Speed and surface steepness affect internal tibial loading during running.

BACKGROUND: Internal tibial loading is influenced by modifiable factors with implications for the risk of stress injury. Runners encounter varied surface steepness (gradients) when running outdoors and may adapt their speed according to the gradient. This study aimed to quantify tibial bending moments and stress at the anterior and posterior peripheries when running at different speeds on surfaces of different gradients. METHODS: Twenty recreational runners ran on a treadmill at 3 different speeds (2.5 m/s, 3.0 m/s, and 3.5 m/s) and gradients (level: 0%; uphill: +5%, +10%, and +15%; downhill: -5%, -10%, and -15%). Force and marker data were collected synchronously throughout. Bending moments were estimated at the distal third centroid of the tibia about the medial-lateral axis by ensuring static equilibrium at each 1% of stance. Stress was derived from bending moments at the anterior and posterior peripheries by modeling the tibia as a hollow ellipse. Two-way repeated-measures analysis of variance were conducted using both functional and discrete statistical analyses. RESULTS: There were significant main effects for running speed and gradient on peak bending moments and peak anterior and posterior stress. Higher running speeds resulted in greater tibial loading. Running uphill at +10% and +15% resulted in greater tibial loading than level running. Running downhill at -10% and -15% resulted in reduced tibial loading compared to level running. There was no difference between +5% or -5% and level running. CONCLUSION: Running at faster speeds and uphill on gradients ≥+10% increased internal tibial loading, whereas slower running and downhill running on gradients ≥-10% reduced internal loading. Adapting running speed according to the gradient could be a protective mechanism, providing runners with a strategy to minimize the risk of tibial stress injuries.

Towards functionally individualised designed footwear recommendation for overuse injury prevention: a scoping review.

Injury prevention is essential in running due to the risk of overuse injury development. Tailoring running shoes to individual needs may be a promising strategy to reduce this risk. Novel manufacturing processes allow the production of individualised running shoes that incorporate features that meet individual biomechanical and experiential needs. However, specific ways to individualise footwear to reduce injury risk are poorly understood. Therefore, this scoping review provides an overview of (1) footwear design features that have the potential for individualisation; and (2) the literature on the differential responses to footwear design features between selected groups of individuals. These purposes focus exclusively on reducing the risk of overuse injuries. We included studies in the English language on adults that analysed: (1) potential interaction effects between footwear design features and subgroups of runners or covariates (e.g., age, sex) for running-related biomechanical risk factors or injury incidences; (2) footwear comfort perception for a systematically modified footwear design feature. Most of the included articles (n = 107) analysed male runners. Female runners may be more susceptible to footwear-induced changes and overuse injury development; future research should target more heterogonous sampling. Several footwear design features (e.g., midsole characteristics, upper, outsole profile) show potential for individualisation. However, the literature addressing individualised footwear solutions and the potential to reduce biomechanical risk factors is limited. Future studies should leverage more extensive data collections considering relevant covariates and subgroups while systematically modifying isolated footwear design features to inform footwear individualisation.

Running-Related Biomechanical Risk Factors for Overuse Injuries in Distance Runners: A Systematic Review Considering Injury Specificity and the Potentials for Future Research.

BACKGROUND: Running overuse injuries (ROIs) occur within a complex, partly injury-specific interplay between training loads and extrinsic and intrinsic risk factors. Biomechanical risk factors (BRFs) are related to the individual running style. While BRFs have been reviewed regarding general ROI risk, no systematic review has addressed BRFs for specific ROIs using a standardized methodology. OBJECTIVE: To identify and evaluate the evidence for the most relevant BRFs for ROIs determined during running and to suggest future research directions. DESIGN: Systematic review considering prospective and retrospective studies. (PROSPERO_ID: 236,832). DATA SOURCES: PubMed. Connected Papers. The search was performed in February 2021. ELIGIBILITY CRITERIA: English language. Studies on participants whose primary sport is running addressing the risk for the seven most common ROIs and at least one kinematic, kinetic (including pressure measurements), or electromyographic BRF. A BRF needed to be identified in at least one prospective or two independent retrospective studies. BRFs needed to be determined during running. RESULTS: Sixty-six articles fulfilled our eligibility criteria. Levels of evidence for specific ROIs ranged from conflicting to moderate evidence. Running populations and methods applied varied considerably between studies. While some BRFs appeared for several ROIs, most BRFs were specific for a particular ROI. Most BRFs derived from lower-extremity joint kinematics and kinetics were located in the frontal and transverse planes of motion. Further, plantar pressure, vertical ground reaction force loading rate and free moment-related parameters were identified as kinetic BRFs. CONCLUSION: This study offers a comprehensive overview of BRFs for the most common ROIs, which might serve as a starting point to develop ROI-specific risk profiles of individual runners. We identified limited evidence for most ROI-specific risk factors, highlighting the need for performing further high-quality studies in the future. However, consensus on data collection standards (including the quantification of workload and stress tolerance variables and the reporting of injuries) is warranted.

Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity.

Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m-2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with 'Janus' surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.

Runners Adapt Different Lower-Limb Movement Patterns With Respect to Different Speeds and Downhill Slopes.

The aim of this study was to investigate the influence of slope and speed on lower-limb kinematics and energy cost of running. Six well-trained runners (VO2max 72 ± 6 mL·kg-1·min-1) were recruited for the study and performed (1) VO2max and energy cost tests and (2) an experimental running protocol at two speeds, 12 km·h-1 and a speed corresponding to 80% of VO2max (V80, 15.8 ± 1.3 km·h-1) on three different slopes (0°, -5°, and -10°), totaling six 5-min workload conditions. The workload conditions were randomly ordered and performed continuously. The tests lasted 30 min in total. All testing was performed on a large treadmill (3 × 5 m) that offered control over both speed and slope. Three-dimensional kinematic data of the right lower limb were captured during the experimental running protocol using eight infrared cameras with a sampling frequency of 150 Hz. Running kinematics were calculated using a lower body model and inverse kinematics approach. The generic model contained three, one, and two degrees of freedom at the hip, knee, and ankle joints, respectively. Oxygen uptake was measured throughout the experimental protocol. Maximum hip extension and flexion during the stance phase increased due to higher speed (p < 0.01 and p < 0.01, respectively). Knee extension at the touchdown and maximal knee flexion in the stance phase both increased on steeper downhill slopes (both p < 0.05). Ground contact time (GCT) decreased as the speed increased (p < 0.01) but was unaffected by slope (p = 0.73). Runners modified their hip movement pattern in the sagittal plane in response to changes in speed, whereas they altered their knee movement pattern during the touchdown and stance phases in response to changes in slope. While energy cost of running was unaffected by speed alone (p = 0.379), a shift in energy cost was observed for different speeds as the downhill gradient increased (p < 0.001). Energy cost was lower at V80 than 12 km·h-1 on a -5° slope but worse on a -10° slope. This indicates that higher speeds are more efficient on moderate downhill slopes (-5°), while lower speeds are more efficient on steeper downhill slopes (-10°).

A new method for measuring treadmill belt velocity fluctuations: effects of treadmill type, body mass and locomotion speed.

Treadmills are essential to the study of human and animal locomotion as well as for applied diagnostics in both sports and medicine. The quantification of relevant biomechanical and physiological variables requires a precise regulation of treadmill belt velocity (TBV). Here, we present a novel method for time-efficient tracking of TBV using standard 3D motion capture technology. Further, we analyzed TBV fluctuations of four different treadmills as seven participants walked and ran at target speeds ranging from 1.0 to 4.5 m/s. Using the novel method, we show that TBV regulation differs between treadmill types, and that certain features of TBV regulation are affected by the subjects' body mass and their locomotion speed. With higher body mass, the TBV reductions in the braking phase of stance became higher, even though this relationship differed between locomotion speeds and treadmill type (significant body mass × speed × treadmill type interaction). Average belt speeds varied between about 98 and 103% of the target speed. For three of the four treadmills, TBV reduction during the stance phase of running was more intense (> 5% target speed) and occurred earlier (before 50% of stance phase) unlike the typical overground center of mass velocity patterns reported in the literature. Overall, the results of this study emphasize the importance of monitoring TBV during locomotor research and applied diagnostics. We provide a novel method that is freely accessible on Matlab's file exchange server ("getBeltVelocity.m") allowing TBV tracking to become standard practice in locomotion research.

Dorsal muscle fatigue increases thoracic spine curvature in all-out recreational ergometer rowing.

The purpose of this study was to investigate fatigue-related changes in spinal kinematics, kinetics, and muscle activity of back muscles during a 2000 m all-out ergometer rowing performance. We analyzed ten male subjects with experience in both rowing and CrossFit exercises. We applied a novel kinematic method to describe spine curvature, determined bending moments at the spine using inverse dynamics and collected EMG data. We identified significant increases in spine curvature of the thoracic spine (i.e. vertebrae Th6 to Th11). Significant increases in peak moments were found only at the upper spine (i.e. Th2). We found no significant changes in EMG amplitudes, while the frequency analysis showed significant decreases in the mean frequencies (MNF) for the M. latissimus dorsi, the M. trapezius descendens and the M. deltoideus posterior. No significant changes on MNF were found for the Mm. erector spinae. We hypothesize that the significant increase in curvature for the thoracic spine is connected to the fatigued back muscles, especially the Mm. trapezius descendens, and might lead to an unbalanced loading of intervertebral discs and other structures. These findings are particularly important for athletes and coaches in CrossFit as strenuous rowing intervals are combined with technical exercises with high loads on the back and spine (e.g. power and Olympic lifting) leading to impaired muscular stabilization and potentially to an increased injury risk.

Salivary testosterone and cortisol concentrations after two different resistance training exercises.

BACKGROUND: The aim of this study was to identify the acute hormonal responses of salivary testosterone (T) and cortisol (C) concentrations during and after two different resistance exercises involving the lower and the upper body, respectively. METHODS: For this reason, 13 healthy recreationally trained male athletes performed an identical strength protocol (5x10 reps, with ~75% of 1 RM) with the exercises bench press and back-squat in a cross-over design. Saliva samples were taken at baseline (t0), mid training (t1), immediately after (t2), 15 (t3) and 45 minutes after the training (t4). Samples were analyzed for T and C, and the T/C ratio was calculated. RESULTS: T concentrations increased significantly from t0 to t2, t3 and t4 and also at t3 and t4 for C in the back-squat protocol (P<0.05). There were no significant changes for T and C in the bench press protocol (P<0.05). The T/C ratio remained constant for the bench press protocol. The T/C ratio increased in the squat protocol at t2 and decreased at t3 and t4. CONCLUSIONS: We conclude that back-squat exercise can change the hormonal state of the body after an intense resistance training workout, while an exercise with a lower amount of muscle mass (i.e. bench press) has almost no influence on T and C.

Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers.

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.

Comparison of serum cardiac specific biomarker release after non-cardiac thoracic surgery.

BACKGROUND: The detection of postoperative myocardial infarction can be difficult in patients after lung surgery. The aim of this study was to verify the clinical significance of elevated Troponin I (cTnI), N-terminal pro-natriuretic peptide (NT-pro-BNP), lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB in the perioperative course. METHODS: Between 2007 and 2010, 64 patients (36 men, 28 women) were includeded in this prospective study and underwent thoracotomy and wedge lung resection (n = 20, group I), lobectomy/bilobectomy (n = 24, group II), and pneumonectomy (n = 20, group III). Peri-operative measurements were done for the serum markers: cTnI, NT-pro-BNP, LDH, CK, and CK-MB preoperatively and at 4 hours, 8 hours, and 24 hours postoperatively. Patients were followed over a 90-day period to evaluate postoperative cardiac mortality. RESULTS: No basal troponin I elevation (or CK-MB) was found prior to surgery. Elevation in concentrations of troponin I (> 0.32 ng/mL) occurring after the procedure were seen in 9 patients. However, there was neither association with 90-day survival, postoperative ECG changes, nor with elevated levels of the other cardiac serum markers. cTnI correlated significantly with intrapericardial procedures in 7 out of 20 patients (Spearman's rank correlation coefficient: 0.406; p < 0.0001). Additionally, of the 20 patients within the pneumonectomy group, 8 patients had postoperative elevated serum cTnI. The grouping of patients into groups I through III was significantly associated with cTnI elevation (Spearman's rank correlation coefficient: 0.455; p < 0.0001). CONCLUSIONS: Despite the excellent sensitivity of troponin I for detection of acute myocardial infarction the fact remains that troponin I elevations were common after intrapericardial procedures and pneumonectomies. Thus, to differentiate between cardiac ischemia provoked chest pain and wound pain related to thoracotomy remains most difficult. Patients with only marginally elevated cTnI concentrations after intrapericardial resections or pneumonectomy should remain in the intensive care unit and should be followed-up carefully by cardiologists.

2'-Deoxy purine, 2'-O-methyl pyrimidine (dRmY) aptamers as candidate therapeutics.

Aptamers are short oligonucleotides that fold into well-defined three-dimensional architectures thereby enabling specific binding to molecular targets such as proteins. To be successful as a novel therapeutic modality, it is important for aptamers to not only bind their targets with high specificity and affinity, but also to exhibit favorable properties with respect to in vivo stability, cost-effective synthesis, and tolerability (i.e., safety). We describe methods for generating aptamers comprising 2 - deoxy purines and 2 -O-methyl pyrimidines (dRmY) that broadly satisfy many of these additional constraints. Conditions under which dRmY transcripts can be efficiently synthesized using mutant T7 RNA polymerases have been identified and used to generate large libraries from which dRmY aptamers to multiple target proteins, including interleukin (IL)-23 and thrombin, have been successfully discovered using the SELEX process. dRmY aptamers are shown to be highly nuclease-resistant, long-lived in vivo, efficiently synthesized, and capable of binding protein targets in a manner that inhibits their biologic activity with K(D) values in the low nM range. We believe that dRmY aptamers have considerable potential as a new class of therapeutic aptamers.

Conjugation to polyethylene glycol polymer promotes aptamer biodistribution to healthy and inflamed tissues.

Here, we examine biodistribution of radiolabeled aptamers and assess the relative ability of different stabilized aptamer compositions (mixed 2'-F/2'-O-Me; fully 2'-O-Me modified) to access inflamed tissues in a murine inflammation model. Biodistribution of 3H-labeled aptamers, including pegylated and unpegylated compositions, was assessed 3 hours postadministration using quantitative whole body autoradiography (QWBA). Aptamer penetration of cells in kidney and liver was also examined at a qualitative level by microautoradiography. To evaluate aptamer distribution to diseased tissues, inflammation was induced locally in animal hind limbs by treatment with carrageenan just prior to aptamer dosing. Aptamer compositions examined exhibited significant variation in distribution levels among organs and tissues. Highest concentrations of radioactivity in whole body tissues for all animals were observed in the kidney and urinary bladder contents. Relatively little radioactivity was associated with brain, spinal cord, and adipose tissue. Overall, the total level of radioactivity in whole body tissues was significantly higher for a 20-kDa PEG conjugate than for other aptamers. Comparatively high levels of the 20-kDa conjugate were seen in well-perfused organs and tissues, including liver, lungs, spleen, bone marrow, and myocardium. A fully 2'-O-Me composition aptamer had the lowest level of radioactivity in whole body tissues but distributed to higher concentrations in the gastrointestinal tract contents relative to other aptamers. Interestingly, the 20-kDa PEG-conjugated aptamer showed significantly higher levels of distribution to inflamed paw tissues than did either unconjugated or fully 2'-O-Me-modified aptamers.

ADP-specific sensors enable universal assay of protein kinase activity.

Two molecular sensors that specifically recognize ADP in a background of over 100-fold molar excess of ATP are described. These sensors are nucleic-acid based and comprise a general method for monitoring protein kinase activity. The ADP-aptamer scintillation proximity assay is configured in a single-step, homogeneous format while the allosteric ribozyme (RiboReporter) sensor generates a fluorescent signal upon ADP-dependent ribozyme self-cleavage. Both systems perform well when configured for high-throughput screening and have been used to rediscover a known protein kinase inhibitor in a high-throughput screening format.

[Current consumer conditions among opioid addicts--implications for maintenance-treatment programmes provided by ambulatory drug treatment centers and physicians]. / Aktuelle Konsumformen bei Drogenabhängigkeit--Implikationen für Substitutionsprogramme in ambulanten Einrichtungen und bei behandelnden Arzten.

BACKGROUND: Anonymous evaluation of the current conditions of drug scene and drug consumption, entrance age, personal motives for drug consumption and satisfaction among opioid-dependent clients with treatments available within an ambulant maintenance treatment setting. METHODS: The questionnaire for the study was based on representative studies and covered 112 questions regarding drug consumption. In addition, an instrument of the "Hessische Landesstelle gegen die Suchtgefahren", which measures satisfaction of opioid clients regarding public drug-treatment centers, was used. RESULTS: A total of 158 opioid clients within an ambulant maintenance treatment setting were enrolled in the study. The mean age at first drug consumption was 15.1 (2.4) years for men and 15.2 (3.5) years for women. The Spearman correlation showed a significant positive correlation (r=0.284) between age and time of first drug consumption (p=0.019). Cannabis was the most frequent entrance drug (55.8%), followed by alcohol (33.8%), opioids (17.6%) and nicotine (11.8%). Additional consumption of benzodiazepines was observed in 44.7% of men and 39.7% of women, of cannabis in 74.5% of men and 52.4% of women, and of sustained-release morphine in 41.4% of men and 33.3% of women. Within the previous 6-12 months cocaine was consumed significantly less (p=0.024) by men (63.8%) than by women (90.5%). 93.3% of the drug users rated a follow-up assistance programme after withdrawal and 71.9% special care programmes for designer drugs very important. IMPLICATIONS: The present study supports the assumption of an earlier age of first drug consumption. In view of our findings on entrance age, and on polytoxicomanic consumption patterns and gender-specific differences, we believe that the objectives of substitution programmes can only be reached if programmes are adequately adapted to the actual conditions of the drug scene and are able to cooperate with other public drug-treatment systems.

A novel strategy for selection of allosteric ribozymes yields RiboReporter sensors for caffeine and aspartame.

We have utilized in vitro selection technology to develop allosteric ribozyme sensors that are specific for the small molecule analytes caffeine or aspartame. Caffeine- or aspartame-responsive ribozymes were converted into fluorescence-based RiboReporter trade mark sensor systems that were able to detect caffeine or aspartame in solution over a concentration range from 0.5 to 5 mM. With read-times as short as 5 min, these caffeine- or aspartame-dependent ribozymes function as highly specific and facile molecular sensors. Interestingly, successful isolation of allosteric ribozymes for the analytes described here was enabled by a novel selection strategy that incorporated elements of both modular design and activity-based selection methods typically used for generation of catalytic nucleic acids.

Pharmacokinetics and biodistribution of novel aptamer compositions.

PURPOSE: Aptamers are highly selective nucleic acid-based drugs that are currently being developed for numerous therapeutic indications. Here, we determine plasma pharmacokinetics and tissue distribution in rat of several novel aptamer compositions, including fully 2'-O-methylated oligonucleotides and conjugates bearing high-molecular weight polyethylene glycol (PEG) polymers, cell-permeating peptides, and cholesterol. METHODS: Levels of aptamer conjugates in biological samples were quantified radiometrically and by a hybridization-based dual probe capture assay with enzyme-linked fluorescent readout. Intact aptamer in urine was detected by capillary gel electrophoresis and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF). RESULTS: Aptamer compositions examined exhibited a wide range of mean residence times in circulation (0.6-16 h) and significant variation in distribution levels among organs and tissues. Among the conjugates tested, in vivo properties of aptamers were altered most profoundly by conjugation with PEG groups. Complexation with a 20 kDa PEG polymer proved nearly as effective as a 40 kDa PEG polymer in preventing renal clearance of aptamers. Conjugation with 20 kDa PEG prolonged aptamer circulatory half-life, while reducing both the extent of aptamer distribution to the kidneys and the rate of urinary elimination. In contrast, the fully 2'-O-Me aptamer composition showed rapid clearance from circulation, and elimination with intact aptamer detectable in urine at 48 h post-administration. CONCLUSIONS: We find that conjugation and chemical composition can alter fundamental aspects of aptamer residence in circulation and distribution to tissues. Though the primary effect of PEGylation was on aptamer clearance, the prolonged systemic exposure afforded by presence of the 20 kDa moiety appeared to facilitate distribution of aptamer to tissues, particularly those of highly perfused organs.

Directed evolution of high-affinity antibody mimics using mRNA display.

We constructed a library of >10(12) unique, covalently coupled mRNA-protein molecules by randomizing three exposed loops of an immunoglobulin-like protein, the tenth fibronectin type III domain (10Fn3). The antibody mimics that bound TNF-alpha were isolated from the library using mRNA display. Ten rounds of selection produced 10Fn3 variants that bound TNF-alpha with dissociation constants (K(d)) between 1 and 24 nM. After affinity maturation, the lowest K(d) measured was 20 pM. Selected antibody mimics were shown to capture TNF-alpha when immobilized in a protein microarray. 10Fn3-based scaffold libraries and mRNA-display allow the isolation of high-affinity, specific antigen binding proteins; potential applications of such binding proteins include diagnostic protein microarrays and protein therapeutics.