bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Variability of Lap Speeds: Differentiating Medalists and Nonmedalists in Middle-Distance Running and Swimming Events
Authors: Mytton Graham J. , Archer David T. , Turner Louise , Skorski Sabrina , Renfree Andrew , Thompson Kevin G. , Gibson Alan St Clair 
Published: September 2014

Purpose:Previous literature has presented pacing data of groups of competition finalists. The aim of this study was to analyze the pacing patterns displayed by medalists and nonmedalists in international competitive 400-m swimming and 1500-m running finals.Methods:Split times were collected from 48 swimming finalists (four 100-m laps) and 60 running finalists (4 laps) in international competitions from 2004 to 2012. Using a cross-sectional design, lap speeds were normalized to whole-race speed and compared to identify variations of pace between groups of medalists and nonmedalists. Lap-speed variations relative to the gold medalist were compared for the whole field.Results:In 400-m swimming the medalist group demonstrated greater variation in speed than the nonmedalist group, being relatively faster in the final lap (P < .001; moderate effect) and slower in laps 1 (P = .03; moderate effect) and 2 (P > .001; moderate effect). There were also greater variations of pace in the 1500-m running medalist group than in the nonmedalist group, with a relatively faster final lap (P = .03; moderate effect) and slower second lap (P = .01; small effect). Swimming gold medalists were relatively faster than all other finalists in lap 4 (P = .04), and running gold medalists were relatively faster than the 5th- to 12th-placed athletes in the final lap (P = .02).Conclusions:Athletes who win medals in 1500-m running and 400-m swimming competitions show different pacing patterns than nonmedalists. End-spurtspeed increases are greater with medalists, who demonstrate a slower relative speed in the early part of races but a faster speed during the final part of races than nonmedalists.
Warm-Up Strategy and High-Intensity Endurance Performance in Trained Cyclists
Authors: Christensen Peter M. , Bangsbo Jens 
Published: September 2014

Purpose:To evaluate the influence of warm-up exercise intensity and subsequent recovery on intense endurance performance, selected blood variables, and the oxygen-uptake (VO2) response.Methods:Twelve highly trained male cyclists (VO2max 72.4 ± 8.0 mL · min−1 · kg−1, incremental-test peak power output (iPPO) 432 ± 31 W; mean ± SD) performed 3 warm-up strategies lasting 20 min before a 4-min maximal-performance test (PT). Strategies consisted of moderate-intensity exercise (50%iPPO) followed by 6 min of recovery (MOD6) or progressive high-intensity exercise (10–100%iPPO and 2 × 20-s sprints) followed by recovery for 6 min (HI6) or 20 min (HI20).Results:Before PT venous pH was lower (P < .001) in HI6 (7.27 ± 0.05) than in HI20 (7.34 ± 0.04) and MOD6 (7.35 ± 0.03). At the same time, differences (P < .001) existed for venous lactate in HI6 (8.2 ± 2.0 mmol/L), HI20 (5.1 ± 1.7 mmol/L), and MOD6 (1.4 ± 0.4 mmol/L), as well as for venous bicarbonate in HI6 (19.3 ± 2.6 mmol/L), HI20 (22.6 ± 2.3 mmol/L), and MOD6 (26.0 ± 1.4 mmol/L). Mean power in PT in HI6 (402 ± 38 W) tended to be lower (P = .11) than in HI20 (409 ± 34 W) and was lower (P = .007) than in MOD6 (416 ± 32 W). Total VO2 (15–120 s in PT) was higher in HI6 (8.18 ± 0.86 L) than in HI20 (7.85 ± 0.82 L, P = .008) and MOD6 (7.90 ± 0.74 L, P = .012).Conclusions:Warm-up exercise including race-pace and sprint intervals combined with short recovery can reduce subsequent performance in a 4-min maximal test in highly trained cyclists. Thus, a reduced time at high exercise intensity, a reduced intensity in the warm-up, or an extension of the recovery period after an intense warm-up is advocated.
Environmental Heterogeneity Drives Within-Host Diversification and Evolution of Pseudomonas aeruginosa
Authors: Markussen Trine , Marvig Rasmus Lykke , Gómez-Lozano María , Aanæs Kasper , Burleigh Alexandra E. , Høiby Niels , Johansen Helle Krogh , Molin Søren , Jelsbak Lars 
Published: September 2014

ABSTRACTMicrobial population polymorphisms are commonly observed in natural environments, including long-term infected hosts. However, the underlying processes promoting and stabilizing diversity are difficult to unravel and are not well understood. Here, we use chronic infection of cystic fibrosis airways by the opportunistic pathogenPseudomonas aeruginosaas a system for investigating bacterial diversification processes during the course of infection. We analyze clonal bacterial isolates sampled during a 32-year period and map temporal and spatial variations in population diversity to different infection sites within the infected host. We show that the ancestral infecting strain diverged into distinct sublineages, each with their own functional and genomic signatures and rates of adaptation, immediately after initial colonization. The sublineages coexisted in the host for decades, suggesting rapid evolution of stable population polymorphisms. Critically, the observed generation and maintenance of population diversity was the result of partitioning of the sublineages into physically separated niches in the CF airway. The results reveal a complex within-host population structure not previously realized and provide evidence that the heterogeneity of the highly structured and complex host environment promotes the evolution and long-term stability of pathogen population diversity during infection.IMPORTANCEWithin-host pathogen evolution and diversification during the course of chronic infections is of importance in relation to therapeutic intervention strategies, yet our understanding of these processes is limited. Here, we investigate intraclonal population diversity inP. aeruginosaduring chronic airway infections in cystic fibrosis patients. We show the evolution of a diverse population structure immediately after initial colonization, with divergence into multiple distinct sublineages that coexisted for decades and occupied distinct niches. Our results suggest that the spatial heterogeneity in CF airways plays a major role in relation to the generation and maintenance of population diversity and emphasize that a single isolate in sputum may not represent the entire pathogen population in the infected individual. A more complete understanding of the evolution of distinct clonal variants and their distribution in different niches could have positive implications for efficient therapy.
Eccentric training for prevention of hamstring injuries may depend on intervention compliance: a systematic review and meta-analysis
Authors: Goode Adam P , Reiman Michael P , Harris Lloyd , DeLisa Lucia , Kauffman Aaron , Beltramo David , Poole Charles , Ledbetter Leila , Taylor Andrea B 
Published: September 2014

BackgroundHamstring injury is a prevalent muscle injury in sports. Inconclusive evidence exists for eccentric hamstring strengthening to prevent hamstring injuries. One reason for this discrepancy may be the influence intervention non-compliance has on individual study estimates, and therefore pooled estimates.ObjectiveThis systematic review aims to determine the effect of eccentric hamstring strengthening on the risk of hamstring injury and quantitatively explores the impact of intervention non-compliance on the precision, heterogeneity and strength of pooled estimates.MethodsA computer-assisted literature search of Medline, CINAHL, Cochrane, EMBASE, AMED, SportDiscus and PEDro databases was conducted with keywords related to eccentric strengthening and hamstring injury. The search was conducted from the end of a previous comprehensive review forward (1 December 2008 to 31 December 2013). Random-effects models were used for both main effects and a sensitivity analysis. Pooled estimate precision was measured with a confidence limit ratio (confidence limit ratio (CLR); upper limit divided by the lower limit) and heterogeneity was assessed with I2, Cochrane's-Q and τ2. A protocol was not registered for this review.ResultsFour out of 349 studies met the inclusion criteria. In main effects analysis, eccentric hamstring training did not reduce the risk of hamstring injury (risk ratio [RR]=0.59 ((95% CI 0.24 to 1.44)). This estimate was imprecise (CLR=6.0) with significant heterogeneity (p value 0.02, 69.6% variation and t2=0.57). Subjects compliant with eccentric strengthening had a significant (RR=0.35 ((95% CI 0.23 to 0.55)) reduction in hamstring injuries. This estimate was precise (CLR=2.4) and homogenous (p value=0.38, 2.8% variation and t2=0.007).ConclusionsThe null-biased effect in using intent-to-treat methods from intervention non-compliance has a substantial impact on the precision, heterogeneity and the direction and strength of pooled estimates. Eccentric strengthening, with good compliance, appears to be successful in prevention of hamstring injury.
Opening research sites in multicentre clinical trials within the UK: a detailed analysis of delays
Authors: Kearney Anna , McKay Andrew , Hickey Helen , Balabanova Silviya , Marson Anthony G , Gamble Carrol , Williamson Paula 
Published: September 2014

ObjectiveTo investigate the length of time taken to open UK research sites in multicentre clinical trials and to identify reasons for any delays.DesignA case study, recording key milestone dates from the time a site receives ethical approval through to opening to recruitment. Delay reasons were prospectively logged by trial staff at a minimum of fortnightly periods using a coding system.SettingSANADII, a phase IV pragmatic trial, managed by the Clinical Trials Research Centre, Liverpool. The trial seeks to work with over 100 National Health Service (NHS) sites to meet its recruitment target of 1510 patients.Outcomes and analysisThe primary outcome was time from Multicentre Regional Ethics Committee (MREC) approval to site opening using survival analysis. Where sites took over a specified time to reach milestones (>3 months from MREC to Site Specific Information (SSI) submission, >30 days from SSI validation to local R&D approval, or >30 days from local Research and Development (R&D) approval to opening to recruitment), the longest continuous delay during that milestone was identified.ResultsThe median opening time for participating sites was 9.7 months (IQR 6.2 to Not Reached). SSI submission took 7 months (IQR 4.1–12.3) from ethics approval, R&D approval took 16 days (IQR 5.0–32.0) from SSI validation and site opening took 15 days (IQR 8.5–40.0) following R&D approval. The longest delays before SSI submission resulted from negotiating excess treatment costs, finalising logistics, collecting CVs and ongoing participation discussions.ConclusionsWhile recently imposed targets are reducing the time taken for R&D departments to approve valid applications, the time taken to open UK research sites remains excessive and must be reduced. At present significant public funds are being used inefficiently in order to navigate NHS systems, challenging the resolve of trial teams and the competitiveness of the UK.
Republished: New age of biological therapies in paediatric rheumatology
Authors: Sen Ethan S , Ramanan A V 
Published: September 2014

Abstract
Many paediatric rheumatic diseases result from the abnormal activation or control of the immune system. Biologic drugs, which are synthesised within a biological system, have been designed to target specific molecules involved in cytokine signalling or cell–cell interactions. The past 15 years have seen a revolution in the range of effective treatments for rheumatic diseases, particularly juvenile idiopathic arthritis (JIA). As a result, the target of inactive disease and minimal long-term disease-associated damage is increasingly becoming achievable. In this article we review evidence from recent trials of the use of biologic drugs in the treatment of systemic JIA, juvenile dermatomyositis and juvenile systemic lupus erythematosus. We also highlight novel agents currently undergoing investigation which may broaden our therapeutic armamentarium over the coming decade. Key to these developments are well-designed multicentre controlled clinical trials and long-term safety monitoring as part of international drug registries.
Trypanosomosis, Its Risk Factors, and Anaemia in Cattle Population of Dale Wabera District of Kellem Wollega Zone, Western Ethiopia
Authors: Biyazen Habtamu , Duguma Reta , Asaye Mebratu 
Published: September 2014

Cross-sectional study was conducted in Dale Wabera district of Kellem Wollega zone, Western Ethiopia, to determine the prevalence of bovine trypanosomosis and to evaluate association of bovine trypanosomosis to anaemia. Blood samples collected from 384 randomly selected cattle were subjected to parasitological and haematological analysis. For the parasitological survey, blood samples were examined using a buffy coat technique. The packed cell volume (PCV) value of each animal was also measured using hematocrit reader. The overall prevalence of trypanosomosis was 2.86%. The most common trypanosome species identified were Trypanosoma congolense (63.64%) followed by T. vivax (27.27%) and T. brucei (9%). The prevalence showed no significant difference in susceptibility between sex categories, age groups, and different body conditioned animals. The overall anaemia prevalence in the area was 19.27%. The anaemia prevalence was significantly higher in trypanosome positive cattle (54.54%) than in noninfected animals (18.23%) (P < 0.05). The mean PCV value of the infected animals was lower (22.36%±7.39%) compared to noninfected animals (27.86±5.38%). There was statistically significant difference (P < 0.05) in the PCV values of infected and noninfected animals. In conclusion, this study confirmed that trypanosomosis poses a threat to cattle production in the area and also contributed to the occurrence of anaemia.
Early Changes in Costameric and Mitochondrial Protein Expression with Unloading Are Muscle Specific
Authors: Flück Martin , Li Ruowei , Valdivieso Paola , Linnehan Richard M. , Castells Josiane , Tesch Per , Gustafsson Thomas 
Published: September 2014

We hypothesised that load-sensitive expression of costameric proteins, which hold the sarcomere in place and position the mitochondria, contributes to the early adaptations of antigravity muscle to unloading and would depend on muscle fibre composition and chymotrypsin activity of the proteasome. Biopsies were obtained from vastus lateralis (VL) and soleus (SOL) muscles of eight men before and after 3 days of unilateral lower limb suspension (ULLS) and subjected to fibre typing and measures for costameric (FAK and FRNK), mitochondrial (NDUFA9, SDHA, UQCRC1, UCP3, and ATP5A1), and MHCI protein and RNA content. Mean cross-sectional area (MCSA) of types I and II muscle fibres in VL and type I fibres in SOL demonstrated a trend for a reduction after ULLS (0.05≤P<0.10). FAK phosphorylation at tyrosine 397 showed a 20% reduction in VL muscle (P=0.029). SOL muscle demonstrated a specific reduction in UCP3 content (-23%;P = 0.012). Muscle-specific effects of ULLS were identified for linear relationships between measured proteins, chymotrypsin activity and fibre MCSA. The molecular modifications in costamere turnover and energy homoeostasis identify that aspects of atrophy and fibre transformation are detectable at the protein level in weight-bearing muscles within 3 days of unloading.
Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells
Authors: Junttila Teemu T. , Li Ji , Johnston Jennifer , Hristopoulos Maria , Clark Robyn , Ellerman Diego , Wang Bu-Er , Li Yijin , Mathieu Mary , Li Guangmin , Young Judy , Luis Elizabeth , Lewis Phillips Gail , Stefanich Eric , Spiess Christoph , Polson Andrew , Irving Bryan , Scheer Justin M. , Junttila Melissa R. , Dennis Mark S. , Kelley Robert , Totpal Klara , Ebens Allen 
Published: September 2014

Abstract
Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti–PD-L1 treatment. Thus, combining HER2-TDB with anti–PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response. Cancer Res; 74(19); 5561–71. ©2014 AACR.
Oral Interleukin-10 Alleviates Polyposis via Neutralization of Pathogenic T-Regulatory Cells
Authors: Chung Allen Y. , Li Qingsheng , Blair Sarah J. , De Jesus Magdia , Dennis Kristen L. , LeVea Charles , Yao Jin , Sun Yijun , Conway Thomas F. , Virtuoso Lauren P. , Battaglia Nicholas G. , Furtado Stacia , Mathiowitz Edith , Mantis Nicholas J. , Khazaie Khashayarsha , Egilmez Nejat K. 
Published: September 2014

Abstract
Immune dysregulation drives the pathogenesis of chronic inflammatory, autoimmune, and dysplastic disorders. While often intended to address localized pathology, most immune modulatory therapies are administered systemically and carry inherent risk of multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles ameliorates local and systemic disease to enhance survival. Mechanistic investigations showed that the therapeutic benefit of this treatment derived from neutralization of disease-promoting FoxP3+RoRγt+IL17+ pathogenic T-regulatory cells (pgTreg), with a concomitant restoration of FoxP3+RoRγt−IL17− conventional T-regulatory cells (Treg). These findings provide a proof-of-principle for the ability of an oral biologic to restore immune homeostasis at the intestinal surface. Furthermore, they implicate local manipulation of IL10 as a tractable therapeutic strategy to address the inflammatory sequelae associated with mucosal premalignancy. Cancer Res; 74(19); 5377–85. ©2014 AACR.
CtBP2 Modulates the Androgen Receptor to Promote Prostate Cancer Progression
Authors: Takayama Ken-ichi , Suzuki Takashi , Fujimura Tetsuya , Urano Tomohiko , Takahashi Satoru , Homma Yukio , Inoue Satoshi 
Published: September 2014

Abstract
The androgen receptor (AR) is the key driver of both early and advanced prostate cancer, making a complete understanding of its regulation important. Here, we report the identification of multiple AR-binding sites in the gene encoding the transcription factor CtBP2 (carboxyl terminal–binding protein), genetic variations of which have been associated with prostate cancer susceptibility. Notably, we found that SNPs in the human CTBP2 gene that were associated with prostate cancer development were correlated with AR-enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human prostate cancer. Consistent with its function as a transcriptional corepressor, CtBP2 repressed tumor-suppressor genes and AR corepressors in prostate cancer cells, such as NCOR and RIP140, by binding with AR to the promoter enhancers of these genes. Global gene-expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with corepressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling. Cancer Res; 74(22); 6542–53. ©2014 AACR.
Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib
Authors: Katayama Ryohei , Friboulet Luc , Koike Sumie , Lockerman Elizabeth L. , Khan Tahsin M. , Gainor Justin F. , Iafrate A. John , Takeuchi Kengo , Taiji Makoto , Okuno Yasushi , Fujita Naoya , Engelman Jeffrey A. , Shaw Alice T. 
Published: September 2014

AbstractPurpose: The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non–small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.Experimental Design: We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure–activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.Results: We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.Conclusions: We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. Clin Cancer Res; 20(22); 5686–96. ©2014 AACR.