Hip contact force pathways in total hip replacement differ between patients and activities of daily living.

One of the main causes of implant failure and revision surgery in total hip replacement (THR) is aseptic loosening often caused by the accumulation of wear debris arising between the contact surfaces of the acetabular cup and femoral head during activities of daily living (ADL's). However, limited information is available regarding the contact force pathways between these two surfaces during specific ADL's. In this study, through musculoskeletal modelling, we aimed to estimate the orientation of the hip contact force pathway on the acetabular cup. One hundred and thirty-two THR patients underwent motion capture analysis whilst undertaking locomotor and non-locomotor ADL's. Musculoskeletal simulations were performed to calculate contact force pathways using inverse dynamics analysis. We then qualitatively compared differences in the contact force pathways between patients and between ADL's. Walking resulted in a typical figure-of-eight pattern, with the peak contact forces occurring in the superior-anterior area of the cup. The non-locomotive activities such as stand up, sit down and squat had a more linear shape, spanning across the superior-posterior quarter of the cup. Our results showed a large inter-patient variability in the shape and location of the contact force pathway. There is a distinct difference in the location and shape of the pathway between locomotor and non-locomotor activities and this could result in different wear accumulations. These results could enhance our understanding why revision rates vary across the population and could inform the development of personalised implant design.

Anatomically and mechanically conforming patient-specific spinal fusion cages designed by full-scale topology optimization.

Cage subsidence after instrumented lumbar spinal fusion surgery remains a significant cause of treatment failure, specifically for posterior or transforaminal lumbar interbody fusion. Recent advancements in computational techniques and additive manufacturing, have enabled the development of patient-specific implants and implant optimization to specific functional targets. This study aimed to introduce a novel full-scale topology optimization formulation that takes the structural response of the adjacent bone structures into account in the optimization process. The formulation includes maximum and minimum principal strain constraints that lower strain concentrations in the adjacent vertebrae. This optimization approach resulted in anatomically and mechanically conforming spinal fusion cages. Subsidence risk was quantified in a commercial finite element solver for off-the-shelf, anatomically conforming and the optimized cages, in two representative patients. We demonstrated that the anatomically and mechanically conforming cages reduced subsidence risk by 91% compared to an off-the-shelf implant with the same footprint for a patient with normal bone quality and 54% for a patient with osteopenia. Prototypes of the optimized cage were additively manufactured and mechanically tested to evaluate the manufacturability and integrity of the design and to validate the finite element model.

An in vitro-in silico workflow for predicting renal clearance of PFAS.

Per- and poly-fluoroalkyl substances (PFAS) have a wide range of elimination half-lives (days to years) in humans, thought to be in part due to variation in proximal tubule reabsorption. While human biomonitoring studies provide important data for some PFAS, renal clearance (CLrenal) predictions for hundreds of PFAS in commerce requires experimental studies with in vitro models and physiologically-based in vitro-to-in vivo extrapolation (IVIVE). Options for studying renal proximal tubule pharmacokinetics include cultures of renal proximal tubule epithelial cells (RPTECs) and/or microphysiological systems. This study aimed to compare CLrenal predictions for PFAS using in vitro models of varying complexity (96-well plates, static 24-well Transwells and a fluidic microphysiological model, all using human telomerase reverse transcriptase-immortalized and OAT1-overexpressing RPTECs combined with in silico physiologically-based IVIVE. Three PFAS were tested: one with a long half-life (PFOS) and two with shorter half-lives (PFHxA and PFBS). PFAS were added either individually (5 µM) or as a mixture (2 µM of each substance) for 48 h. Bayesian methods were used to fit concentrations measured in media and cells to a three-compartmental model to obtain the in vitro permeability rates, which were then used as inputs for a physiologically-based IVIVE model to estimate in vivo CLrenal. Our predictions for human CLrenal of PFAS were highly concordant with available values from in vivo human studies. The relative values of CLrenal between slow- and faster-clearance PFAS were most highly concordant between predictions from 2D culture and corresponding in vivo values. However, the predictions from the more complex model (with or without flow) exhibited greater concordance with absolute CLrenal. Overall, we conclude that a combined in vitro-in silico workflow can predict absolute CLrenal values, and effectively distinguish between PFAS with slow and faster clearance, thereby allowing prioritization of PFAS with a greater potential for bioaccumulation in humans.

Comprehensive assessment of global spinal sagittal alignment and related normal spinal loads in a healthy population.

Abnormal postoperative global sagittal alignment (GSA) is associated with an increased risk of mechanical complications after spinal surgery. Typical assessment of sagittal alignment relies on a few selected measures, disregarding global complexity and variability of the sagittal curvature. The normative range of spinal loads associated with GSA has not yet been considered in clinical evaluation. The study objectives were to develop a new GSA assessment method that holistically describes the inherent relationships within GSA and to estimate the related spinal loads. Vertebral endplates were annotated on radiographs of 85 non-pathological subjects. A Principal Component Analysis (PCA) was performed to derive a Statistical Shape Model (SSM). Associations between identified GSA variability modes and conventional alignment measures were assessed. Simulations of respective Shape Modes (SMs) were performed using an established musculoskeletal AnyBody model to estimate normal variation in cervico-thoraco-lumbar loads. The first six principal components explained 97.96% of GSA variance. The SSM provides the normative range of GSA and a visual representation of the main variability modes. Normal variation relative to the population mean in identified alignment features was found to influence spinal loads, e.g. the lower bound of the second shape mode (SM2-2σ) corresponds to an increase in L4L5-compression by 378.64 N (67.86%). Six unique alignment features were sufficient to describe GSA almost entirely, demonstrating the value of the proposed method for an objective and comprehensive analysis of GSA. The influence of these features on spinal loads provides a normative biomechanical reference, eventually guiding surgical planning of deformity correction in the future.

Lower trapezius and latissimus dorsi transfer relieve teres minor activity into the physiological range in Collin D irreparable posterosuperior massive rotator cuff tears: a biomechanical analysis.

BACKGROUND: Tendon transfers are established techniques to regain external rotation mobility in patients with an irreparable, posterosuperior massive rotator cuff tear (MRCT). Posterosuperior MRCT with intact teres minor (type D MRCT) can lead to excessive teres minor loading to maintain external rotation. We hypothesize that tendon transfers are effective in relieving teres minor loading in type D MRCTs. Our aim was to biomechanically assess muscle synergism with latissimus dorsi (LD transfer) and lower trapezius (LT transfer) tendon transfer during external rotation at different abduction heights. METHODS: Using musculoskeletal modeling, we analyzed and compared the moment arm, muscle torque, and muscle activity between a healthy and type D MRCT pathologic model with and without the LD- or LT transfer at infraspinatus and teres minor insertion sites. Output measures were analyzed during external rotation at different abduction angles and 10-50 N resistance against external rotation. We assessed its impact on teres minor loading in a type D MRCT. Morphologic variations were parameterized using the critical shoulder angle and the acromiohumeral distance to address variations among patients. RESULTS: Both transfer types reduced teres minor torque and activity significantly, reaching physiological state at 40 N external resistance (P < .001), with insertion to infraspinatus site being more effective than teres minor site (P < .001). External rotation moment arms of LD transfer were larger than LT transfer at 90° abduction (25.1 ± 0.8 mm vs. 21.2 ± 0.6 mm, P < .001) and vice versa at 0° abduction (17.4 ± 0.5 mm vs. 24.0 ± 0.2 mm, P < .001). Although the healthy infraspinatus was the main external rotator in all abduction angles (50%-70% torque), a type D MRCT resulted in a 70%-90% increase of teres minor torque and an up to 7-fold increase in its activity leading to excessive loadings beyond 10 N resistance against external rotation. Varying the critical shoulder angle and the acromiohumeral distance led to minor variations in muscle moment arm and muscle activity. CONCLUSION: We identified biomechanical efficacy of both tendon transfers in type D MRCT regarding teres minor load relief and superior performance of the transfers at the infraspinatus insertion site.

CT image-based biomarkers for opportunistic screening of osteoporotic fractures: a systematic review and meta-analysis.

The use of opportunistic computed tomography (CT) image-based biomarkers may be a low-cost strategy for screening older individuals at high risk for osteoporotic fractures and populations that are not sufficiently targeted. This review aimed to assess the discriminative ability of image-based biomarkers derived from existing clinical routine CT scans for hip, vertebral, and major osteoporotic fracture prediction. A systematic search in PubMed MEDLINE, Embase, Cochrane, and Web of Science was conducted from the earliest indexing date until July 2023. The evaluation of study quality was carried out using a modified Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) checklist. The primary outcome of interest was the area under the curve (AUC) and its corresponding 95% confidence intervals (CIs) obtained for four main categories of biomarkers: areal bone mineral density (BMD), image attenuation, volumetric BMD, and finite element (FE)-derived biomarkers. The meta-analyses were performed using random effects models. Sixty-one studies were included in this review, among which 35 were synthesized in a meta-analysis and the remaining articles were qualitatively synthesized. In comparison to the pooled AUC of areal BMD (0.73 [95% CI 0.71-0.75]), the pooled AUC values for predicting osteoporotic fractures for FE-derived parameters (0.77 [95% CI 0.72-0.81]; p < 0.01) and volumetric BMD (0.76 [95% CI 0.71-0.81]; p < 0.01) were significantly higher, but there was no significant difference with the pooled AUC for image attenuation (0.73 [95% CI 0.66-0.79]; p = 0.93). Compared to areal BMD, volumetric BMD and FE-derived parameters may provide a significant improvement in the discrimination of osteoporotic fractures using opportunistic CT assessments.

In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation.

One of the main hallmarks of Parkinson's disease (PD) is abnormal alpha-synuclein (α-syn) aggregation which forms the main component of intracellular Lewy body inclusions. This short report used preformed α-syn fibrils, as well as an A53T mutant α-syn adenovirus to mimic conditions of pathological protein aggregation in dopaminergic human derived SH-SY5Y neural cells. Since there is evidence that the mTOR pathway and glutamatergic signaling each influence protein aggregation, we also assessed the impact of the mTOR inhibitor, rapamycin and the mGluR5 allosteric modulator, CTEP. We found that both rapamycin and CTEP induced a significant reduction of α-syn fibrils in SH-SY5Y cells and this effect was associated with a reduction in mTOR signaling and enhancement in autophagic pathway factors. These data support the possibility that CTEP (or rapamycin) might be a useful pharmacological approach to target abnormal α-syn accumulation by promoting intracellular degradation or enhanced clearance.

The role of muscle degeneration and spinal balance in the pathophysiology of lumbar spinal stenosis: Study protocol of a translational approach combining in vivo biomechanical experiments with clinical and radiological parameters.

OBJECTIVE: To describe a study protocol for investigating the functional association between posture, spinal balance, ambulatory biomechanics, paraspinal muscle fatigue, paraspinal muscle quality and symptoms in patients with symptomatic lumbar spinal stenosis (sLSS) before and 1-year after elective surgical intervention. DESIGN: Single-centre prospective, experimental, multimodal (clinical, biomechanical, radiological) study with three instances of data collection: baseline (study visit 1), 6-month follow-up (remote) and 1-year follow-up (study visit 2). Both study visits include an in vivo experiment aiming to elicit paraspinal muscle fatigue for postural assessment in a non-fatigued and fatigued state. EXPERIMENTAL PROTOCOL: At baseline and 1-year follow-up, 122 patients with sLSS will be assessed clinically, perform the back-performance scale assessment and complete several patient-reported outcome measure (PROMs) questionnaires regarding overall health, disease-related symptoms and kinesiophobia. Posture and biomechanical parameters (joint kinematics, kinetics, surface electromyography, back curvature) will be recorded using an optoelectronic system and retroreflective markers during different tasks including overground walking and movement assessments before and after a modified Biering-Sørensen test, used to elicit paraspinal muscle fatigue. Measurements of muscle size and quality and the severity of spinal stenosis will be obtained using magnetic resonance imaging (MRI) and sagittal postural alignment data from EOS radiographies. After each study visit, physical activity level will be assessed during 9 days using a wrist-worn activity monitor. In addition, physical activity level and PROMs will be assessed remotely at 6-month follow-up. CONCLUSION: The multimodal set of data obtained using the study protocol described in this paper will help to expand our current knowledge on the pathophysiology, biomechanics, and treatment outcome of degenerative sLSS. The results of this study may contribute to defining and/or altering patient treatment norms, surgery indication criteria and post-surgery rehabilitation schedules. TRIAL REGISTRATION: The protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov (NCT05523388).

3D-printed LEGO®-inspired titanium scaffolds for patient-specific regenerative medicine.

Despite the recent advances in 3D-printing, it is often difficult to fabricate implants that optimally fit a defect size or shape. There are some approaches to resolve this issue, such as patient-specific implant/scaffold designs based on CT images of the patients, however, this process is labor-intensive and costly. Especially in developing countries, affordable treatment options are required, while still not excluding these patient groups from potential material and manufacturing advances. Here, a selective laser melting (SLM) 3D-printing strategy was used to fabricate a hierarchical, LEGO®-inspired Assemblable Titanium Scaffold (ATS) system, which can be manually assembled in any shape or size with ease. A surgeon can quickly create a scaffold that would fit to the defect right before the implantation during the surgery. Additionally, the direct inclusion of micro- and macroporous structures via 3D-printing, as well as a double acid-etched surface treatment (ST) in the ATS, ensure biocompatibility, sufficient nutrient flow, cell migration and enhanced osteogenesis. Three different structures were designed (non-porous:NP, semi-porous:SP, ultra-porous:UP), 3D-printed with the SLM technique and then surface treated for the ST groups. After analyzing characteristics of the ATS such as printing quality, surface roughness and interconnected porosity, mechanical testing and finite element analysis (FEA) demonstrated that individual and stacked ATS have sufficient mechanical properties to withstand loading in a physiological system. All ATS showed high cell viability, and the SP and UP groups demonstrated enhanced cell proliferation rates compared to the NP group. Furthermore, we also verified that cells were well-attached and spread on the porous structures and successful cell migration between the ATS units was seen in the case of assemblies. The UP and SP groups exhibited higher calcium deposition and RT-qPCR proved higher osteogenic gene expression compared to NP group. Finally, we demonstrate a number of possible medical applications that reveal the potential of the ATS through assembly.

A 3D-Printed Assemblable Bespoke Scaffold as a Versatile Microcryogel Carrier for Site-Specific Regenerative Medicine.

Advances in additive manufacturing have led to diverse patient-specific implant designs utilizing computed tomography, but this requires intensive work and financial implications. Here, Digital Light Processing is used to fabricate a hive-structured assemblable bespoke scaffold (HIVE). HIVE can be manually assembled in any shape/size with ease, so a surgeon can create a scaffold that will best fit a defect before implantation. Simultaneously, it can have site-specific treatments by working as a carrier filled with microcryogels (MC) incorporating different biological factors in different pockets of HIVE. After characterization, possible site-specific applications are investigated by utilizing HIVE as a versatile carrier with incorporated treatments such as growth factors (GF), bioceramic, or cells. HIVE as a GF-carrier shows a controlled release of bone morphogenetic protein/vascular endothelial growth factor (BMP/VEGF) and induced osteogenesis/angiogenesis from human mesenchymal stem cells (hMSC)/human umbilical vein endothelial cells (HUVECs). Furthermore, as a bioceramic-carrier, HIVE demonstrates enhanced mineralization and osteogenesis, and as a HUVEC carrier, it upregulates both osteogenic and angiogenic gene expression of hMSCs. HIVE with different combinations of MCs yields a distinct local effect and successful cell migration is confirmed within assembled HIVEs. Finally, an in vivo rat subcutaneous implantation demonstrates site-specific osteogenesis and angiogenesis.

Combined electric and magnetic field therapy for bone repair and regeneration: an investigation in a 3-mm and an augmented 17-mm tibia osteotomy model in sheep.

BACKGROUND: Therapies using electromagnetic field technology show evidence of enhanced bone regeneration at the fracture site, potentially preventing delayed or nonunions. METHODS: Combined electric and magnetic field (CEMF) treatment was evaluated in two standardized sheep tibia osteotomy models: a 3-mm non-critical size gap model and a 17-mm critical size defect model augmented with autologous bone grafts, both stabilized with locking compression plates. CEMF treatment was delivered across the fracture gap twice daily for 90 min, starting 4 days postoperatively (post-OP) until sacrifice (9 or 12 weeks post-OP, respectively). Control groups received no CEMF treatment. Bone healing was evaluated radiographically, morphometrically (micro-CT), biomechanically and histologically. RESULTS: In the 3-mm gap model, the CEMF group (n = 6) exhibited higher callus mineral density compared to the Control group (n = 6), two-fold higher biomechanical torsional rigidity and a histologically more advanced callus maturity (no statistically significant differences). In the 17-mm graft model, differences between the Control (n = 6) and CEMF group (n = 6) were more pronounced. The CEMF group showed a radiologically more advanced callus, a higher callus volume (p = 0.003) and a 2.6 × higher biomechanical torsional rigidity (p = 0.024), combined with a histologically more advanced callus maturity and healing. CONCLUSIONS: This study showed that CEMF therapy notably enhanced bone healing resulting in better new bone structure, callus morphology and superior biomechanical properties. This technology could transform a standard inert orthopedic implant into an active device stimulating bone tissue for accelerated healing and regeneration.

Ibuprofen-loaded electrospun poly(ethylene-co-vinyl alcohol) nanofibers for wound dressing applications.

Chronic wounds are characterized by a prolonged inflammation phase preventing the normal processes of wound healing and natural regeneration of the skin. To tackle this issue, electrospun nanofibers, inherently possessing a high surface-to-volume ratio and high porosity, are promising candidates for the design of anti-inflammatory drug delivery systems. In this study, we evaluated the ability of poly(ethylene-co-vinyl alcohol) nanofibers of various chemical compositions to release ibuprofen for the potential treatment of chronic wounds. First, the electrospinning of poly(ethylene-co-vinyl alcohol) copolymers with different ethylene contents (32, 38 and 44 mol%) was optimized in DMSO. The morphology and surface properties of the membranes were investigated via state-of-the-art techniques and the influence of the ethylene content on the mechanical and thermal properties of each membrane was evaluated. Furthermore, the release kinetics of ibuprofen from the nanofibers in a physiological temperature range revealed that more ibuprofen was released at 37.5 °C than at 25 °C regardless of the ethylene content. Additionally, at 25 °C less drug was released when the ethylene content of the membranes increased. Finally, the scaffolds showed no cytotoxicity to normal human fibroblasts collectively paving the way for the design of electrospun based patches for the treatment of chronic wounds.

Association between sagittal alignment and loads at the adjacent segment in the fused spine: a combined clinical and musculoskeletal modeling study of 205 patients with adult spinal deformity.

PURPOSE: Sagittal malalignment is a risk factor for mechanical complications after surgery for adult spinal deformity (ASD). Spinal loads, modulated by sagittal alignment, may explain this relationship. The aims of this study were to investigate the relationships between: (1) postoperative changes in loads at the proximal segment and realignment, and (2) absolute postoperative loads and postoperative alignment measures. METHODS: A previously validated musculoskeletal model of the whole spine was applied to study a clinical sample of 205 patients with ASD. Based on clinical and radiographic data, pre-and postoperative patient-specific alignments were simulated to predict loads at the proximal segment adjacent to the spinal fusion. RESULTS: Weak-to-moderate associations were found between pre-to-postop changes in lumbar lordosis, LL (r = - 0.23, r = - 0.43; p < 0.001), global tilt, GT (r = 0.26, r = 0.38; p < 0.001) and the Global Alignment and Proportion score, GAP (r = 0.26, r = 0.37; p < 0.001), and changes in compressive and shear forces at the proximal segment. GAP score parameters, thoracic kyphosis measurements and the slope of upper instrumented vertebra were associated with changes in shear. In patients with T10-pelvis fusion, moderate-to-strong associations were found between postoperative sagittal alignment measures and compressive and shear loads, with GT showing the strongest correlations (r = 0.75, r = 0.73, p < 0.001). CONCLUSIONS: Spinal loads were estimated for patient-specific full spinal alignment profiles in a large cohort of patients with ASD pre-and postoperatively. Loads on the proximal segments were greater in association with sagittal malalignment and malorientation of proximal vertebra. Future work should explore whether they provide a causative mechanism explaining the associated risk of proximal junction complications.

The acetabular labrum tissue shows unique transcriptome signatures compared to cartilage and responds to combined cyclic compression and surface shearing.

The labrum is a fibrocartilaginous ring surrounding the acetabulum. Loss of labrum function contributes to the degeneration of the hip joint, leading to osteoarthritis. Successful labrum restoration requires profound knowledge about the tissue being replaced. The aim of this study was to characterize the transcriptome and the mechanobiological function of the labrum. RNA-seq was performed to compare the transcriptome of bovine labrum against articular cartilage tissue. Differential expression and gene ontology (GO) term pathway analysis were applied using the SUSHI framework. Bovine labrum explants were cultured for 5 days with / without mechanical loading and targeted gene expression was analyzed by real time quantitative polymerase chain reaction. More than 6'000 genes were significantly differentially expressed in the labrum compared to cartilage. Up- and downregulated genes were associated with the GO term extracellular matrix organization. The study established an extracellular matrix gene expression profile of healthy labrum tissue and identified significantly upregulated extracellular matrix related genes compared to cartilage tissue. Mechanical loading significantly upregulated aggrecan (ACAN), cartilage oligomeric matrix protein (COMP), fibronectin (FN1) and proteoglycan 4 (PRG4). MMP1/3/9 and IL6, which were upregulated by an inflammatory stimulus (IL-1b), were statistically unaffected by the loading, although IL6 was upregulated in each donor immediately after the loading. Unique ECM related features may guide the development of labrum tissue-engineering solutions. Despite the transcriptome differences between labrum and cartilage tissue, gene expression response to mechanical loading showed similarities with previously reported responses in cartilage, indicating a preserved tissue adaptation mechanism to mechanical loading. Running title: Acetabular Labrum Mechanobiology.

Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation.

Currently, approximately 80,000 chemicals are used in commerce. Most have little-to-no toxicity information. The U.S. Toxicology in the 21st Century (Tox21) program has conducted a battery of in vitro assays using a quantitative high-throughput screening (qHTS) platform to gain toxicity information on environmental chemicals. Due to technical challenges, standard methods for providing xenobiotic metabolism could not be applied to qHTS assays. To address this limitation, we screened the Tox21 10,000-compound (10K) library, with concentrations ranging from 2.8 nM to 92 µM, using a p53 beta-lactamase reporter gene assay (p53-bla) alone or with rat liver microsomes (RLM) or human liver microsomes (HLM) supplemented with NADPH, to identify compounds that induce p53 signaling after biotransformation. Two hundred and seventy-eight compounds were identified as active under any of these three conditions. Of these 278 compounds, 73 gave more potent responses in the p53-bla assay with RLM, and 2 were more potent in the p53-bla assay with HLM compared with the responses they generated in the p53-bla assay without microsomes. To confirm the role of metabolism in the differential responses, we re-tested these 75 compounds in the absence of NADPH or with heat-attenuated microsomes. Forty-four compounds treated with RLM, but none with HLM, became less potent under these conditions, confirming the role of RLM in metabolic activation. Further evidence of biotransformation was obtained by measuring the half-life of the parent compounds in the presence of microsomes. Together, the data support the use of RLM in qHTS for identifying chemicals requiring biotransformation to induce biological responses.

Intraoperative Load Tolerance of the Thumb Carpometacarpal Joint After Resection-Suspension-Interposition Arthroplasty.

Purpose: The objective was to measure the intraoperative load tolerance of the thumb carpometacarpal (CMC) joint after trapeziectomy, tendon suspension, and interposition. Methods: In this single-center prospective study, preoperative pinch grip, thumb mobility, and hypermobility of the thumb CMC joint were determined by 2 hand surgeons. Patients completed the brief Michigan Hand Outcomes Questionnaire. During surgery and upon removal of the trapezium, the surgeon subjectively rated the degree of thumb CMC load tolerance as "stable," "medium stable," or "unstable." A measurement system with an integrated force sensor was used to measure intraoperative thumb CMC load tolerance. The thumb ray was displaced manually by 10 mm toward the scaphoid, and the counteracting force was measured over the entire displacement. The objective load tolerance was determined as the maximal measured force after trapezium resection, tendon suspension, and interposition. Analysis of variance was used to test for the differences in load tolerance between the surgical steps. Spearman's coefficient was used to find correlations between load tolerance and clinical or patient-reported variables. Results: Twenty-nine patients with a mean age of 70 years (SD, 8.1 years) were available for analysis. The measured intraoperative load tolerance after trapeziectomy was 15.5 N (SD, 5.4 N) and significantly increased to 18.7 N (SD, 5.5 N) after suspension. Load tolerance only slightly increased after tendon interposition, increasing the force to 20.3 N (SD, 6.7 N). Neither the surgeon's subjective stability rating nor the clinical or patient-reported variables correlated with the measured load tolerance after trapeziectomy. Conclusions: Our results show that tendon suspension leads to the highest increase in thumb CMC load tolerance during resection-suspension-interposition arthroplasty. Clinical relevance: Tendon suspension appears to be the most important step in stabilizing the metacarpal base after trapeziectomy, whereas tendon interposition does not seem to have a relevant additional effect regarding load tolerance, at least immediately after surgery.

Key Characteristics of Human Hepatotoxicants as a Basis for Identification and Characterization of the Causes of Liver Toxicity.

Hazard identification regarding adverse effects on the liver is a critical step in safety evaluations of drugs and other chemicals. Current testing paradigms for hepatotoxicity rely heavily on preclinical studies in animals and human data (epidemiology and clinical trials). Mechanistic understanding of the molecular and cellular pathways that may cause or exacerbate hepatotoxicity is well advanced and holds promise for identification of hepatotoxicants. One of the challenges in translating mechanistic evidence into robust decisions about potential hepatotoxicity is the lack of a systematic approach to integrate these data to help identify liver toxicity hazards. Recently, marked improvements were achieved in the practice of hazard identification of carcinogens, female and male reproductive toxicants, and endocrine disrupting chemicals using the key characteristics approach. Here, we describe the methods by which key characteristics of human hepatotoxicants were identified and provide examples for how they could be used to systematically identify, organize, and use mechanistic data when identifying hepatotoxicants.

High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures.

The ToxCast in vitro screening program has provided concentration-response bioactivity data across more than a thousand assay endpoints for thousands of chemicals found in our environment and commerce. However, most ToxCast screening assays have evaluated individual biological targets in cancer cell lines lacking integrated physiological functionality (such as receptor signaling, metabolism). We evaluated differentiated HepaRGTM cells, a human liver-derived cell model understood to effectively model physiologically relevant hepatic signaling. Expression of 93 gene transcripts was measured by quantitative polymerase chain reaction using Fluidigm 96.96 dynamic arrays in response to 1060 chemicals tested in eight-point concentration-response. A Bayesian framework quantitatively modeled chemical-induced changes in gene expression via six transcription factors including: aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, androgen receptor, and peroxisome proliferator-activated receptor alpha. For these chemicals the network model translates transcriptomic data into Bayesian inferences about molecular targets known to activate toxicological adverse outcome pathways. These data also provide new insights into the molecular signaling network of HepaRGTM cell cultures.

Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK3ß/ZBTB16, mTOR/ULK1 signaling in autophagy.

Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gαq/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical Gαq/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK3ß/ZBTB16 pathways in both Alzheimer's and Huntington's disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK3ß/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK3ß/ZBTB16 and mTOR/ULK1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.

Contact force path in total hip arthroplasty: effect of cup medialisation in a whole-body simulation.

BACKGROUND: Cup medialisation down to the true acetabular floor in total hip arthroplasty with a compensatory femoral offset increase seems to be mechanically advantageous for the abductor muscles due to the relocation of the lever arms (body weight lever arm decreased, abductor lever arm increased). However, limited information is currently available about the effects of this reconstruction type at the head cup interface, compared to an anatomical reconstruction that maintains the natural lever arms. Through a whole-body simulation analysis, we compared medialised versus anatomical reconstruction in THA to analyse the effects on: (1) contact force magnitude at the head cup interface; (2) contact force path in the cup; and (3) abductor activity. METHODS: Musculoskeletal simulations were performed to calculate the above-mentioned parameters using inverse dynamics analysis. The differences between the virtually implanted THAs were calculated to compare the medialised versus anatomical reconstruction. RESULTS: Cup medialisation with compensatory femoral offset increase led to: (1) a reduction in contact force magnitude at the head cup interface up to 6.6%; (2) a similar contact force path in the cup in terms of sliding distance and aspect ratio; and (3) a reduction in abductor activity up to 17.2% (gluteus medius). CONCLUSIONS: In our opinion, these potential biomechanical gains do not generally justify a fully medialised reconstruction, especially in younger patients that are more likely to undergo revision surgery in their lifetime. Cup medialisation should be performed until sufficient press fit and bony coverage of a properly sized and oriented cup can be achieved.