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Abstract Kinematic analysis is a central component of movement biomechanics, describing the relative motion of joint segments during different activities, in different subject cohorts, and at different timepoints. Establishing whether two sets of kinematic signals represent fundamentally similar or different underlying motion patterns is especially challenging, given 1) the lack of consensus around reference frame and joint axis definition, and 2) the substantial effect that minimal variations in frame position and orientation are known to have on signal magnitude and characteristics. As such, enormous variability in the reporting of tibiofemoral kinematics has resulted in joint movement patterns that remain controversially discussed. Previously, we demonstrated the ability of the REference FRame Alignment MEthod (REFRAME) to reorientate and reposition differently aligned local segment frames to achieve convergence in signals representing the same underlying motion, thereby offering a novel approach to consistently report joint motion. In this study, for the first time, we apply REFRAME to assess the rotational and translational in vivo tibiofemoral motion of ten healthy subjects during stair descent based on kinematic signals collected using a moving videofluoroscope. Kinematics were analysed before and after different REFRAME implementations, revealing generally neutral ab/adduction behaviour, accompanied by varying degrees of a sinusoidal int/external tibial rotation pattern over the activity cycle. Our data demonstrate that different selected implementations of REFRAME are able to highlight different characteristics of the motion patterns: Minimisation of the translational root-mean-square revealed proximodistal translation patterns with overall neutral progression, while anteroposterior translation showed seemingly different levels of correlation with flexion/extension in different subjects. On the other hand, REFRAME minimisation of translational variances exposed differences in the relative mean displacement between the femoral and tibial origins between subjects, highlighting differences in mean centre of rotation positions. This early application of REFRAME for providing an understanding of tibiofemoral kinematics demonstrates the potential of this novel approach to bring clarity to an otherwise complex representation of highly variable time-series signals, while highlighting the philosophical challenges of clinically interpretating kinematic signals in the first place.

Aims: This study aimed to analyze kinematics and kinetics of the tibiofemoral joint in healthy subjects with valgus, neutral, and varus limb alignment throughout multiple gait activities using dynamic videofluoroscopy. Methods: Five subjects with valgus, 12 with neutral, and ten with varus limb alignment were assessed during multiple complete cycles of level walking, downhill walking, and stair descent using a combination of dynamic videofluoroscopy, ground reaction force plates, and optical motion capture. Following 2D/3D registration, tibiofemoral kinematics and kinetics were compared between the three limb alignment groups. Results: No significant differences for the rotational or translational patterns between the different limb alignment groups were found for level walking, downhill walking, or stair descent. Neutral and varus aligned subjects showed a mean centre of rotation located on the medial condyle for the loaded stance phase of all three gait activities. Valgus alignment, however, resulted in a centrally located centre of rotation for level and downhill walking, but a more medial centre of rotation during stair descent. Knee adduction/abduction moments were significantly influenced by limb alignment, with an increasing knee adduction moment from valgus through neutral to varus. Conclusion: Limb alignment was not reflected in the condylar kinematics, but did significantly affect the knee adduction moment. Variations in frontal plane limb alignment seem not to be a main modulator of condylar kinematics. The presented data provide insights into the influence of anatomical parameters on tibiofemoral kinematics and kinetics towards enhancing clinical decision-making and surgical restoration of natural knee joint motion and loading. Cite this article: Bone Joint Res 2024;13(9):485–496.

Abstract This study investigates the effects of varying loading conditions on excitability in neural pathways and gait dynamics. We focussed on evaluating the magnitude of the Hoffman reflex (H‐reflex), a neurophysiological measure representing the capability to activate motor neurons and the timing and placement of the foot during walking. We hypothesized that weight manipulation would alter H‐reflex magnitude, footfall and lower body kinematics. Twenty healthy participants were recruited and subjected to various weight‐loading conditions. The H‐reflex, evoked by stimulating the tibial nerve, was assessed from the dominant leg during walking. Gait was evaluated under five conditions: body weight, 20% and 40% additional body weight, and 20% and 40% reduced body weight (via a harness). Participants walked barefoot on a treadmill under each condition, and the timing of electrical stimulation was set during the stance phase shortly after the heel strike. Results show that different weight‐loading conditions significantly impact the timing and placement of the foot and gait stability. Weight reduction led to a 25% decrease in double limb support time and an 11% narrowing of step width, while weight addition resulted in an increase of 9% in step width compared to body weight condition. Furthermore, swing time variability was higher for both the extreme weight conditions, while the H‐reflex reduced to about 45% between the extreme conditions. Finally, the H‐reflex showed significant main effects on variability of both stance and swing phases, indicating that muscle‐motor excitability might serve as feedback for enhanced regulation of gait dynamics under challenging conditions.

Understanding tendon mechanical properties, such as stiffness and hysteresis, can provide insights into injury mechanisms. This research addresses the inconsistency of previously reported in-vivo and in-vitro tendon hysteresis properties. Although limited, our preliminary findings suggest that in-vivo hystereses (Mean ± SD; 55% ± 9%) are greater than in-vitro hystereses (14% ± 1%) when directly comparing the same tendon for the same loading conditions in a sheep model in-vivo versus within 24 h post-mortem. Overall, it therefore appears that the tendon mechanical properties are affected by the testing environment, possibly related to differences in muscle-tendon interactions and fluid flow experienced in-vivo versus in-vitro. This communication advocates for more detailed investigations into the mechanisms resulting in the reported differences in tendon behaviour. Overall, such knowledge contributes to our understanding of tendon function towards improving modelling and clinical interventions, bridging the gap between in-vivo and in-vitro observations and enhancing the translational relevance of biomechanical studies.

As a solution to restore knee function and reduce pain, the demand for Total Knee Arthroplasty (TKA) has dramatically increased in recent decades. The high rates of dissatisfaction and revision makes it crucially important to understand the relationships between surgical factors and post-surgery knee performance. Tibial implant alignment in the sagittal plane (i.e., posterior tibia slope, PTS) is thought to play a key role in quadriceps muscle forces and contact conditions of the joint, but the underlying mechanisms and potential consequences are poorly understood. To address this biomechanical challenge, we developed a subject-specific musculoskeletal model based on the bone anatomy and precise implantation data provided within the CAMS-Knee datasets. Using the novel COMAK algorithm that concurrently optimizes joint kinematics, together with contact mechanics, and muscle and ligament forces, enabled highly accurate estimations of the knee joint biomechanics (RMSE

Abstract Background Manual wheelchair propulsion is widely accepted to be biomechanically inefficient, with a high prevalence of shoulder pain and injuries among users. Directional control during wheelchair movement is a major, yet largely overlooked source of energy loss: changing direction or maintaining straightforward motion on tilted surfaces requires unilateral braking. This study evaluates the efficiency of a novel steering-by-leaning mechanism that guides wheelchair turning through upper body leaning. Methods 16 full-time wheelchair users and 15 able-bodied novices each completed 12 circuits of an adapted Illinois Agility Test-course that included tilted, straight, slalom, and 180° turning sections in a prototype wheelchair at a self-selected functional speed. Trials were alternated between conventional and steering-by-leaning modes while propulsion forces were recorded via instrumented wheelchair wheels. Time to completion, travelled distance, positive/negative power, and work done, were all calculated to allow comparison of the control modes using repeated measures analysis of variance. Results Substantial average energy reductions of 51% (able-bodied group) and 35% (wheelchair user group) to complete the task were observed when using the steering-by-leaning system. Simultaneously, able-bodied subjects were approximately 23% faster whereby completion times did not differ for wheelchair users. Participants in both groups wheeled some 10% further with the novel system. Differences were most pronounced during turning and on tilted surfaces where the steering-by-leaning system removed the need for braking for directional control. Conclusions Backrest-actuated steering systems on manual wheelchairs can make a meaningful contribution towards reducing shoulder usage while contributing to independent living. Optimisation of propulsion techniques could further improve functional outcomes.

Introduction: Non-invasive assays are needed to better discriminate patients with prostate cancer (PCa) to avoid over-treatment of indolent disease. We analyzed 14 methylated DNA markers (MDMs) from urine samples of patients with biopsy-proven PCa relative to healthy controls and further studied discrimination of clinically significant PCa (csPCa) from healthy controls and Gleason 6 cancers. Methods: To evaluate the panel, urine from 24 healthy male volunteers with no clinical suspicion for PCa and 24 men with biopsy-confirmed disease across all Gleason scores was collected. Blinded to clinical status, DNA from the supernatant was analyzed for methylation signal within specific DNA sequences across 14 genes (HES5, ZNF655, ITPRIPL1, MAX.chr3.6187, SLCO3A1, CHST11, SERPINB9, WNT3A, KCNB2, GAS6, AKR1B1, MAX.chr3.8028, GRASP, ST6GALNAC2) by target enrichment long-probe quantitative-amplified signal assays. Results: Utilizing an overall specificity cut-off of 100% for discriminating normal controls from PCa cases across the MDM panel resulted in 71% sensitivity (95% CI: 49–87%) for PCa detection (4/7 Gleason 6, 8/12 Gleason 7, 5/5 Gleason 8+) and 76% (50–92%) for csPCa (Gleason ≥ 7). At 100% specificity for controls and Gleason 6 patients combined, MDM panel sensitivity was 59% (33–81%) for csPCa (5/12 Gleason 7, 5/5 Gleason 8+). Conclusions: MDMs assayed in urine offer high sensitivity and specificity for detection of clinically significant prostate cancer. Prospective evaluation is necessary to estimate discrimination of patients as first-line screening and as an adjunct to prostate-specific antigen (PSA) testing.

Guideline-recommended screening programs exist for only a few cancer types. Although all these programs are understood to lead to reductions in cancer-related mortality, standard-of-care screening tests vary in accuracy, adherence and effectiveness. Recent advances in high-throughput technologies and machine learning have facilitated the development of blood-based multi-cancer cancer early detection (MCED) tests. MCED tests are positioned to be complementary to standard-of-care screening and they may broaden screening availability, especially for individuals who are not adherent with current screening programs and for individuals who may harbor cancers with no available screening options. In this article, we outline some key features that should be considered for study design and MCED test development, provide an example of the developmental pathway undertaken for an emerging multi-biomarker class MCED test and propose a clinical algorithm for an imaging-based diagnostic resolution strategy following MCED testing.

Abstract Achilles’ tendon (AT) injuries such as ruptures and tendinopathies have experienced a dramatic rise in the mid- to older-aged population. Given that the AT plays a key role at all stages of locomotion, unsuccessful rehabilitation after injury often leads to long-term, deleterious health consequences. Understanding healthy in vivo strains as well as the complex muscle–tendon unit interactions will improve access to the underlying aetiology of injuries and how their functionality can be effectively restored post-injury. The goals of this survey of the literature with a systematic search were to provide a benchmark of healthy AT strains measured in vivo during functional activities and identify the sources of variability observed in the results. Two databases were searched, and all articles that provided measured in vivo peak strains or the change in strain with respect to time were included. In total, 107 articles that reported subjects over the age of 18 years with no prior AT injury and measured while performing functional activities such as voluntary contractions, walking, running, jumping, or jump landing were included in this review. In general, unclear anatomical definitions of the sub-tendon and aponeurosis structures have led to considerable confusion in the literature. MRI, ultrasound, and motion capture were the predominant approaches, sometimes coupled with modelling. The measured peak strains increased from 4% to over 10% from contractions, to walking, running, and jumping, in that order. Importantly, measured AT strains were heavily dependent on measurement location, measurement method, measurement protocol, individual AT geometry, and mechanical properties, as well as instantaneous kinematics and kinetics of the studied activity. Through a comprehensive review of approaches and results, this survey of the literature therefore converges to a united terminology of the structures and their common underlying characteristics and presents the state-of-knowledge on their functional strain patterns.

Abstract In clinical movement biomechanics, kinematic data are often depicted as waveforms (i.e. signals), characterising the motion of articulating joints. Clinically meaningful interpretations of the underlying joint kinematics, however, require an objective understanding of whether two different kinematic signals actually represent two different underlying physical movement patterns of the joint or not. Previously, the accuracy of IMU-based knee joint angles was assessed using a six-degrees-of-freedom joint simulator guided by fluoroscopy-based signals. Despite implementation of sensor-to-segment corrections, observed errors were clearly indicative of cross-talk, and thus inconsistent reference frame orientations. Here, we address these limitations by exploring how minimisation of dedicated cost functions can harmonise differences in frame orientations, ultimately facilitating consistent interpretation of articulating joint kinematic signals. In this study, we present and investigate a frame orientation optimisation method (FOOM) that aligns reference frames and corrects for cross-talk errors, hence yielding a consistent interpretation of the underlying movement patterns. By executing optimised rotational sequences, thus producing angular corrections around each axis, we enable a reproducible frame definition and hence an approach for reliable comparison of kinematic data. Using this approach, root-mean-square errors between the previously collected (1) IMU-based data using functional joint axes, and (2) simulated fluoroscopy-based data relying on geometrical axes were almost entirely eliminated from an initial range of 0.7°–5.1° to a mere 0.1°–0.8°. Our results confirm that different local segment frames can yield different kinematic patterns, despite following the same rotation convention, and that appropriate alignment of reference frame orientation can successfully enable consistent kinematic interpretation.

BackgroundFreezing of Gait (FOG) is a motor symptom frequently observed in advanced Parkinson’s disease. However, due to its paroxysmal nature and diverse presentation, assessing FOG in a clinical setting can be challenging. Before FOG can be fully investigated, it is critical that a reliable experimental setting is established in which FOG can be evoked in a standardized manner, but the efficacy of various gait tasks and triggers for eliciting FOG remains unclear.ObjectivesThis study aimed to conduct a systematic review of the existing literature and evaluate the available evidence for the relationship between specific motor tasks, triggers, and FOG episodes in individuals with Parkinson’s disease (PwPD).MethodsWe conducted a literature search on four online databases (PubMed, Web of Science, EMBASE, and Cochrane Library) using the keywords “Parkinson’s disease,” “Freezing of Gait”, “triggers” and “tasks”. A total of 128 articles met the inclusion criteria and were included in our analysis.ResultsThe review found that a wide range of gait tasks were employed in studies assessing FOG among PD patients. However, three tasks (turning, dual tasking, and straight walking) emerged as the most frequently used. Turning (28%) appears to be the most effective trigger for eliciting FOG in PwPD, followed by walking through a doorway (14%) and dual tasking (10%).ConclusionThis review thereby supports the utilisation of turning, especially a 360-degree turn, as a reliable trigger for FOG in PwPD. This finding could be beneficial to clinicians conducting clinical evaluations and researchers aiming to assess FOG in a laboratory environment.

Background: Paediatric movement disorders such as cerebral palsy often negatively impact walking behaviour. Although clinical gait analysis is usually performed to guide therapy decisions, not all respond positively to their assigned treatment. Identifying these individuals based on their pre-treatment characteristics could guide clinicians towards more appropriate and personalized interventions. Using routinely collected pre-treatment gait and anthropometric features, we aimed to assess whether standard machine learning approaches can be effective in identifying patients at risk of negative treatment outcomes. Methods: Observational data of 119 patients with movement disorders were retrospectively extracted from a local clinical database, comprising sagittal joint angles and spatiotemporal parameters, derived from motion capture data pre- and post-treatment (physiotherapy, orthosis, botulin toxin injections, or surgery). Participants were labelled based on their change in gait profile score (GPS, non-responders with a decline in GPS of

Introduction: Mechanical loading is known to determine the course of bone fracture healing. We hypothesise that lower limb long bone loading differs with knee flexion angle during walking and frontal knee alignment, which affects fracture healing success.Materials and methods: Using our musculoskeletal in silico modelling constrained against in vivo data from patients with instrumented knee implants allowed us to assess internal loads in femur and tibia. These internal forces were associated with the clinical outcome of fracture healing in a relevant cohort of 178 extra-articular femur and tibia fractures in patients using a retrospective approach.Results: Mean peak forces differed with femoral compression (1,330–1,936 N at mid-shaft) amounting to about half of tibial compression (2,299–5,224 N). Mean peak bending moments in the frontal plane were greater in the femur (71–130 Nm) than in the tibia (from 26 to 43 Nm), each increasing proximally. Bending in the sagittal plane showed smaller mean peak bending moments in the femur (−38 to 43 Nm) reaching substantially higher values in the tibia (−63 to −175 Nm) with a peak proximally. Peak torsional moments had opposite directions for the femur (−13 to −40 Nm) versus tibia (15–48 Nm) with an increase towards the proximal end in both. Femoral fractures showed significantly lower scores in the modified Radiological Union Scale for Tibia (mRUST) at last follow-up (p < 0.001) compared to tibial fractures. Specifically, compression (r = 0.304), sagittal bending (r = 0.259), and frontal bending (r = −0.318) showed strong associations (p < 0.001) to mRUST at last follow-up. This was not the case for age, body weight, or localisation alone.Discussion: This study showed that moments in femur and tibia tend to decrease towards their distal ends. Tibial load components were influenced by knee flexion angle, especially at push-off, while static frontal alignment played a smaller role. Our results indicate that femur and tibia are loaded differently and thus require adapted fracture fixation considering load components rather than just overall load level.

AimTo investigate whether multiple domains of gait variability change during motor maturation and if this change over time could differentiate children with a typical development (TDC) from those with cerebral palsy (CwCP).MethodsThis cross-sectional retrospective study included 42 TDC and 129 CwCP, of which 99 and 30 exhibited GMFCS level I and II, respectively. Participants underwent barefoot 3D gait analysis. Age and parameters of gait variability (coefficient of variation of stride-time, stride length, single limb support time, walking speed, and cadence; as well as meanSD for hip flexion, knee flexion, and ankle dorsiflexion) were used to fit linear models, where the slope of the models could differ between groups to test the hypotheses.ResultsMotor-developmental trajectories of gait variability were able to distinguish between TDC and CwCP for all parameters, except the variability of joint angles. CwCP with GMFCS II also showed significantly higher levels of gait variability compared to those with GMFCS I, these levels were maintained across different ages.InterpretationThis study showed the potential of gait variability to identify and detect the motor characteristics of high functioning CwCP. In future, such trajectories could provide functional biomarkers for identifying children with mild movement related disorders and support the management of expectations.

Approximately 40–60% of falls in the elderly lead to injuries, resulting in disability and loss of independence. Despite the higher prevalence of falls and morbidity rates in cognitively impaired individuals, most fall risk assessments fail to account for mental status. In addition, successful fall prevention programmes in cognitively normal adults have generally failed in patients with cognitive impairment. Identifying the role of pathological aging on fall characteristics can improve the sensitivity and specificity of fall prevention approaches. This literature review provides a thorough investigation into fall prevalence and fall risk factors, the accuracy of fall risk assessments, and the efficacy of fall prevention strategies in individuals with diverse cognitive profiles. We show that fall-related characteristics differ between cognitive disorders and fall risk assessment tools as well as fall prevention strategies should critically consider each patient’s cognitive status to facilitate the identification of fallers at an earlier stage and support clinical decision-making.

Objective: Steering-by-leaning is a promising innovation for manual wheelchairs. It may enable improved energy efficiency, one-handed manoeuvrability, and increased trunk activity during wheelchair use in daily life. To explore the feasibility of this concept, the lateral trunk function of active wheelchair users was assessed before comparing 3 preliminary dynamic backrest designs in a virtual steering exercise. Design: Repeated measures, cross-over study. Subjects: A convenience sample of 15 individuals who had been full-time users of manual wheelchair for at least 1 year. Methods: Active core strength and lateral leaning range of motion were captured while sitting freely. Participants subsequently tested 3 dynamic wheelchair backrest designs on an individually adjusted laboratory wheelchair prototype by performing a virtual steering exercise. Deviations from a target movement path were analysed using repeated measures analysis of variance and Pearson correlation coefficients. Results: Functional leaning range of motion ranged from below 10° to almost 70°, but increased significantly with use of the simplest backrest design based on a 2-dimensional hinge joint. No correlation was found between functional levels and performance parameters in the virtual steering exercise. Conclusion: Using an individually fitted and calibrated design, upper body-actuated wheelchair steering using a laterally tilting backrest is accessible to wheelchair users across a wide spectrum of physical abilities. LAY ABSTRACT Manual wheelchairs not only enable mobility, but also provide postural support to users through passive seating elements. The consequences of static sitting, however, include pain, deformities, and pressure injuries. The concept of backrest steering in manual wheelchairs may improve overall energy efficiency while promoting active trunk movement, but its applicability is questionable given the varying levels of trunk control among users. In this study, active trunk function of 15 full-time users of manual wheelchairs was measured prior to testing 3 prototype dynamic backrest designs in a virtual steering exercise. The results highlight the broad spectrum of abilities in this population, but suggest that active movement can be supported by simple mechanisms. No meaningful relationship was found between trunk abilities and performance in the virtual steering exercise, indicating that upper body-actuated steering of manual wheelchairs is accessible to users across a wide spectrum of physical abilities.

IntroductionGait analysis is increasingly used to support clinical decision-making regarding diagnosis and treatment planning for movement disorders. As a key part of gait analysis, inverse dynamics can be applied to estimate internal loading conditions during movement, which is essential for understanding pathological gait patterns. The inverse dynamics calculation uses external kinetic information, normally collected using force plates. However, collection of external ground reaction forces (GRFs) and moments (GRMs) can be challenging, especially in subjects with movement disorders. In recent years, a musculoskeletal modeling-based approach has been developed to predict external kinetics from kinematic data, but its performance has not yet been evaluated for altered locomotor patterns such as toe-walking. Therefore, the goal of this study was to investigate how well this prediction method performs for gait in children with cerebral palsy.MethodsThe method was applied to 25 subjects with various forms of hemiplegic spastic locomotor patterns. Predicted GRFs and GRMs, in addition to associated joint kinetics derived using inverse dynamics, were statistically compared against those based on force plate measurements.ResultsThe results showed that the performance of the predictive method was similar for the affected and unaffected limbs, with Pearson correlation coefficients between predicted and measured GRFs of 0.71–0.96, similar to those previously reported for healthy adults, despite the motor pathology and the inclusion of toes-walkers within our cohort. However, errors were amplified when calculating the resulting joint moments to an extent that could influence clinical interpretation.ConclusionTo conclude, the musculoskeletal modeling-based approach for estimating external kinetics is promising for pathological gait, offering the possibility of estimating GRFs and GRMs without the need for force plate data. However, further development is needed before implementation within clinical settings becomes possible.

Adolescent idiopathic scoliosis (AIS) is a prevalent musculoskeletal disorder that causes abnormal spinal deformities. The early screening of children and adolescents is crucial to identify and prevent the further progression of AIS. In clinical examinations, scoliometers are often used to noninvasively estimate the primary Cobb angle, and optical 3D scanning systems have also emerged as alternative noninvasive approaches for this purpose. The recent advances in low-cost 3D scanners have led to their use in several studies to estimate the primary Cobb angle or even internal spinal alignment. However, none of these studies demonstrate whether such a low-cost scanner satisfies the minimal requirements for capturing the relevant deformities of the human back. To practically quantify the minimal required spatial resolution and camera resolution to capture the geometry and shape of the deformities of the human back, we used multiple 3D scanning methodologies and systems. The results from an evaluation of 30 captures of AIS patients and 76 captures of healthy subjects showed that the minimal required spatial resolution is between 2 mm and 5 mm, depending on the chosen error tolerance. Therefore, a minimal camera resolution of 640 × 480 pixels is recommended for use in future studies.

Background and Aims: Methylated DNA markers (MDMs) accurately identify several different cancer types, but there are limited data for pancreatic neuroendocrine tumors (pNETs). We aimed to identify MDM candidates in tissue that differentiate pNETs from normal pancreas. Methods: wUsing DNA from frozen normal pancreas (13) and pNET (51) tissues, we performed reduced representation bisulfite sequencing for MDM discovery. Validation in independent formalin fixed paraffin embedded tissues used pNET cases (67; solid = 50, cystic = 17), normal pancreas (24), and buffy coat (36) controls. Primary pNET MDM distributions were compared with lung (36), small bowel (36) NETs, and metastatic pNET (25) tissues. The discrimination accuracy was summarized as the area under the receiver operator characteristic curve (AUC) with corresponding 95% confidence intervals (CIs). Fisher’s linear discriminant analysis was performed to estimate a linear discriminate score (LDS) differentiating normal from pNET tissue and applied to all patient groups; discrimination accuracy of the LDS was summarized as the bootstrap cross-validated AUC. Results: Median AUC for distinguishing normal pancreas from pNET tissue was 0.91 (interquartile range: 0.80–0.93). The cross-validated AUC for the LDS discriminating normal pancreatic tissue from primary and metastatic pNETs was 0.957 (95% CI 0.858–1.0, P < .0001) and 0.963 (95% CI 0.865–1.0, P < .0001), respectively. The LDS for the MDM panel was significantly higher for primary pNET, metastatic pNET, lung NET, and small bowel NET, each compared with normal pancreas tissue (P < .0001). There was no statistical difference between primary pNET and metastatic pNET (P = .1947). Conclusion: In independent tissue validation, MDMs accurately discriminate pNETs from normal pancreas. These results provide scientific rationale for exploration of these tissue MDMs in a plasma-based assay for clinical application.

Cholangiocarcinoma (CCA) has poor prognosis due to late‐stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced‐representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin‐fixed, paraffin‐embedded CCA tumors and adjacent hepatobiliary control tissues using methylation‐specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95‐1.0). In the clinical pilot on plasma, a cross‐validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81‐0.95]) but not for primary sclerosing cholangitis–associated eCCA (AUC, 0.54 [0.35‐0.73]). Conclusion: Next‐generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.

Understanding the sources of error is critical before models of the musculoskeletal system can be usefully translated. Using in vivo measured tibiofemoral forces, the impact of uncertainty in muscle–tendon parameters on the accuracy of knee contact force estimates of a generic musculoskeletal model was investigated following a probabilistic approach. Population variability was introduced to the routine musculoskeletal modeling framework by perturbing input parameters of the lower limb muscles around their baseline values. Using ground reaction force and skin marker trajectory data collected from six subjects performing body-weight squat, the knee contact force was calculated for the perturbed models. The combined impact of input uncertainties resulted in a considerable variation in the knee contact force estimates (up to 2.1 BW change in the predicted force), especially at larger knee flexion angles, hence explaining up to 70% of the simulation error. Although individual muscle groups exhibited different contributions to the overall error, variation in the maximum isometric force and pathway of the muscles showed the highest impacts on the model outcomes. Importantly, this study highlights parameters that should be personalized in order to achieve the best possible predictions when using generic musculoskeletal models for activities involving deep knee flexion.

Abstract Extracellular vesicles (EVs) are of growing interest due to their potential diagnostic, disease surveillance, and therapeutic applications. While several studies have evaluated EV isolation methods in various biofluids, there are few if any data on these techniques when applied to stool. The latter is an ideal biospecimen for studying EVs and colorectal cancer (CRC) because the release of tumour markers by luminal exfoliation into stool occurs earlier than vascular invasion. Since EV release is a conserved mechanism, bacteria in stool contribute to the overall EV population. In this study, we assessed five EV separation methods (ultracentrifugation [UC], precipitation [EQ‐O, EQ‐TC], size exclusion chromatography [SEC], and ultrafiltration [UF]) for total recovery, reproducibility, purity, RNA composition, and protein expression in stool supernatant. CD63, TSG101, and ompA proteins were present in EV fractions from all methods except UC. Human (18s) and bacterial (16s) rRNA was detected in stool EV preparations. Enzymatic treatment prior to extraction is necessary to avoid non‐vesicular RNA contamination. Ultrafiltration had the highest recovery, RNA, and protein yield. After assessing purity further, SEC was the isolation method of choice. These findings serve as the groundwork for future studies that use high throughput omics technologies to investigate the potential of stool‐derived EVs as a source for novel biomarkers for early CRC detection.

Abstract Background Symmetry during lifting is considered critical for allowing balanced power production and avoidance of injury. This investigation assessed the influence of elevating the heels on bilateral lower limb symmetry during loaded (50% of body weight) high-bar back squats. Methods Ten novice (mass 67.6 ± 12.4 kg, height 1.73 ± 0.10 m) and ten regular weight trainers (mass 66.0 ± 10.7 kg, height 1.71 ± 0.09 m) were assessed while standing on both the flat level floor and on an inclined board. Data collection used infra-red motion capture procedures and two force platforms to record bilateral vertical ground reaction force (GRFvert) and ankle, knee and hip joint kinematic and kinetic data. Paired t-tests and statistical parametric mapping (SPM1D) procedures were used to assess differences in discrete and continuous bilateral symmetry data across conditions. Results Although discrete joint kinematic and joint moment symmetry data were largely unaffected by raising the heels, the regular weight trainers presented greater bilateral asymmetry in these data than the novices. The one significant finding in these discrete data showed that raising the heels significantly reduced maximum knee extension moment asymmetry (P = 0.02), but in the novice group only. Time-series analyses indicated significant bilateral asymmetries in both GRFvert and knee extension moments mid-way though the eccentric phase for the novice group, with the latter unaffected by heel lift condition. There were no significant bilateral asymmetries in time series data within the regular weight training group. Conclusions This investigation highlights that although a degree of bilateral lower limb asymmetry is common in individuals performing back squats, the degree of this symmetry is largely unaffected by raising the heels. Differences in results for discrete and time-series symmetry analyses also highlight a key issue associated with relying solely on discrete data techniques to assess bilateral symmetry during tasks such as the back squat.

For people with physical disabilities, manual wheelchairs are essential enablers of mobility, participation in society, and a healthy lifestyle. Their most general design offers great flexibility and direct feedback, but has been described to be inefficient and demands good coordination of the upper extremities while critically influencing users’ actions. Multiple research groups have used Inertial Measurement Units (IMUs) to quantify physical activities in wheelchairs arguing that knowledge over behavioural patterns in manual wheelchair usage can guide technological development and improved designs. The present study investigates turning behaviour among fulltime wheelchair users, laying the foundation of the development of novel steering systems that allow directing kinetic energy by means other than braking. Three wearable sensors were installed on the wheelchairs of 14 individuals for tracking movement over an entire week. During detected “moving windows”, phases where the velocities of the two rear wheels differed by more than 0.05 m/s were considered as turns. Kinematic characteristics for both turns-on-the-spot as well as for moving turns were then derived from the previously reconstructed wheeled path. For the grand total of 334 km of recorded wheelchair movement, a turn was detected every 3.6 m, which equates to about 900 turns per day on average and shows that changing and adjusting direction is fundamental in wheelchair practice. For moving turns, a median turning radius of 1.09 m and a median turning angle of 39° were found. With a median of 89°, typical turning angles were considerably larger for turns-on-the-spot, which accounted for roughly a quarter of the recognised turns and often started from a standstill. These results suggest that a frequent pattern in daily wheelchair usage is to initiate movement with an orienting turn-on-the-spot, and cover distances with short, straightforward sections while adjusting direction in small and tight moving turns. As large bends often require simultaneous pushing and breaking, this is, perhaps, the result of users intuitively optimising energy efficiency, but more research is needed to understand how the design of the assistive devices implicitly directs users’ movement.

The success of kinematic analysis that relies on inertial measurement units (IMUs) heavily depends on the performance of the underlying algorithms. Quantifying the level of uncertainty associated with the models and approximations implemented within these algorithms, without the complication of soft-tissue artefact, is therefore critical. To this end, this study aimed to assess the rotational errors associated with controlled movements. Here, data of six total knee arthroplasty patients from a previously published fluoroscopy study were used to simulate realistic kinematics of daily activities using IMUs mounted to a six-degrees-of-freedom joint simulator. A model-based method involving extended Kalman filtering to derive rotational kinematics from inertial measurements was tested and compared against the ground truth simulator values. The algorithm demonstrated excellent accuracy (root-mean-square error ≤0.9°, maximum absolute error ≤3.2°) in estimating three-dimensional rotational knee kinematics during level walking. Although maximum absolute errors linked to stair descent and sit-to-stand-to-sit rose to 5.2° and 10.8°, respectively, root-mean-square errors peaked at 1.9° and 7.5°. This study hereby describes an accurate framework for evaluating the suitability of the underlying kinematic models and assumptions of an IMU-based motion analysis system, facilitating the future validation of analogous tools.

Some approaches in total knee arthroplasty aim for an oblique joint line to achieve an even medio-lateral load distribution across the condyles during the stance phase of gait. While there is much focus on the angulation of the joint line in static frontal radiographs, precise knowledge of the associated dynamic joint line orientation and the internal joint loading is limited. The aim of this study was to analyze how static alignment in frontal radiographs relates to dynamic alignment and load distribution, based on direct measurements of the internal joint loading and kinematics. A unique and novel combination of telemetrically measured in vivo knee joint loading and simultaneous internal joint kinematics derived from mobile fluoroscopy (“CAMS-Knee dataset”) was employed to access the dynamic alignment and internal joint loading in 6 TKA patients during level walking. Static alignment was measured in standard frontal postoperative radiographs while external adduction moments were computed based on ground reaction forces. Both static and dynamic parameters were analyzed to identify correlations using linear and non-linear regression. At peak loading during gait, the joint line was tilted laterally by 4°–7° compared to the static joint line in most patients. This dynamic joint line tilt did not show a strong correlation with the medial force (R2: 0.17) or with the mediolateral force distribution (pseudo R2: 0.19). However, the external adduction moment showed a strong correlation with the medial force (R2: 0.85) and with the mediolateral force distribution (pseudo R2: 0.78). Alignment measured in static radiographs has only limited predictive power for dynamic kinematics and loading, and even the dynamic orientation of the joint line is not an important factor for the medio-lateral knee load distribution. Preventive and rehabilitative measures should focus on the external knee adduction moment based on the vertical and horizontal components of the ground reaction forces.

For interpreting outcomes of clinical gait analysis, an accurate estimation of gait events, such as initial contact (IC) and toe-off (TO), is essential. Numerous algorithms to automatically identify timing of gait events have been developed based on various marker set configurations as input. However, a systematic overview of the effect of the marker selection on the accuracy of estimating gait event timing is lacking. Therefore, we aim to evaluate (1) if the marker selection influences the accuracy of kinematic algorithms for estimating gait event timings and (2) what the best marker location is to ensure the highest event timing accuracy across various gait patterns. 104 individuals with cerebral palsy (16.0 ± 8.6 years) and 31 typically developing controls (age 20.6 ± 7.8) performed clinical gait analysis, and were divided into two out of eight groups based on the orientation of their foot, in sagittal and frontal plane at mid-stance. 3D marker trajectories of 11 foot/ankle markers were used to estimate the gait event timings (IC, TO) using five commonly used kinematic algorithms. Heatmaps, for IC and TO timing per group were created showing the median detection error, compared to detection using vertical ground reaction forces, for each marker. Our findings indicate that median detection errors can be kept within 7 ms for IC and 13 ms for TO when optimizing the choice of marker and detection algorithm toward foot orientation in midstance. Our results highlight that the use of markers located on the midfoot is robust for detecting gait events across different gait patterns.

For humans, the ability to effectively adapt footfall rhythm to perturbations is critical for stable locomotion. However, only limited information exists regarding how dynamic stability changes when individuals modify their footfall rhythm. In this study, we recorded 3D kinematic activity from 20 participants (13 males, 18–30 years old) during walking on a treadmill while synchronizing with an auditory metronome sequence individualized to their baseline walking characteristics. The sequence then included unexpected temporal perturbations in the beat intervals with the subjects required to adapt their footfall rhythm accordingly. Building on a novel approach to quantify resilience of locomotor behavior, this study found that, in response to auditory perturbation, the mean center of mass (COM) recovery time across all participants who showed deviation from steady state (N = 15) was 7.4 (8.9) s. Importantly, recovery of footfall synchronization with the metronome beats after perturbation was achieved prior (+3.4 [95.0% CI +0.1, +9.5] s) to the recovery of COM kinematics. These results highlight the scale of temporal adaptation to perturbations and provide implications for understanding regulation of rhythm and balance. Thus, our study extends the sensorimotor synchronization paradigm to include analysis of COM recovery time toward improving our understanding of an individual’s resilience to perturbations and potentially also their fall risk.

Background: Lateral interbody fusion (LIF) is traditionally performed with the patient in lateral decubitus, requiring repositioning to prone for adjunctive posterior procedures, or modifying traditional posterior techniques to be done while positioned lateral. The benefits of lateral anterior column access may be achievable with the patient prone, allowing for concomitant posterior techniques in a more familiar single-position setting. Methods: Prone transpsoas (PTP) access was outlined and vetted by a group of LIF-experienced spine surgeons. Early clinical experience included prospectively capturing procedural details and perioperative outcomes across a multi-centre cohort of clinicians to assess feasibility and to identify efficiencies and/or challenges. Results: Perioperative data was prospectively collected from 120 consecutive cases (176 levels) from 22 surgeons. Lateral exposure was achieved in an average 18 min/level, guided by triggered EMG; and retraction time averaged 25 min/level, with continued plexus monitoring via saphenous SSEP. Fixation was via percutaneous pedicle screws (65%), open pedicle screws (24%), other (11%). No re-positioning was required. Concomitant procedures facilitated by prone position included direct decompression (37%), treatment at L5-S1 (18%), posterior instrumentation revision (7%), and osteotomy/bony releases (9%). PTP procedure time, blood loss, and length of stay were consistent with established LIF experience. Challenges included patient movement with lateral instrument forces, retractor sag, stability of access relative to the patient, and surgeon ergonomics of the working channel. These challenges were overcome later in the experience through development of a specialized positioner and retractor system specific to this approach and a prescribed workflow developed by consensus of the surgeons. Conclusion: Initial multi-centre clinical experience suggests that PTP is not only feasible but creates efficiencies by allowing for single-position surgery maximizing both anterior and posterior column access and corrective techniques, with perioperative outcomes consistent with lateral decubitus experience. Learnings included the need for development of procedure-specific technologies and technique refinement.

Background case description: Prone transposoas (PTP) is a novel approach to the lateral lumbar interbody fusion that harnesses the advantages of minimally invasive surgery with circumferential access to the lumbar spine in a single position. We present the peri-operative course of four index cases of patients having undergone PTP at a single institution. Outcome: Pre and post-operative spinal imaging with alignment parameters, operative approach, and patient outcome are reviewed for each index case. Conclusion: As advances in neuromonitoring and minimally invasive technology continue to evolve, new lumbar interbody fusion approaches are becoming operatively feasible.

Abstract Background The measurement of finger and wrist range of motion (ROM) is of great importance to clinicians when assessing functional outcomes of therapeutic interventions and surgical procedures. The purpose of the study was to assess the repeatability of ROM measurements of the hand joints with manual goniometer and 3D motion capture system and to calculate the minimal detectable difference for both methods. Methods Active finger and wrist joints ROM of 20 healthy volunteers were assessed using a manual goniometer and 3D motion capture system. Minimal detectable difference (MDD) and standard error of measurement (SEM) were calculated for both measurement systems and compared within the same task. Maximal ROM of all joints was registered twice on two different days to evaluate the test-retest repeatability. The intraclass correlation coefficients (ICC) was calculated and examined to determine if reliability ≥ 0.70 existed. Results MDD for the 3D motion capture was between 5 and 12° except for the metacarpophalangeal joint (MCP) 1, interphalangeal joint (IP), and MCP5. SEM values lay between 2 and 4° for all joints except for the MCP5, IP, and MCP1. For the goniometric measurements, MDD and SEM were between 12–30° and 4–11°, respectively. The reliability criterion (ICC > 0.7) was achieved for the ROM measurement with the 3D motion capture system for 94% of the joints and in only 65% of the joints with the manual goniometer. Conclusions Joint ROM assessed with 3D motion analysis showed higher test-retest agreement demonstrating overall better repeatability for this method. Because of the smaller measurement error, the 3D motion capture system has a smaller MDD. Only individual test-rest differences bigger than the MDD can be considered as real changes, and therefore, in an experimental situation, the use of a more precise measurement method can greatly reduce the number of subjects needed for a statistical significance. Goniometer measurements of some joints should be carefully interpreted, due to a low repeatability and reliability. Trial registration This study is approved by the Ethical Committee Zurich (Kek-ZH-Nr: 2015-0395).

Human physiological signals are inherently rhythmic and have a hallmark feature in that even distant intrasignal measurements are related to each other. This relationship is termed long-range correlation and has been recognized as an indicator of the optimal state of the observed physiological systems, among which the locomotor system. Loss of long-range correlations has been found as a result of aging as well as disease, which can be evaluated with detrended fluctuation analysis (DFA). Recently, DFA and the scaling exponent α have been employed for understanding the degeneration of temporal regulation of human walking biorhythms in, for example, Parkinson disease (PD). However, heterogeneous evidence on scaling exponent α values reported in the literature across different population groups has put into question what constitutes a healthy physiological pattern. Therefore, the purpose of this systematic review was to investigate the functional thresholds of scaling exponent α in young vs. older adults, as well as between patients with PD and age-matched asymptomatic controls. Aging and PD exhibited a negative effect size (i.e., led to decreased long-range correlations) of −0.20 and −0.53, respectively. Our meta-analysis based on 14 studies provides evidence that a mean scaling exponent α threshold of 0.86 [2 standard error (0.76, 0.96)] is able to optimally discriminate temporal organization of stride interval between young and old, whereas 0.82 (0.72, 0.92) differentiates patients with PD and age-matched asymptomatic controls. The optimal thresholds presented in this review together with the consensus guidelines for using DFA might allow a more sensitive and reliable application of this metric for understanding human walking physiology than has been achieved to date.

ABSTRACT Colorectal adenomas are precancerous lesions of colorectal cancer (CRC) that offer a means of viewing the events key to early CRC development. A number of studies have investigated the changes and roles of gut microbiota in adenoma and carcinoma development, highlighting its impact on carcinogenesis. However, there has been less of a focus on the gut metabolome, which mediates interactions between the host and gut microbes. Here, we investigated metabolomic profiles of stool samples from patients with advanced adenoma (n = 102), matched controls (n = 102), and patients with CRC (n = 36). We found that several classes of bioactive lipids, including polyunsaturated fatty acids, secondary bile acids, and sphingolipids, were elevated in the adenoma patients compared to the controls. Most such metabolites showed directionally consistent changes in the CRC patients, suggesting that those changes may represent early events of carcinogenesis. We also examined gut microbiome-metabolome associations using gut microbiota profiles in these patients. We found remarkably strong overall associations between the microbiome and metabolome data and catalogued a list of robustly correlated pairs of bacterial taxa and metabolomic features which included signatures of adenoma. Our findings highlight the importance of gut metabolites, and potentially their interplay with gut microbes, in the early events of CRC pathogenesis. IMPORTANCE Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.

BackgroundWalking patterns can provide important indications of a person’s health status and be beneficial in the early diagnosis of individuals with a potential walking disorder. For appropriate gait analysis, it is critical that natural functional walking characteristics are captured, rather than those experienced in artificial or observed settings. To better understand the extent to which setting influences gait patterns, and particularly whether observation plays a varying role on subjects of different ages, the current study investigates to what extent people walk differently in lab versus real-world environments and whether age dependencies exist.MethodsThe walking patterns of 20 young and 20 elderly healthy subjects were recorded with five wearable inertial measurement units (ZurichMOVE sensors) attached to both ankles, both wrists and the chest. An automated detection process based on dynamic time warping was developed to efficiently identify the relevant sequences. From the ZurichMOVE recordings, 15 spatio-temporal gait parameters were extracted, analyzed and compared between motion patterns captured in a controlled lab environment (10 m walking test) and the non-controlled ecologically valid real-world environment (72 h recording) in both groups.ResultsSeveral parameters (Cluster A) showed significant differences between the two environments for both groups, including an increased outward foot rotation, step width, number of steps per 180° turn, stance to swing ratio, and cycle time deviation in the real-world. A number of parameters (Cluster B) showed only significant differences between the two environments for elderly subjects, including a decreased gait velocity (p = 0.0072), decreased cadence (p = 0.0051) and increased cycle time (p = 0.0051) in real-world settings. Importantly, the real-world environment increased the differences in several parameters between the young and elderly groups.ConclusionElderly test subjects walked differently in controlled lab settings compared to their real-world environments, which indicates the need to better understand natural walking patterns under ecologically valid conditions before clinically relevant conclusions can be drawn on a subject’s functional status. Moreover, the greater inter-group differences in real-world environments seem promising regarding the sensitive identification of subjects with indications of a walking disorder.

Abstract Background Internal and external rotation exercises of the shoulder are frequently performed to avoid injury and pain. Knowledge about the motion and loadings of the upper extremities during these exercises is crucial for the development of optimal training recommendations. However, a comparison of the angles and corresponding moments in the upper extremities that are achieved during internal and external rotation exercises for the shoulder by using different resistance types has not yet been performed. Therefore, the aim of the study was to examine upper extremity kinetics and kinematics in 3D of the internal and external rotation exercises. Methods The kinematics and kinetics of 12 participants while they performed 10 different exercises with a constant and with an elastic external load corresponding to 2% body mass was assessed. The motion of the upper extremities was recorded three-dimensionally with a motion capture system, using a newly developed marker set and joint coordinate systems with 28 markers. The applied external load was measured with a load cell placed in series with the external resistance, and moments were calculated using an inverse dynamics approach. Results The range of motion and the joint loading was highly dependent on the exercises. The range of motion in the glenohumeral joint did not differ significantly between the two resistance types, whereas internal/external rotation moments were significantly higher with constant resistance than those with elastic resistance. Conclusions Larger or lower moments can, therefore, be achieved through selection of the appropriate resistance type, while the range of motion can be altered through the selection of exercise type. Therefore, the loading motion patterns identified in this study can help to choose suitable shoulder exercises dependent on the training objective.

Abstract Background Squatting is a core exercise for many purposes. The tissue loading during squatting is crucial for positive adaptation and to avoid injury. This study aimed to evaluate the effect of narrow, hip and wide stance widths, foot position angles (0°, 21°, and 42°), strength exercise experience, and barbell load (0 and 50% body weight, experts only) during squatting. Methods Novice (N = 21) and experienced (N = 21) squatters performed 9 different variations of squats (3 stance widths, 3 foot placement angles). A 3D motion capture system (100 Hz) and two force plates (2000 Hz) were used to record mediolateral knee displacement (ΔD*), range of motion (RoM) at the hip and knee joints, and joint moments at the hip, knee, and lower back. Results Both stance width and foot placement angles affected the moments at the hip and knee joints in the frontal and sagittal planes. ΔD* varied with stance width, foot placement angles and between the subjects’ level of experience with the squat exercise as follows: increasing foot angle led to an increased foot angle led to an increased ΔD*, while an increased stance width resulted in a decreased ΔD*; novice squatters showed a higher ΔD*, while additional weight triggered a decreased ΔD*. Conclusions Suitable stance width and foot placement angles should be chosen according to the targeted joint moments. In order to avoid injury, special care should be taken in extreme positions (narrow stand-42° and wide stance-0°) where large knee and hips joint moments were observed.

Abstract Background MicroRNA (miRNA) profiling is an important step in studying biological associations and identifying marker candidates. miRNA exists in isoforms, called isomiRs, which may exhibit distinct properties. With conventional profiling methods, limitations in assay and analysis platforms may compromise isomiR interrogation. Results We introduce a comprehensive approach to sequence-oriented isomiR annotation (CASMIR) to allow unbiased identification of global isomiRs from small RNA sequencing data. In this approach, small RNA reads are maintained as independent sequences instead of being summarized under miRNA names. IsomiR features are identified through step-wise local alignment against canonical forms and precursor sequences. Through customizing the reference database, CASMIR is applicable to isomiR annotation across species. To demonstrate its application, we investigated isomiR profiles in normal and neoplastic human colorectal epithelia. We also ran miRDeep2, a popular miRNA analysis algorithm to validate isomiRs annotated by CASMIR. With CASMIR, specific and biologically relevant isomiR patterns could be identified. We note that specific isomiRs are often more abundant than their canonical forms. We identify isomiRs that are commonly up-regulated in both colorectal cancer and advanced adenoma, and illustrate advantages in targeting isomiRs as potential biomarkers over canonical forms. Conclusions Studying miRNAs at the isomiR level could reveal new insight into miRNA biology and inform assay design for specific isomiRs. CASMIR facilitates comprehensive annotation of isomiR features in small RNA sequencing data for isomiR profiling and differential expression analysis.

Forward modelling has indicated hip internal rotation as a secondary physical effect to plantar flexion under load. It could therefore be of interest to focus the treatment for patients with unilateral spastic cerebral palsy on achieving a heel–toe gait pattern, to prevent development of asymmetrical hip internal rotation. The aim of this preliminary retrospective cohort investigation was to evaluate the effect of restoring heel–toe gait, through use of functional orthoses, on passive hip internal rotation. In this study, the affected foot was kept in an anatomically correct position, aligned to the leg and the gait direction. In case of gastrosoleus shortness, a heel raise was attached to compensate for the equinus and yet to provide heel–floor contact (mean equinus = −2.6 degrees of dorsiflexion). Differences in passive hip internal rotation between the two sides were clinically assessed while the hip was extended. Two groups were formed according to the achieved correction of their gait patterns through orthotic care: patients with a heel-toe gait (with anterograde rocking) who wore the orthosis typically for at least eight hours per day for at least a year, or patients with toe-walking (with retrograde rocking) in spite of wearing the orthosis who used the orthosis less in most cases. A Student’s t-test was used to compare the values of clinically assessed passive hip rotation (p < 0.05) between the groups and the effect size (Hedges’ g) was estimated. Of the 70 study participants, 56 (mean age 11.5 y, majority GMFCS 1, similar severity of pathology) achieved a heel-toe gait, while 14 remained as toe-walkers. While patients with heel–toe gait patterns showed an almost symmetrical passive hip internal rotation (difference +1.5 degrees, standard deviation 9.6 degrees), patients who kept toe-walking had an increased asymmetrical passive hip internal rotation (difference +10.4 degrees, standard deviation 7.5 degrees; p = 0.001, Hedges’s g = 0.931). Our clinical findings are in line with the indications from forward modelling that treating the biomechanical problem might prevent development of a secondary deformity. Further prospective studies are needed to verify the presented hypothesis.

Normal pressure hydrocephalus (NPH) is a chronic and progressive disease that affects predominantly elderly subjects. The most prevalent symptoms are gait disorders, generally determined by visual observation or measurements taken in complex laboratory environments. However, controlled testing environments can have a significant influence on the way subjects walk and hinder the identification of natural walking characteristics. The study aimed to investigate the differences in walking patterns between a controlled environment (10 m walking test) and real-world environment (72 h recording) based on measurements taken via a wearable gait assessment device. We tested whether real-world environment measurements can be beneficial for the identification of gait disorders by performing a comparison of patients’ gait parameters with an aged-matched control group in both environments. Subsequently, we implemented four machine learning classifiers to inspect the individual strides’ profiles. Our results on twenty young subjects, twenty elderly subjects and twelve NPH patients indicate that patients exhibited a considerable difference between the two environments, in particular gait speed (p-value p=0.0073), stride length (p-value p=0.0073), foot clearance (p-value p=0.0117) and swing/stance ratio (p-value p=0.0098). Importantly, measurements taken in real-world environments yield a better discrimination of NPH patients compared to the controlled setting. Finally, the use of stride classifiers provides promise in the identification of strides affected by motion disorders.

Abstract Background In order to find correlated pairs of positions between proteins, which are useful in predicting interactions, it is necessary to concatenate two large multiple sequence alignments such that the sequences that are joined together belong to those that interact in their species of origin. When each protein is unique then the species name is sufficient to guide this match, however, when there are multiple related sequences (paralogs) in each species then the pairing is more difficult. In bacteria a good guide can be gained from genome co-location as interacting proteins tend to be in a common operon but in eukaryotes this simple principle is not sufficient. Results The methods developed in this paper take sets of paralogs for different proteins found in the same species and make a pairing based on their evolutionary distance relative to a set of other proteins that are unique and so have a known relationship (singletons). The former constitute a set of unlabelled nodes in a graph while the latter are labelled. Two variants were tested, one based on a phylogenetic tree of the sequences (the topology-based method) and a simpler, faster variant based only on the inter-sequence distances (the distance-based method). Over a set of test proteins, both gave good results, with the topology method performing slightly better. Conclusions The methods develop here still need refinement and augmentation from constraints other than the sequence data alone, such as known interactions from annotation and databases, or non-trivial relationships in genome location. With the ever growing numbers of eukaryotic genomes, it is hoped that the methods described here will open a route to the use of these data equal to the current success attained with bacterial sequences.

Abstract Background To ensure an efficient and targeted adaptation with low injury risk during strength exercises, knowledge of the participant specific internal loading conditions is essential. The goal of this study was to calculate the lower limb muscles forces during the strength exercises deadlifts, goodmornings and splits squats by means of musculoskeletal simulation. Methods 11 participants were assessed performing 10 different variations of split squats by varying the step length as well as the maximal frontal tibia angle, and 13 participants were measured performing deadlift and goodmorning exercises. Using individualised musculoskeletal models, forces of the Quadriceps (four parts), Hamstrings (four parts) and m. gluteus maximus (three parts) were computed. Results Deadlifts resulted highest loading for the Quadriceps, especially for the vasti (18–34 N/kg), but not for the rectus femoris (8–10 N/kg), which exhibited its greatest loading during split squats (13–27 N/kg) in the rear limb. Hamstrings were loaded isometrically during goodmornings but dynamically during deadlifts. For the m. gluteus maximus, the highest loading was observed during split squats in the front limb (up to 25 N/kg), while deadlifts produced increasingly, large loading over large ranges of motion in hip and knee. Conclusions Acting muscle forces vary between exercises, execution form and joint angle. For all examined muscles, deadlifts produced considerable loading over large ranges of motion, while split squats seem to be highly dependent upon exercise variation. This study provides key information to design strength-training programs with respect to loading conditions and ranges of motion of lower extremity muscles.

Abstract Background Back extension (BE) is a strength exercise for training the dorsal trunk and hip muscles. To optimise training recommendations that avoid overloading and possible injury, the aim of this study was to determine the loading conditions and the influence of different execution forms of BE on spine, hip and knee ranges of motion (RoMs), joint moments and muscle activity. Methods The kinematics, kinetics and muscle activity (EMG) of two execution types (BEh: dynamic hip, BEs: dynamic spine) and two versions (one-legged and two-legged) of BE were measured in 16 subjects. RoMs and external joint moments were calculated using an inverse dynamics approach and analysed with a linear mixed model. Results Although lumbar spine flexion was observed in both execution types, thoracic spine flexion predominantly occurred during BEs, whereas thoracic spine extension was observed during BEh. Larger maximal back and hip moments were observed for BEh than for BEs. The activity of the dorsal back and hip muscles, as observed using EMG, was increased for one-legged executions. Conclusion To strengthen the hips and lower back, BEh seem to be more efficient due to the higher moments, with higher or similar RoMs in the hip and lower back. One-legged BEs seem to provide an effective training for the hamstrings and hip regions without subjecting the spine to excessive loading, possibly promoting this as an effective exercise during training and rehabilitation.

The primary aim of this study was to assess the effects of total knee arthroplasty (TKA) implant design on collateral ligament elongation patterns that occur during level walking, downhill walking, and stair descent. Using a moving fluoroscope, tibiofemoral kinematics were captured in three groups of patients with different TKA implant designs, including posterior stabilized, medial stabilized, and ultra-congruent. The 3D in vivo joint kinematics were then fed into multibody models of the replaced knees and elongation patterns of virtual bundles connecting origin and insertion points of the medial and lateral collateral ligaments (MCL and LCL) were determined throughout complete cycles of all activities. Regardless of the implant design and activity type, non-isometric behavior of the collateral ligaments was observed. The LCL shortened with increasing knee flexion, while the MCL elongation demonstrated regional variability, ranging from lengthening of the anterior bundle to slackening of the posterior bundle. The implant component design did not demonstrate statistically significant effects on the collateral elongation patterns and this was consistent between the studied activities. This study revealed that post-TKA collateral ligament elongation is primarily determined by the knee flexion angle. The different anterior translation and internal rotation that were induced by three distinctive implant designs had minimal impact on the length change patterns of the collateral ligaments.

Following publication of the original article [1], the authors reported an error in the following sentence on page 8: “In general, knee varus (negative ΔD*) is a much more common deficit than valgus, and a more negative ΔD* value in the novice squatters compared to the experienced ones was therefore expected.”

The model of protein folding proposed by Ptitsyn and colleagues involves the accretion of secondary structures around a nucleus. As developed by Efimov, this model also provides a useful way to view the relationships among structures. Although somewhat eclipsed by later databases based on the pairwise comparison of structures, Efimov’s approach provides a guide for the more automatic comparison of proteins based on an encoding of their topology as a string. Being restricted to layers of secondary structures based on beta sheets, this too has limitations which are partly overcome by moving to a more generalised secondary structure lattice that can encompass both open and closed (barrel) sheets as well as helical packing of the type encoded by Murzin and Finkelstein on small polyhedra. Regular (crystalline) lattices, such as close-packed hexagonals, were found to be too limited so pseudo-latticses were investigated including those found in quasicrystals and the Bernal tetrahedron-based lattice that he used to represent liquid water. The Bernal lattice was considered best and used to generate model protein structures. These were much more numerous than those seen in Nature, posing the open question of why this might be.

Lower extremity dysfunction is often associated with hip muscle strength deficiencies. Detailed knowledge of the muscle forces generated in the hip under specific external loading conditions enables specific structures to be trained. The aim of this study was to find the most effective movement type and loading direction to enable the training of specific parts of the hip muscles using a standing posture and a pulley system. In a novel approach to release the predictive power of musculoskeletal modelling techniques based on inverse dynamics, flexion/extension and ab-/adduction movements were virtually created. To demonstrate the effectiveness of this approach, three hip orientations and an external loading force that was systematically rotated around the body were simulated using a state-of-the art OpenSim model in order to establish ideal designs for training of the anterior and posterior parts of the M. gluteus medius (GM). The external force direction as well as the hip orientation greatly influenced the muscle forces in the different parts of the GM. No setting was found for simultaneous training of the anterior and posterior parts with a muscle force higher than 50% of the maximum. Importantly, this study has demonstrated the use of musculoskeletal models as an approach to predict muscle force variations for different strength and rehabilitation exercise variations.

Motor variability is an inherent feature of all human movements and reflects the quality of functional task performance. Depending on the requirements of the motor task, the human sensory-motor system is thought to be able to flexibly govern the appropriate level of variability. However, it remains unclear which neurophysiological structures are responsible for the control of motor variability. In this study, we tested the contribution of cortical cognitive resources on the control of motor variability (in this case postural sway) using a dual-task paradigm and furthermore observed potential changes in control strategy by evaluating Ia-afferent integration (H-reflex). Twenty healthy subjects were instructed to stand relaxed on a force plate with eyes open and closed, as well as while trying to minimize sway magnitude and performing a “subtracting-sevens” cognitive task. In total 25 linear and non-linear parameters were used to evaluate postural sway, which were combined using a Principal Components procedure. Neurophysiological response of Ia-afferent reflex loop was quantified using the Hoffman reflex. In order to assess the contribution of the H-reflex on the sway outcome in the different standing conditions multiple mixed-model ANCOVAs were performed. The results suggest that subjects were unable to further minimize their sway, despite actively focusing to do so. The dual-task had a destabilizing effect on PS, which could partly (by 4%) be counter-balanced by increasing reliance on Ia-afferent information. The effect of the dual-task was larger than the protective mechanism of increasing Ia-afferent information. We, therefore, conclude that cortical structures, as compared to peripheral reflex loops, play a dominant role in the control of motor variability.

Stability boots can protect the ankle ligaments from overloading after serious injury and facilitate protected movement in order to aid healing of the surrounding soft tissue structures. For comparing different stability shoe designs and prototypes, a reliable and fast testing method (FTM) is required. The aim of this study was to assess the reliability of a novel custom-built device. Six different stability boots were tested in a novel device that allowed body weight to be taken into account using a pneumatic actuator. The fixation of the boots was controlled using two air pad pressure sensors. The range of motion (RoM) was then assessed during 5 trials at physiological ankle joint torques during flexion/extension and inversion/eversion. Furthermore the intraclass correlation coefficient ICC was determined to assess the repetitive reliability of the testing approach. The measured ankle angles ranged from 3.4° to 25° and proved to be highly reliable (ICC=0.99), with standard deviations