CETZOLE Analogs as Potent Ferroptosis Inducers and Their Target Identification Using Covalent/Affinity Probes.

Ferroptosis is a recently discovered cell death mechanism triggered by iron-dependent elevation of reactive oxygen species leading to lipid membrane peroxidation. We previously reported the development of a new class of ferroptosis inducers referred to as CETZOLEs with CC50 values in the low micromolar range. Structure-activity relationship study of these compounds led to the development of more potent analogs with CC50 values in the nanomolar range. Cells exposed to these compounds displayed the hallmarks of ferroptosis including cell death through ROS accumulation. Cancer cells were found to be more sensitive to these compounds than normal cells. Proteomic studies using covalent and affinity probes led to the identification of cystathionine ß-synthase, peroxiredoxins, ADP/ATP carriers, and glucose dehydrogenase as enriched proteins. The binding of CETZOLEs to these proteins as well as GPX4 was validated by Western blotting. This group of proteins is known to be associated with cellular antioxidant pathways.

The role of limb alignment on natural tibiofemoral kinematics and kinetics.

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.

In-vivo and in-vitro environments affect the storage and release of energy in tendons.

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.

An investigation of plasma cell-free RNA for the detection of colorectal cancer: From transcriptome marker selection to targeted validation.

Regular screening for colorectal cancer (CRC) is critical for early detection and long-term survival. Despite the current screening options available and advancements in therapies there will be around 53,000 CRC related deaths this year. There is great interest in non-invasive alternatives such as plasma cell-free RNA (cfRNA) for diagnostic, prognostic, and predictive applications. In the current study, our aim was to identify and validate potential cfRNA candidates to improve early CRC diagnosis. In phase 1 (n = 49; 25 controls, 24 cancers), discovery total RNA sequencing was performed. Select exons underwent validation in phase 2 (n = 73; 35 controls, 29 cancers, 9 adenomas) using targeted capture sequencing (n = 10,371 probes). In phase 3 (n = 57; 30 controls, 27 cancers), RT-qPCR was performed on previously identified candidates (n = 99). There were 895 exons that were differentially expressed (325 upregulated, 570 downregulated) among cancers versus controls. In phases 2 and 3, fewer markers were validated than expected in independent sets of patients, most of which were from previously published literature (FGA, FGB, GPR107, CDH3, and RP23AP7). In summary, we optimized laboratory processes and data analysis strategies which can serve as methodological framework for future plasma RNA studies beyond just the scope of CRC detection. Additionally, further exploration is needed in order to determine if the few cfRNA candidates identified in this study have clinical utility for early CRC detection. Over time, advancements in technologies, data analysis, and RNA preservation methods at time of collection may improve the biological and technical reproducibility of cfRNA biomarkers and enhance the feasibility of RNA-based liquid biopsies.

Spinal column shortening with single-stage prone lateral vertebral osteotomy for tethered cord syndrome: illustrative case.

BACKGROUND: Tethered cord syndrome (TCS) is a rare neurological disorder characterized by longitudinal stretching on the distal end of the spinal cord. The condition commonly manifests in lumbosacral and lower-extremity pain and weakness, sensory disturbances, and incontinence. Traditionally, tethered cord release has been the first-line management for TCS, but retethering and complications such as cerebrospinal fluid leakage are commonly reported. As a result, spinal column shortening (SCS) vertebral osteotomy has emerged as a potential alternative. OBSERVATIONS: Herein, the authors describe the first single-stage prone lateral SCS vertebral osteotomy with simultaneous posterior exposure in a 48-year-old male patient with multiple prior direct detethering procedures. The authors highlight the case presentation, operative technique, and postoperative course. Following surgery, there were no immediate surgical complications, and the patient noted clinical improvement in his radicular pain and neurological function. LESSONS: This case further supports SCS vertebral osteotomy as an effective treatment option for patients with TCS. It also demonstrates the potential for a single-stage lateral approach with posterior exposure as a minimally invasive option for spinal shortening procedures. However, further studies using expanded cohorts and assessing various surgical techniques are warranted. https://thejns.org/doi/10.3171/CASE24185.

Shifting the Cancer Screening Paradigm: Developing a Multi-Biomarker Class Approach to Multi-Cancer Early Detection 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.

Methylated DNA Markers in Voided Urine for the Identification of Clinically Significant Prostate Cancer.

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.

Mutant p53 reactivators protect breast cancer cells from ferroptosis.

Ferroptosis is a novel nonapoptotic form of cell death characterized by iron-dependent reactive oxygen species-mediated lipid peroxidation. In several different cell systems, the tumor suppressor p53 can enhance sensitivity to ferroptotic inducers. At least half of all human cancers show loss of function of p53. Furthermore, many of those tumors express mutant forms of p53 that has lost its wild-type function. Several groups have designed small molecules that can reactivate the wild-type function of these missense p53 mutants. We reasoned that p53 reactivators may also enhance sensitivity of certain cancer cells to ferroptosis stimuli. To test this idea we combined a number of different p53 reactivators with small molecule inducers of ferroptosis. In contrast, we observed that several p53 reactivators protected cells from cell death induced by ferroptotic inducers. Surprisingly, this protection still occurred in p53-null cell lines. We observed that these reactivators were neither free radical scavengers nor ion chelators. One of these p53 reactivator molecules, NSC 59984, reduced expression of GPX4, which is unlikely to explain its ability to reduce sensitivity to ferroptosis. We suggest that these p53 reactivators function via an unknown, p53-independent manner to suppress ferroptosis.

Posterior tibial slope influences joint mechanics and soft tissue loading after total knee arthroplasty.

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 <0.16 BW of joint contact force) throughout level walking and squatting. Once confirmed for accuracy, this baseline modelling framework was then used to systematically explore the influence of PTS on knee joint biomechanics. Our results indicate that PTS can greatly influence tibio-femoral translations (mainly in the anterior-posterior direction), while also suggesting an elevated risk of patellar mal-tracking and instability. Importantly, however, an increased PTS was found to reduce the maximum tibio-femoral contact force and improve efficiency of the quadriceps muscles, while also reducing the patellofemoral contact force (by approximately 1.5% for each additional degree of PTS during walking). This study presents valuable findings regarding the impact of PTS variations on the biomechanics of the TKA joint and thereby provides potential guidance for surgically optimizing implant alignment in the sagittal plane, tailored to the implant design and the individual deficits of each patient.

Algorithm Training and Testing for a Nonendoscopic Barrett's Esophagus Detection Test in Prospective Multicenter Cohorts.

BACKGROUND & AIMS: Endoscopic Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) detection is invasive and expensive. Nonendoscopic BE/EAC detection tools are guideline-endorsed alternatives. We previously described a 5-methylated DNA marker (MDM) panel assayed on encapsulated sponge cell collection device (CCD) specimens. We aimed to train a new algorithm using a 3-MDM panel and test its performance in an independent cohort. METHODS: Algorithm training and test samples were from 2 prospective multicenter cohorts. All BE cases had esophageal intestinal metaplasia (with or without dysplasia/EAC); control subjects had no endoscopic evidence of BE. The CCD procedure was followed by endoscopy. From CCD cell lysates, DNA was extracted, bisulfite treated, and MDMs were blindly assayed. The algorithm was set and locked using cross-validated logistic regression (training set) and its performance was assessed in an independent test set. RESULTS: Training (N = 352) and test (N = 125) set clinical characteristics were comparable. The final panel included 3 MDMs (NDRG4, VAV3, ZNF682). Overall sensitivity was 82% (95% CI, 68%-94%) at 90% (79%-98%) specificity and 88% (78%-94%) sensitivity at 84% (70%-93%) specificity in training and test sets, respectively. Sensitivity was 90% and 68% for all long- and short-segment BE, respectively. Sensitivity for BE with high-grade dysplasia and EAC was 100% in training and test sets. Overall sensitivity for nondysplastic BE was 82%. Areas under the receiver operating characteristic curves for BE detection were 0.92 and 0.94 in the training and test sets, respectively. CONCLUSIONS: A locked 3-MDM panel algorithm for BE/EAC detection using a nonendoscopic CCD demonstrated excellent sensitivity for high-risk BE cases in independent validation samples. (Clinical trials.gov: NCT02560623, NCT03060642.).

Adaptive gait responses to varying weight-bearing conditions: Inferences from gait dynamics and H-reflex magnitude.

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.

The influence of implant design and limb alignment on in vivo wear rates of fixed-bearing and rotating-platform knee implant retrievals.

Analysis of polyethylene (PE) wear in knee implants is crucial for understanding the factors leading to revision in total knee arthroplasty. Importantly, current experimental and computational methods for predicting insert wear can only be validated against true in vivo measurements from retrievals. This study quantitatively investigated in vivo PE wear rates in fixed-bearing (FB) (n = 21) and rotating-platform (n = 53) implant retrievals. 3D surface geometry of the retrievals was measured using a structured light scanner. Then, a reference surface that included the deformation, but not the wear that the retrievals had experienced in vivo, was constructed using a fully automatic surface reconstruction algorithm. Finally, wear volume was calculated from the deviation between the worn and reconstructed surfaces. The measurement and analysis techniques were validated and the algorithm was found to produce errors of only 0.2% relative to the component volumes. In addition to quantifying cohort-level wear rates, the effect of mechanical axis limb alignment on mediolateral wear distribution was examined for a subset of the retrievals (n = 14 + 26). Our results show that FB implants produce significantly (p = 0.04) higher topside wear rates (24.6 ± 10.1 mm3/year) than rotating-platform implants (15.3 ± 8.0 mm3/year). This effect was larger than that of limb alignment, which had a smaller and nonsignificant influence on overall wear rates (+4.5 ± 11.6 mm3/year, p = 0.43). However, increased varus alignment was associated significantly with greater medial compartment wear in both the FB and rotating-platform designs (+1.7 ± 1.3%/° and +1.8 ± 1.6%/°). Our findings emphasize the importance of implant design and limb alignment on wear outcomes, providing reference data for improving implant performance and longevity.

Reliability of a Novel Classification System for Thoracic Disc Herniations.

STUDY DESIGN: This is a cross-sectional survey. OBJECTIVE: The aim was to assess the reliability of a proposed novel classification system for thoracic disc herniations (TDHs). SUMMARY OF BACKGROUND DATA: TDHs are complex entities varying substantially in many factors, including size, location, and calcification. To date, no comprehensive system exists to categorize these lesions. METHODS: Our proposed system classifies 5 types of TDHs using anatomic and clinical characteristics, with subtypes for calcification. Type 0 herniations are small (≤40% of spinal canal) TDHs without significant spinal cord or nerve root effacement; type 1 are small and paracentral; type 2 are small and central; type 3 are giant (>40% of spinal canal) and paracentral; and type 4 are giant and central. Patients with types 1 to 4 TDHs have correlative clinical and radiographic evidence of spinal cord compression. Twenty-one US spine surgeons with substantial TDH experience rated 10 illustrative cases to determine the system's reliability. Interobserver and intraobserver reliability were determined using the Fleiss kappa coefficient. Surgeons were also surveyed to obtain consensus on surgical approaches for the various TDH types. RESULTS: High agreement was found for the classification system, with 80% (range 62% to 95%) overall agreement and high interrater and intrarater reliability (kappa 0.604 [moderate to substantial agreement] and kappa 0.630 [substantial agreement], respectively). All surgeons reported nonoperative management of type 0 TDHs. For type 1 TDHs, most respondents (71%) preferred posterior approaches. For type 2 TDHs, responses were roughly equivalent for anterolateral and posterior options. For types 3 and 4 TDHs, most respondents (72% and 68%, respectively) preferred anterolateral approaches. CONCLUSIONS: This novel classification system can be used to reliably categorize TDHs, standardize description, and potentially guide the selection of surgical approach. Validation of this system with regard to treatment and clinical outcomes represents a line of future study.

Plasma Assay of Cell-Free Methylated DNA Markers of Colorectal Cancer: A Tumor-Agnostic Approach to Monitor Recurrence and Response to Anticancer Therapies.

BACKGROUND: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. METHODS: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. RESULTS: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90-232 days). CONCLUSIONS: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring.

Identifying treatment non-responders based on pre-treatment gait characteristics - A machine learning approach.

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 <1.6° vs. responders). Their pre-treatment features (sagittal joint angles, spatiotemporal parameters, anthropometrics) were used to train a support vector machine classifier with 5-fold cross-validation and Bayesian optimization within a MATLAB-based Classification Learner App. Results: An average accuracy of 88.2 ± 0.5 % was achieved for identifying participants whose gait will not respond to treatment, with 64 % true negative rate and an area under the curve of 88 %. Conclusion: Overall, a classical machine learning model was able to identify patients at risk of not responding to treatment, based on gait features and anthropometrics collected prior to treatment. The output of such a model could function as a warning signal, notifying clinicians that a certain individual might not respond well to the standard of care and that a more personalized intervention might be needed.

Steering-by-leaning facilitates intuitive movement control and improved efficiency in manual wheelchairs.

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.

Knee kinematics are primarily determined by implant alignment but knee kinetics are mainly influenced by muscle coordination strategy.

Implant malalignment has been reported to be a primary reason for revision total knee arthroplasty (TKA). In addition, altered muscle coordination patterns are commonly observed in TKA patients, which is thought to alter knee contact loads. A comprehensive understanding of the influence of surgical implantation and muscle recruitment strategies on joint contact mechanics is crucial to improve surgical techniques, increase implant longevity, and inform rehabilitation protocols. In this study, a detailed musculoskeletal model with a 12 degrees of freedom knee was developed to represent a TKA subject from the CAMS-Knee datasets. Using motion capture and ground reaction force data, a level walking cycle was simulated and the joint movement and loading patterns were estimated using a novel technique for concurrent optimization of muscle activations and joint kinematics. In addition, over 12'000 Monte Carlo simulations were performed to predict knee contact mechanics during walking, considering numerous combinations of implant alignment and muscle activation scenarios. Validation of our baseline simulation showed good agreement between the model kinematics and loading patterns against the in vivo data. Our analyses reveal a considerable impact of implant alignment on the joint kinematics, while variation in muscle activation strategies mainly affects knee contact loading. Moreover, our results indicate that high knee compressive forces do not necessarily originate from extreme kinematics and vice versa. This study provides an improved understanding of the complex inter-relationships between loading and movement patterns resulting from different surgical implantation and muscle coordination strategies and presents a validated framework towards population-based modelling in TKA.

Lower-limb internal loading and potential consequences for fracture healing.

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.

Can developmental trajectories in gait variability provide prognostic clues in motor adaptation among children with mild cerebral palsy? A retrospective observational cohort study.

Aim: To 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). Methods: This 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. Results: Motor-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. Interpretation: This 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.

Cognitive and biomarker responses in healthy older adults to a 18-hole golf round and different walking types: a randomised cross-over study.

Introduction: The global burden of age-related cognitive decline is increasing, with the number of people aged 60 and over expected to double by 2050. This study compares the acute effects of age-appropriate cognitively demanding aerobic exercises involving walking, on cognitive functions and exerkine responses such as brain-derived neurotrophic factor (BDNF) and cathepsin B (CTSB) in older, healthy adults. Methods/design: Healthy older golfers (n=25, 16 male and 9 female, 69±4 years) were enrolled in a 5-day randomised cross-over study and completed three different exercise trials (18-hole golf round, 6 km Nordic walking, 6 km walking) in a real-life environment, in random order and at a self-selected pace. Differences in cognition (the Trail-Making Test (TMT) AB) and exerkines (BDNF and CTSB) were analysed within groups using the Wilcoxon signed-rank test and between groups using the Kruskal-Wallis test. Results: All exercise types resulted in a significant decrease in the TMT A-test (p<0.05; golf: -4.43±1.5 s, Nordic walking: -4.63±1.6 s, walking: -6.75±2.26 s), where Nordic walking and walking demonstrated a decrease in the TMT B-test (p<0.05; Nordic walking: -9.62±7.2 s, walking: -7.55±3.2 s). In addition, all exercise types produced significant decreases in the TMT AB test scores (p<0.05), and Nordic walking (p=0.035) showed decreases in the TMTB-TMTA-test. There were no immediate postexercise changes in the levels of BDNF or CTSB. Conclusion: Acute bouts of golf, Nordic walking and walking improved cognitive functions irrespective of exerkines in healthy older adults. In addition, Nordic walking and walking in general enhanced executive functions. No significant effects were seen on the levels of BDNF and CTSB. Trial registration number: ISRCTN10007294.