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The aims of this study were to: a) examine the relationships between high-intensity distances covered above generic and relative speed thresholds in English Premier League (EPL) matches across two consecutive seasons and b) analyze the effects of playing position and team possession. Sixteen elite male soccer players (seven defenders, six midfielders and three forwards) participated in this study (age 27.8 ± 3.5 years, height 183.7 ± 5.4 cm, body mass 83.9 ± 7.1 kg). An Optical Tracking System was used to collect the following variables: total distance covered; high-speed running distance (HSRD) (> 5.5 m/s); high-intensity running distance (HIRD) (5.5-7 m/s); sprint distance (> 7 m/s); total distance covered above Maximal Aerobic Speed (MAS); distance covered > 85% peak speed (PS); and distance > 30% Anaerobic Speed Reserve (ASR). All measures were analyzed as whole match totals and as distances covered in the periods of the team in possession (TIP), opponent team in possession (OTIP), and ball out of play (BOP). Analysis by position based on defenders, midfielders and forwards was also performed. Distance > 30% ASR was almost perfectly correlated with HSRD (r = 0.98), while distances > MAS were highly correlated with both HIRD (r = 0.91) and HSRD (r = 0.91), and distance > 85% PS were highly correlated with SD (r = 0.70). Although the generic and relative speed thresholds show almost perfect correlation, the differences between HSRD, HIRD and distance > MAS indicate that players may be exposed to more HIRD when using relative thresholds., Competing Interests: The authors declared no conclict of interest., (Copyright © Institute of Sport – National Research Instutite.)

This study explored physical match demands across different playing positions during transitional play, to inform the need for position-specific training interventions. Data was collected using 10 Hz GPS units from 10 competitive matches including 23 elite soccer players of the 1 st Polish Division (Ekstraklasa) in season 2020-21. A total of 4249 positional observations were made; center backs (n = 884), full backs (n = 972), central defensive midfielders (n = 236), central attacking midfielders (n = 270), central midfielders (n = 578), wingers (n = 778), and attackers (n = 531). Match data reflected distances covered per minute (m · min -1 ): total distance (TD), high-speed running distance (HSRD, > 19.8 km · h -1 ), sprint distance (SD, > 25.2 km · h -1 ), and the frequency of high-intensity accelerations and decelerations (A+D, > 3 m · s -2 ; n · min -1 ). Total absolute sprint distance (SD, > 25.2 km · h -1 ) and total relative sprint distance (Rel B5) were also quantified. A univariate analysis of variance revealed position-specific differences. Significant effects of position were found for all analysed metrics during transitional play (large ESs; p <.001). Central attacking midfielders displayed higher TD (m · min -1 ), fullbacks covered highest SD (m · min -1 ) and wingers achieved the highest A+D (n · min -1 ) (p ≤ 0.05). Centre backs displayed the lowest physical outputs when compared to all other positions, except in A+D (n · min -1 ) during defensive transitions (p ≤ 0.05). Attackers displayed the highest physical metrics during high pressure activities (p ≤ 0.05). Coaches should carefully consider positional transitional demands to better inform training design. With specific attention paid to drills that replicate game play., Competing Interests: The authors declare no conflict of interest., (Copyright © Biology of Sport 2024.)

Objectives: To analyze the positional distances covered above generic and individualized speed thresholds within the most demanding phases of match play. Categorized by position, 17 English Premier League players' match data were analyzed over 2 consecutive seasons (2019-20 and 2020-21). The most demanding phases of play were determined using a rolling average across 4 periods of 1, 3, 5, and 10 minutes. Distance covered in the time above the standard speed of 5.5 m/s was analyzed, with individualized metrics based on the maximal aerobic speed (MAS) test data., Results: Central defenders displayed lower values for high-intensity periods when compared with fullbacks, midfielders, and wide midfielders for both generic and individualized metrics. MAS during 1-minute periods was significantly higher for forwards when compared with central defenders (82.9 [18.9] vs 67.5 [14.8] for maximum high-speed running [HSR] and 96.0 [15.9] vs 75.7 [13.8] HSR for maximum MAS activity). The maximum effect size differences between the central midfielders, wide midfielders, and fullbacks for HSR and MAS measures under the maximum HSR criterion was 0.28 and 0.18 for the 1-minute period, 0.36 and 0.19 for the 3-minute period, 0.46 and 0.31 for the 5-minute period, and 0.49 and 0.315 for the 10-minute period., Conclusions: Individualized speed metrics may provide a more precise and comparable measure than generic values. Data appear to be consistent across playing positions except for central defenders. This information may allow practitioners to directly compare individualized physical outputs of non-central defenders during the most demanding phases of play regardless of the players' positional group. This may provide coaches with important information regarding session design, training load, and fatigue monitoring.

Background: Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT., Methods: Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 [ Ucp1 ]-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq (RNA sequencing) was performed in BAT from WT and Ucp1 -/- mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in Bmp3b (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b., Results: Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, Bmp3b -deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to Bmp3b -deficient mice reduced I/R injury whereas transplanting BAT from Bmp3b -deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury., Conclusions: The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury., Competing Interests: Disclosures None.

In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the post-MI cardiac function of mice in which lymphangiogenesis had been blocked genetically by pan-endothelial or lymphatic endothelial loss of the lymphangiogenic receptor VEGFR3 or global loss of the VEGF-C and VEGF-D ligands. The results obtained using all 3 genetic approaches were highly concordant and demonstrated that loss of lymphatic vessel growth did not impair left ventricular ejection fraction 2 weeks after MI in mice. We observed a trend toward excess fluid in the infarcted region of the left ventricle, but immune cell infiltration and clearance were unchanged with loss of expanded lymphatics. These studies refute the hypothesis that lymphangiogenesis contributes significantly to cardiac function after MI, and suggest that any effect of exogenous VEGF-C is likely to be mediated by nonlymphangiogenic mechanisms.

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Fibrosis is observed in nearly every form of myocardial disease 1 . Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure 2 . However, clinical interventions and therapies that target fibrosis remain limited 3 . Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8 + T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.

Purpose: We tested the hypothesis that collagen cross-linking (CXL) could be used to promote adhesion in mock corneal grafts., Methods: Donated human corneal tissue underwent epithelial debridement and was cut into sections measuring 4mm×3mm. Paired sections were sutured together with 10-0 vicryl, forming mock corneal grafts. Looped 6-0 sutures were placed at each end to facilitate tension measurement. Mock grafts underwent CXL before being cultured for 2days in Eagle's MEM culture medium. Control mock grafts did not undergo CXL treatment before culture. Tissue was obtained from 4 donors and a maximum of 2 controls and 2 treated grafts was obtained from each donor. Following the culture period, the 10-0 sutures were cut. The mock grafts were mounted on force transducers and were put under increasing tension until eventually the sections were pulled apart., Results: The mean applied stress required to generate graft failure was calculated for all mock grafts±standard error of the mean. In the control group 0.236±0.09mPa of applied stress was required to cause graft failure, in comparison to 0.691±0.12mPa in the treated group. A paired t-test showed this result to be significant, (p=0.0087)., Conclusion: The results of our study are consistent with our hypothesis that CXL treatment could be used to promote early adhesion between separate sections of corneal tissue., (Copyright © 2016 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

The authors led the development of a framework for ethical decision-making for an Academic Health Sciences Centre. They understood the existing mission, vision, and values statement (MVVs) of the centre as a foundational assertion that embodies an ethical commitment of the institution. Reflecting the Patient and Family Centred Model of Care the institution is living, the MVVs is a suitable base on which to construct an ethics framework. The resultant framework consists of a set of questions for each of the MVVs. Users of the framework are expected to identify two or more possible decisions to address the issue at hand and then, by applying the provided sequence of questions to each, examine these options and determine the overall ethically preferable decision. The construction of such a framework requires the creative involvement of the institution's staff. Thus the development of the framework can represent a training process in ethical decision-making as well as advance the ethical atmosphere of the institution. This novel approach has the advantage of placing the MVVs on active duty, at the centre of ethical decision-making, and lifts it from its otherwise relative obscurity in most institutions.

Purpose: The aim of the study was to investigate the vascular and stromal architecture of preclinical tumor models and patient tumor specimens from malignancies with known clinical outcomes to VEGFi treatment, to gain insight into potential determinants of intrinsic sensitivity and resistance., Experimental Design: The tumor stroma architecture of preclinical and clinical tumor samples were analyzed by staining for CD31 and α-smooth muscle actin (α-SMA). Tumor models representative of each phenotype were then tested for sensitivity to the VEGFR2-blocking antibody DC101., Results: Human tumor types with high response rates to VEGF inhibitors (e.g., renal cell carcinoma) have vessels distributed amongst the tumor cells (a "tumor vessel" phenotype, TV). In contrast, those malignancies where single-agent responses are lower, such as non-small cell lung cancer (NSCLC), display a complex morphology involving the encapsulation of tumor cells within stroma that also supports the majority of vessels (a "stromal vessel" phenotype). Only 1 of 31 tumor xenograft models displayed the stromal vessel phenotype. Tumor vessel models were sensitive to VEGFR2-blocking antibody DC101, whereas the stromal vessel models were exclusively refractory. The tumor vessel phenotype was also associated with a better Response Evaluation Criteria in Solid Tumors (RECIST) response to bevacizumab + chemotherapy in metastatic colorectal cancer (CRC)., Conclusion: The tumor stromal architecture can differentiate between human tumor types that respond to a VEGF signaling inhibitor as single-agent therapy. In addition to reconciling the clinical experience with these agents versus their broad activity in preclinical models, these findings may help to select solid tumor types with intrinsic sensitivity to a VEGFi or other vascular-directed therapies., (©2013 AACR.)

Aim: To identify factors influencing older people's ability to keep warm and well in winter., Method: This qualitative study used in-depth individual interviews with older people (n=50) and health and social care staff,(n=25), alongside six focus groups with 43 participants and a consultation event. Temperatures were measured in the homes of the older people interviewed. Framework analysis techniques were used., Findings: The data indicated a lack of awareness among participants of the importance to a person's health of keeping warm. A summary of findings related to the themes of awareness, money, mindset and machinery is presented here, with reflections on their relevance to nursing in terms of identifying older people at risk of the negative health effects of cold, their assessment and support., Conclusion: The study revealed a number of ways older people are vulnerable to cold at home. Timely interventions from nurses in various sectors could help avoid cold-related harm.

Purpose: Canine cone-rod dystrophy 1 (cord1) has been previously mapped to CFA15, and a homozygous 44-bp insertion in exon 2 (Ins44) of canine RPGRIP1 (cRPGRIP1(Ins/Ins)) has been associated with the disease. However, from the recent identification of a significant discordance in genotype-phenotype association, we have reexamined the role of cRPGRIP1 in cord1., Methods: Retinal structure and function was assessed by clinical retinal examination, noninvasive imaging, electroretinography, and histopathology/immunohistochemistry. cRPGRIP1 splicing was analyzed by RT-PCR. Retinal gene expression was determined by quantitative RT-PCR (qRT-PCR). Five markers spanning the entire cRPGRIP1 were identified and used for haplotyping., Results: Electroretinography demonstrated that cone responses were absent or present in cRPGRIP1(Ins/Ins) individuals. Moreover, performance in vision testing and optical coherence tomography (OCT) were comparable in cRPGRIP1(Ins/Ins) dogs, regardless of the cone ERG status. While histologic changes in retinal structure were minimal, immunohistochemistry demonstrated a lack of cone opsin labeling in cRPGRIP1(Ins/Ins) dogs. cDNA analysis revealed that Ins44 disrupts a putative exonic splicing enhancer that allows for skipping of exon 2, while retaining the functional RPGR-interacting domain (RID) of the protein. New cRPGRIP1 sequence changes were identified, including a 3-bp deletion affecting the 3' acceptor splice site of alternative exon 19c. The extended haplotype spanning cRPGRIP1 was identical in cRPGRIP1(Ins/Ins) dogs with and without retinal degeneration. Gene expression analysis showed that expression levels were not associated with Ins44 genotype., Conclusions: The results indicated that cRPGRIP1 Ins44 is an unlikely primary cause of cord1, and that the causal gene and mutation are likely located elsewhere in the critical disease interval.

Inhibition of VEGFR-2 signaling reduces angiogenesis and retards tumor growth. Current biotherapeutics that inhibit VEGFR-2 signaling by either sequestering VEGF ligand or inhibiting VEGF binding to VEGFR-2 may be compromised by high VEGF concentrations. Here we describe a biotherapeutic that targets VEGFR-2 signaling by binding to Ig domains 4-7 of VEGFR-2 and therefore has the potential to work independently of ligand concentration. 33C3, a fully human VEGFR-2 antibody, was generated using XenoMouse technology. To elucidate the mechanism of action of 33C3, we have used a number of competition and binding assays. We show that 33C3 binds VEGFR-2 Ig domains 4-7, has no impact on VEGF-A binding to VEGFR-2, and does not compete with an antibody that interacts at the ligand binding site. 33C3 has a high affinity for VEGFR-2 (K(D) < 1 nmol/L) and inhibits VEGF-A induced phosphorylation of VEGFR-2 with an IC(50) of 99 ± 3 ng/mL. In vitro, in a 2D angiogenesis assay, 33C3 potently inhibits both tube length and number of branch points, and endothelial tubule formation in a 3D assay. In vivo, 33C3 is a very effective inhibitor of angiogenesis in both a human endothelial angiogenesis assay and in a human skin chimera model. These data show targeting VEGFR-2 outside of the ligand binding domain results in potent inhibition of VEGFR-2 signaling and inhibition of angiogenesis in vitro and in vivo.

In Saccharomyces cerevisiae, OLE1 encodes a delta9 fatty acid desaturase, an enzyme that plays a critical role in maintaining the correct ratio of saturated to monounsaturated fatty acids in the cell membrane. Previous studies have demonstrated that (i) OLE1 expression is repressed by unsaturated fatty acids (UFAs) and induced by low oxygen tension, (ii) a component of this regulation is mediated through the same low oxygen response element (LORE) in the OLE1 promoter, and (iii) Mga2p is involved in LORE-dependent hypoxic induction of OLE1. We now report that LORE-CYC1 basal promoter-lacZ fusion reporter assays demonstrate that UFAs repress the reporter expression under hypoxic conditions in a dose-dependent manner via LORE. Electrophoretic mobility shift assays show that UFAs repress the hypoxia-induced complex formation with LORE. Studies with a construct encoding a truncated form of Mga2p support the hypothesis that both hypoxia and UFA signals affect the processing of Mga2p and the UFA repression of OLE1 hypoxic induction is mediated through Mga2p. Data from Western blot assays provide evidence that under normoxic conditions, Mga2p processing produces approximately equimolar levels of the membrane-bound and processed forms and is unaffected by UFAs. Hypoxic induction of OLE1, however, is associated with increased processing of the protein, resulting in an approximately fivefold increase in the soluble active form that is counteracted by exposure of the cells to unsaturated fatty acids. Data from this study suggest that the Mga2p-LORE interaction plays an important role in OLE1 expression under both normoxic and hypoxic conditions.

Allogeneic donor leukocytes can be used after nonmyeloablative conditioning to exploit their graft-versus-tumor (GVT) activity in the setting of reduced conditioning-regimen toxicity. This approach may be particularly useful for patients who relapse after autologous stem cell transplantation (SCT). However, GVT activity, toxicity, and ability to establish mixed chimerism may differ in patients who were heavily pretreated prior to SCT compared with patients treated earlier in the course of their disease. We have performed a series of studies of nonmyeloablative allogeneic transplantation and present data on the subset of 14 patients treated for relapse after autologous SCT: 4 patients received no conditioning and unstimulated donor leukocyte infusions (DLI), 10 patients received conditioning with fludarabine and cyclophosphamide followed by unstimulated or granulocyte-colony-stimulating factor (G-CSF)-stimulated allogeneic peripheral blood stem cells (PBSCs), 4 patients received no graft-versus-host disease (GVHD) prophylaxis, and 10 patients received cyclosporine GVHD prophylaxis. All but 1 patient had sustained donor chimerism at least 30 days after allogeneic cell therapy (ACT), and 8 patients had more than 80% donor chimerism after ACT. Acute GVHD developed in 11 patients (grade III-IV, n = 6). Aplasia was more frequent in the patients receiving unstimulated PBSCs, despite the development of mixed chimerism. There were 6 complete responses and 4 partial responses; response was independent of conditioning and growth-factor stimulation of the donor graft. Five patients died of treatment-related causes and 4 patients died from progressive disease. Four patients remained alive 27 to 194 weeks (median, 66 weeks) after ACT. Prior autologous SCT may define a subset of patients at particularly high risk for GVHD and other toxicity after ACT. However, these data show that ACT with either DLI or G-CSF-stimulated blood cells results in direct GVT activity in some patients with Hodgkin's disease, myeloma, and non-Hodgkin's lymphoma, even after relapse from autologous SCT. Most patients developed donor chimerism with minimal conditioning. Alternative prophylactic regimens that control GVHD while maintaining GVT are needed to improve outcomes in these heavily pretreated patients.