, morphine equivalent administered, and presence of nausea requiring anti-emetic medication. Results: Mid-term analysis revealed no benefit to the fascia iliaca block; this regional anesthesia technique showed no significant effect on any of the measured post-operative variables when compared to general anesthesia alone. We therefore abandoned this block in favor of the lumbar plexus block. Patients receiving a lumbar plexus block exhibited significantly decreased pain at each time point when compared to the fascia iliaca group, and at all but one time point when compared to the general anesthesia group (P

Pritchard, HJ, Tod, DA, Barnes, MJ, Keogh, JW, and McGuigan, MR. Tapering practices of New Zealand's elite raw powerlifters. J Strength Cond Res 30(7): 1796-1804, 2016-The major aim of this study was to determine tapering strategies of elite powerlifters. Eleven New Zealand powerlifters (28.4 ± 7.0 years, best Wilks score of 431.9 ± 43.9 points) classified as elite were interviewed, using semistructured interviews, about their tapering strategies. Interviews were transcribed verbatim and content analyzed. Total training volume peaked 5.2 ± 1.7 weeks from competition while average training intensity (of 1 repetition maximum) peaked 1.9 ± 0.8 weeks from competition. During tapering, volume was reduced by 58.9 ± 8.4% while intensity was maintained (or slightly reduced) and the final weight training session was performed 3.7 ± 1.6 days out from competition. Participants generally stated that tapering was performed to achieve full recovery; that accessory work was removed around 2 weeks out from competition; and deadlifting takes longer to recover from than other lifts. Typically participants stated that trial and error, and changes based on "feel" were the sources of tapering strategies; equipment used and movements performed during tapering are the same as in competition; nutrition was manipulated during the taper (for weight cutting or performance aims); and poor tapering occurred when too long (1 week or more) was taken off training. These results suggest that athletes may benefit from continuing to strength train before important events with reduced volume and maintained intensity. Only exercises that directly assist sports performance should remain in the strength program during tapering, to assist with reductions in fatigue while maintaining/improving strength expression and performance.

Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.

Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2+ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2+ precursors and that the EGL maintains a rare fraction of Sox2+ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2+ cells are within the Atoh1+ lineage, contribute extensively to adult granule neurons, and resemble Sox2+ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB.

Background Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention. Methods The By‐Band study was designed in the UK in 2009–2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux‐en‐Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation. Results The pilot phase recruited over 13 months in 2013–2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder. Conclusion Adaptation of a two‐group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (http://www.isrctn.com/)., Something to consider

Purpose: To investigate the effects of strength-training tapers of different intensities but equal volume reductions on neuromuscular performance. Methods: Eleven strength-trained men (21.3 [3.3] y, 92.3 [17.6] kg, relative 1-repetition-maximum deadlift 1.9 [0.2] times bodyweight) completed a crossover study. Specifically, two 4-wk strength-training blocks were followed by a taper week with reduced volume (∼70%) involving either increased (5.9%) or decreased (−8.5%) intensity. Testing occurred pretraining (T1), posttraining (T2), and posttaper (T3). Salivary testosterone and cortisol, plasma creatine kinase, a Daily Analysis of Life Demands in Athletes questionnaire, countermovement jump (CMJ), isometric midthigh pull, and isometric bench press were measured. Results: CMJ height improved significantly over time (P P = .010) and T3 (40.0 [5.3] cm; P = .001) and from T2 to T3 (P = .002). CMJ flight time:contraction time increased significantly over time (P = .004), with significant increases from T1 (0.747 [0.162]) to T2 (0.791 [0.163]; P = .012). Isometric midthigh-pull relative peak force improved significantly over time (P = .033), with significant increases from T1 (34.7 [5.0] N/kg) to T2 (35.9 [4.8] N/kg; P = .013). No significant changes were found between tapers. However, the higher-intensity taper produced small effect-size increases at T3 vs T1 for isometric midthigh-pull relative peak force, CMJ height, and flight time:contraction time, while the lower-intensity taper only produced small effect-size improvements at T3 vs T1 for CMJ height. Conclusions: A strength-training taper with volume reductions had a positive effect on power, with a tendency for the higher-intensity taper to produce more favorable changes in strength and power.

SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB (∼60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis.

Winwood, PW, Dudson, MK, Wilson, D, Mclaren-Harrison, JKH, Redjkins, V, Pritchard, HJ, and Keogh, JWL. Tapering practices of strongman athletes. J Strength Cond Res 32(5): 1181-1196, 2018-This study provides the first empirical evidence of how strongman athletes taper for strongman competitions. Strongman athletes (n = 454) (mean ± SD: 33.2 ± 8.0 years, 178.1 ± 10.6 cm, 108.6 ± 27.9 kg, 12.6 ± 8.9 years general resistance training, 5.3 ± 5.0 years strongman implement training) completed a self-reported 4-page internet survey on tapering practices. Analysis by sex (male and female), age (≤30 and >30 years), body mass (≤105 and >105 kg), and competitive standard (local/regional amateur, national amateur and professional) was conducted. Eighty-seven percent (n = 396) of strongman athletes reported that they used a taper. Athletes stated that their typical taper length was 8.6 ± 5.0 days, with the step taper the most commonly performed taper (52%). Training volume decreased during the taper by 45.5 ± 12.9%, and all training ceased 3.9 ± 1.8 days out from competition. Typically, athletes reported that training frequency and training duration stayed the same or decreased and training intensity decreased to around 50% in the last week. Athletes generally stated that tapering was performed to achieve recovery, rest, and peak performance; the deadlift, yoke walk, and stone lifts/work took longer to recover from than other lifts; assistance exercises were reduced or removed in the taper; massage, foam rolling, nutritional changes, and static stretching were strategies used in the taper; and, poor tapering occurred when athletes trained too heavy/hard or had too short a taper. These data will assist strongman athletes and coaches in the optimization of tapering variables leading to more peak performances. Future research could investigate the priming and preactivation strategies strongman athletes use on competition day.

β-catenin is a multifunctional protein that not only acts in the canonical Wnt/β-catenin pathway to regulate gene expression but also binds to cadherin proteins in adherens junctions, where it plays a key role in regulating cytoskeleton linked with these junctions. Recently, evidence has been presented indicating an essential role for β-catenin in regulating the trafficking of insulin vesicles in β-cells and showing that changes in nutrient levels rapidly alter levels of β-catenin in these cells. Given the importance of neuroendocrine hormone secretion in the regulation of whole body glucose homeostasis, the present study aimed to investigate whether β-catenin signalling is regulated in the hypothalamus during the normal physiological response to food intake. Rats were subjected to a fasting/re-feeding paradigm, and then samples were collected at specific timepoints for analysis of β-catenin expression by immunohistochemistry and western blotting. Changes in gene expression were assessed by a quantitative reverse transcriptase-polymerase chain reaction. Using immunohistochemistry, feeding acutely increased detectable cytoplasmic levels of β-catenin (‘stabilised β-catenin’) in neurones in specific regions of the hypothalamus involved in metabolic regulation, including the arcuate, dorsomedial and paraventricular nuclei of the hypothalamus. Feeding-induced elevations in β-catenin in these nuclei were associated with an increased transcription of several genes known to be responsive to Wnt/β-catenin signalling. The effect of feeding was mimicked by administration of the GLP-1 agonist exendin-4 and was also characterised by cAMP-dependent phosphorylation of β-catenin at serine residues 552 and 675. These data suggest that β-catenin/T cell factor signalling is involved in metabolic sensing in the hypothalamus. Refereed/Peer-reviewed

Our understanding of how form, orientation and size are processed within and outside of awareness is limited and requires further investigation. Therefore, we investigated whether or not the visual discrimination of basic object features can be influenced by subliminal processing of stimuli presented beforehand. Visual masking was used to render stimuli perceptually invisible. Three experiments examined if visible and invisible primes could facilitate the subsequent feature discrimination of visible targets. The experiments differed in the kind of perceptual discrimination that participants had to make. Namely, participants were asked to discriminate visual stimuli on the basis of their form, orientation, or size. In all three experiments, we demonstrated reliable priming effects when the primes were visible but not when the primes were made invisible. Our findings underscore the importance of conscious awareness in facilitating the perceptual discrimination of basic object features.

Healthcare-associated infections (HAIs) represent serious complications for patients within pediatric cardiac intensive care units (CICU). HAIs are associated with increased morbidity, mortality and resource utilization. There are few studies describing the epidemiology of HAIs across the entire spectrum of patients (surgical and nonsurgical) receiving care in dedicated pediatric CICUs.Retrospective analyses of 22,839 CICU encounters from October 2013 to September 2016 across 22 North American CICUs contributing data to the Pediatric Cardiac Critical Care Consortium clinical registry.HAIs occurred in 2.4% of CICU encounters at a rate of 3.3 HAIs/1000 CICU days, with 73% of HAIs occurring in children1 year. Eighty encounters (14%) had ≥2 HAIs. Aggregate rates for the 4 primary HAIs are as follows: central line-associated blood stream infection, 1.1/1000 line days; catheter-associated urinary tract infections, 1.5/1000 catheter days; ventilator-associated pneumonia, 1.9/1000 ventilator days; surgical site infections, 0.81/100 operations. Surgical and nonsurgical patients had similar HAIs rates/1000 CICU days. Incidence was twice as high in surgical encounters and increased with surgical complexity; postoperative infection occurred in 2.8% of encounters. Prematurity, younger age, presence of congenital anomaly, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Categories (STAT) 4-5 surgery, admission with an active medical condition, open sternum and extracorporeal membrane oxygenation were independently associated with HAIs. In univariable analysis, HAI was associated with longer hospital length of stay and durations of urinary catheter, central venous catheter and ventilation. Mortality was 24.4% in patients with HAIs versus 3.4% in those without, P0.0001.We provide comprehensive multicenter benchmark data regarding rates of HAIs within dedicated pediatric CICUs. We confirm that although rare, HAIs of all types are associated with significant resource utilization and mortality.

Background: Little is currently known about the tapering practices of strongman athletes. We have developed an Internet-based comprehensive self-report questionnaire examining the training and tapering practices of strongman athletes. Objective: The objective of this study was to document the test-retest reliability of questions associated with the Internet-based comprehensive self-report questionnaire on the tapering practices of strongman athletes. The information will provide insight on the reliability and usefulness of the online questionnaire for use with strongman athletes. Methods: Invitations to complete an Internet questionnaire were sent via Facebook Messenger to identified strongman athletes. The survey consisted of four main areas of inquiry, including demographics and background information, training practices, tapering, and tapering practices. Of the 454 athletes that completed the survey over the 8-week period, 130 athletes responded on Facebook Messenger indicating that they intended to complete, or had completed, the survey. These participants were asked if they could complete the online questionnaire a second time for a test-retest reliability analysis. Sixty-four athletes (mean age 33.3 years, standard deviation [SD] 7.7; mean height 178.2 cm, SD 11.0; mean body mass 103.7 kg, SD 24.8) accepted this invitation and completed the survey for the second time after a minimum 7-day period from the date of their first completion. Agreement between athlete responses was measured using intraclass correlation coefficients (ICCs) and kappa statistics. Confidence intervals (at 95%) were reported for all measures and significance was set at P

Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

The closer a line extends toward a surrounding frame, the longer it appears. This is known as a framing effect. Over 70 years ago, Teodor Kunnapas demonstrated that the shape of the visual field itself can act as a frame to influence the perceived length of lines in the vertical-horizontal illusion. This illusion is typically created by having a vertical line rise from the center of a horizontal line of the same length creating an inverted T figure. We aimed to determine if the degree to which one fixates on a spatial location where the two lines bisect could influence the strength of the illusion, assuming that the framing effect would be stronger when the retinal image is more stable. We performed two experiments: the visual-field and vertical-horizontal illusion experiments. The visual-field experiment demonstrated that the participants could discriminate a target more easily when it was presented along the horizontal versus vertical meridian, confirming a framing influence on visual perception. The vertical-horizontal illusion experiment determined the effects of orientation, size, and eye gaze on the strength of the illusion. As predicted, the illusion was strongest when the stimulus was presented in either its standard inverted T orientation or when it is rotated 180° compared to other orientations, and in conditions in which the retinal image was more stable, as indexed by eye tracking. Taken together, we conclude that the results provide support for Teodor Kunnapas’ explanation of the vertical-horizontal illusion.

Purified glycan standards are required for glycan arrays, characterizing substrate specificities of glycan-active enzymes, and to serve as retention-time or mobility standards for various separation techniques. This chapter describes a method for the rapid separation, and subsequent desalting, of glycans labeled with the highly fluorescent fluorophore 8-aminopyrene 1,3,6-trisulfonate (APTS). By using fluorophore-assisted carbohydrate electrophoresis (FACE) on polyacrylamide gels, which utilizes equipment readily available in most molecular biology laboratories, many APTS-labeled glycans can be simultaneously resolved. Excising specific gel bands containing the desired APTS-labeled glycans, followed by glycan elution from the gel and subsequent solid-phase extraction (SPE), yields single glycan species free of excess labeling reagents and buffer components. This chapter describes a FACE/SPE procedure ideal for preparing glycans for capillary electrophoresis (CE)-based enzyme assays, as well as for the purification of rare, commercially unavailable glycans from tissue culture samples.

The Fontan operation has low mortality, but is associated with significant postoperative morbidity, including prolonged chest tube output (PCTO), which is associated with prolonged hospital length of stay (PLOS). We sought to identify variables present early in the clinical course that could predict patients at high risk for PCTO and PLOS. Retrospective data were collected on 84 Fontan (extracardiac conduit) operations from 1/2008 to 12/2013 at a single institution. PCTO was defined as ≥8 days (75th percentile); PLOS was defined as ≥12 days postoperatively (75th percentile). Multivariate regression was used to determine covariates associated with PCTO and PLOS. Median age was 3.5 years (IQR 3-5); weight was 14.5 kg (IQR 13-17). There was no mortality. LOS was 9 days (IQR 3-11), and duration of chest tube drainage 6 days (IQR 5-8) at 15 ml/kg/day (IQR 9-20). In univariate analysis, only systemic right ventricle, 24-h 5 % albumin administration, 24-h fluid balance, and 12-h inotrope score were associated with PCTO. In multivariate analysis, only 5 % albumin administration in first 24 h (p 0.001) and PCTO were independently associated with PLOS. ROC curve analysis showed patients receiving25 ml/kg of 5 % albumin in first 24-h predicted PLOS (94 % specificity, 93 % sensitivity, AUC = 0.95, p 0.001). Increased colloid in the first 24-h post-CPB strongly predicts PCTO and PLOS after Fontan operation, potentially providing an early identification of a cohort with unfavorable Fontan physiology. A better understanding of the role of colloid resuscitation after Fontan is necessary, and efforts to reduce perioperative colloid administration could decrease hospital morbidity.

Ammonia is used as a stimulant in strength based sports to increase arousal and offset fatigue however little is known about its physiological and performance effects. The purpose of this study was twofold (1) establish the physiological response to acute ammonia inhalation (2) determine whether the timing of the physiological response corresponds with a performance enhancement, if any.Fifteen healthy males completed two trials. Trial one investigated the beat-to-beat middle cerebral artery blood flow velocity (MCAv), heart rate (HR) and mean arterial pressure (MAP) response to ammonia inhalation. During trial two, participants performed a maximal single mid-thigh pull (MTP) at various time points following ammonia inhalation in a randomised order: MTPs were conducted immediately, 15, 30 and 60 s following ammonia inhalation. A MTP with no ammonia inhalation served as the control. During this trial maximal MTP force, rate of force development (RFD) and electromyography (EMG) activity were recorded.MCAvmean increased and peaked on average by 6 cm s(-1) (P 0.001), 9.4 ± 5.5 s following ammonia inhalation. Similarly, HR was increased by 6 ± 11 beats per minute 15 s following ammonia inhalation (P 0.001). MAP remained unchanged following inhalation (P = 0.51). The use and timing of ammonia inhalation had no effect on maximal force, RFD or EMG (all P 0.2) compared to control.MCAv was elevated despite no increase in MAP occurring; this is indicative of a cerebrovascular vasodilation. Despite the marked cerebrovascular and cardiovascular response to ammonia inhalation no ergogenic effect was observed during the MTP, irrespective of the timing of administration.

Development of the cerebellum proceeds under the precise spatio-temporal control of several key developmental signalling pathways, including the Wnt/β-catenin pathway. We recently reported the activity of Wnt/β-catenin signalling in the perinatal cerebellar ventricular zone (VZ), a germinal centre in the developing cerebellum that gives rise to GABAergic and glial cells. In order to investigate the normal function of Wnt/β-catenin signalling in the VZ and the cell lineages it gives rise to, we used a combination of ex vivo cerebellar slice culture and in vivo genetic manipulation to dysregulate its activity during late embryonic development. Activation of the pathway at the cerebellar ventricular zone led to a reduction in the number of cells expressing the glial lineage markers Sox9 and GFAP and the interneuron marker Pax2, but had no consistent effect on either proliferation or apoptosis. Our findings suggest that activation of the Wnt/β-catenin pathway in the cerebellar ventricular zone causes a shift in the cell types produced, most likely due to disruption of normal differentiation. Thus, we propose that regulation of Wnt/β-catenin signalling levels are required for normal development of cells arising from the cerebellar ventricular zone during late embryogenesis.

The adult cerebellum is composed of several distinct cell types with well defined developmental origins. However, the molecular mechanisms that govern the generation of these cell types are only partially resolved. Wnt/β-catenin signalling has a wide variety of roles in generation of the central nervous system, though the specific activity of this pathway during cerebellum development is not well understood. Here, we present data that delineate the spatio-temporal specific pattern of Wnt/β-catenin signaling during mouse cerebellum development between E12.5 and P21. Using the BAT-gal Wnt/β-catenin reporter mouse, we found that Wnt/β-catenin activity is present transiently at the embryonic rhombic lip but not at later stages during the expansion of cell populations that arise from there. At late embryonic and early postnatal stages, Wnt/β-catenin activity shifts to the cerebellar ventricular zone and to cells arising from this germinal centre. Subsequently, the expression pattern becomes progressively restricted to Bergmann glial cells, which show expression of the reporter at P21. These results indicate a variety of potential functions for Wnt/β-catenin activity during cerebellum development.