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.

Plasma Methylated DNA Markers for Melanoma Surveillance.

PURPOSE: Surveillance after primary melanoma treatment aims to detect early signs of low-volume systemic disease. The current standard of care, surveillance imaging, is costly and difficult to access. We therefore sought to develop methylated DNA markers (MDMs) as promising alternatives for disease surveillance. METHODS: We used reduced representation bisulfite sequencing (RRBS) to identify MDMs in DNA samples obtained from metastatic melanoma, benign nevi, and normal skin tissues. The identified MDMs underwent validation in an independent cohort of tissue and buffy coat DNA samples. Subsequently, we tested the validated MDMs in the plasma DNA of patients with metastatic melanoma undergoing surveillance with total body imaging and compared them with cancer-free controls. To estimate the overall predictive accuracy of the MDMs, we used random forest modeling with bootstrap cross-validation. RESULTS: Forty MDMs demonstrated discrimination between melanoma cases and controls consisting of benign nevi and normal skin. Nine MDMs passing biological validation in tissue were run on 77 plasma samples from individuals with a history of metastatic melanoma, 49 of whom had evidence of disease detected by imaging at the time of blood draw, and 100 cancer-free controls. The cross-validated sensitivity of the panel for imaging-positive disease was 80% with a specificity of 100% in cancer-free controls, resulting in an overall AUC of 0.88 (95% CI, 0.81 to 0.96). The survival estimates for patients with melanoma who tested positive for the panel at 6 months and 1 year were 67% and 56%, respectively, while those who tested negative had survival rates of 100% and 92%. CONCLUSION: MDMs identified by RRBS demonstrate a high degree of concordance with imaging results in the plasma of patients with metastatic melanoma. Further prospective studies in larger intended use cohorts are needed to confirm these findings.

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.

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.

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.

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.

Minimal Required Resolution to Capture the 3D Shape of the Human Back-A Practical Approach.

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.

Assessing the capacity of methylated DNA markers of cervical squamous cell carcinoma to discriminate oropharyngeal squamous cell carcinoma in human papillomavirus mediated disease.

OBJECTIVE: Early identification of human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) is challenging and novel biomarkers are needed. We hypothesized that a panel of methylated DNA markers (MDMs) found in HPV(+) cervical squamous cell carcinoma (CSCC) will have similar discrimination in HPV(+)OPSCC tissues. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissues were obtained from patients with primary HPV(+)OPSCC or HPV(+)CSCC; control tissues included normal oropharynx palatine tonsil (NOP) and cervix (NCS). Using a methylation-specific polymerase chain reaction, 21 previously validated cervical MDMs were evaluated on tissue-extracted DNA. Discrimination between case and control cervical and oropharynx tissue was assessed using area under the curve (AUC). RESULTS: 34 HPV(+)OPSCC, 36 HPV(+)CSCC, 26 NOP, and 24 NCS patients met inclusion criteria. Within HPV(+)CSCC, 18/21 (86%) of MDMs achieved an AUC ≥ 0.9 and all MDMs exhibited better than chance classifications relative to control cervical tissue (all p < 0.001). In contrast, within HPV(+)OPSCC only 5/21 (24%) MDMs achieved an AUC ≥ 0.90 but 19/21 (90%) exhibited better than chance classifications relative to control tonsil tissue (all p < 0.001). Overall, 13/21 MDMs had statistically significant lower AUCs in the oropharyngeal cohort compared to the cervical cohort, and only 1 MDM exhibited a statistically significant increase in AUC. CONCLUSIONS: Previously validated MDMs exhibited robust performance in independent HPV(+)CSCC patients. However, most of these MDMs exhibited higher discrimination for HPV(+)CSCC than for HPV(+)OPSCC. This suggests that each SCC subtype requires a unique set of MDMs for optimal discrimination. Future studies are necessary to establish an MDM panel for HPV(+)OPSCC.

Methylated DNA Markers for Sporadic Colorectal and Endometrial Cancer Are Strongly Associated with Lynch Syndrome Cancers.

Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population. PREVENTION RELEVANCE: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.

In Vivo Strain Patterns in the Achilles Tendon During Dynamic Activities: A Comprehensive Survey of the Literature.

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.

Complications of the Prone Transpsoas Lateral Lumbar Interbody Fusion for Degenerative Lumbar Spine Disease: A Multicenter Study.

BACKGROUND AND OBJECTIVES: The prone transpsoas (PTP) approach for lateral lumbar interbody fusion (LLIF) is a novel technique for degenerative lumbar spine disease. However, there is a paucity of information in the literature on the complications of this procedure, with all published data consisting of small samples. We aimed to report the intraoperative and postoperative complications of PTP in the largest study to date. METHODS: A retrospective electronic medical record review was conducted at 11 centers to identify consecutive patients who underwent LLIF through the PTP approach between January 1, 2021, and December 31, 2021. The following data were collected: intraoperative characteristics (operative time, estimated blood loss [EBL], intraoperative complications [anterior longitudinal ligament (ALL) rupture, cage subsidence, vascular and visceral injuries]), postoperative complications, and hospital stay. RESULTS: A total of 365 patients were included in the study. Among these patients, 2.2% had ALL rupture, 0.3% had cage subsidence, 0.3% had a vascular injury, 0.3% had a ureteric injury, and no other visceral injuries were reported. Mean operative time was 226.2 ± 147.9 minutes. Mean EBL was 138.4 ± 215.6 mL. Mean hospital stay was 2.7 ± 2.2 days. Postoperative complications included new sensory symptoms-8.2%, new lower extremity weakness-5.8%, wound infection-1.4%, cage subsidence-0.8%, psoas hematoma-0.5%, small bowel obstruction and ischemia-0.3%, and 90-day readmission-1.9%. CONCLUSION: In this multicenter case series, the PTP approach was well tolerated and associated with a satisfactory safety profile.

A frame orientation optimisation method for consistent interpretation of kinematic signals.

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.