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The mission of the Orthopaedic Research Society is to promote and advance musculoskeletal research worldwide. With this in mind, the Annual Meeting Program Committee sought to establish a debate as a key component of the meeting. Our purpose was to provoke discussion on topics that are core to our mission and to engage all constituencies within the society by examining questions of broad relevance. To this end, the topic "Regenerative medicine will make orthopaedic implants obsolete in our time" was selected as the title of the inaugural debate. The arguments for and against the motion are presented in this perspectives article. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2579-2585, 2018.

Background: The rate of revision for some designs of total hip replacements due to idiopathic aseptic loosening has been reported as higher for women. However, whether this is environmental or inherently sex-related is not clear. Objective: Can particle induced osteolysis be sex dependent? And if so, is this dependent on the type of implant debris (e.g. metal vs polymer)? The objective of this study was to test for material dependent inflammatory osteolysis that may be linked to sex using CoCrMo and implant grade conventional polyethylene (UHMWPE), using an in vivo murine calvaria model. Methods: Healthy 12 week old female and male C57BL/6J mice were treated with UHMWPE (1.0um ECD) or CoCrMo particles (0.9um ECD) or received sham surgery. Bone resorption was assessed by micro-computed tomography, histology and histomorphometry on day 12 post challenge. Results: Female mice that received CoCrMo particles showed significantly more inflammatory osteolysis and bone destruction compared to the females who received UHMWPE implant debris. Moreover, females challenged with CoCrMo particles exhibited 120% more inflammatory bone loss compared to males (p Conclusion: We demonstrated sex-specific differences in the amount of osteolysis resulting from CoCrMo particle challenge. This suggests osteo-immune responses to metal debris are preferentially higher in female compared to male mice, and supports the contention that there may be inherent sex related susceptibility to some types of implant debris.

Background The fretting-corrosion behavior of mixed metal contacts is affected by various mechanical and electrochemical parameters. Crevice conditions at the junction and patient-specific pathologies can affect the pH of the prosthetic environment. The main objective of this study is to understand the effect of pH variation at the stem/head junction of the hip implant under fretting corrosion exposure. We hypothesized that pH will have a significant influence on the fretting-corrosion behavior hip implant modular junctions. Materials and methods A custom-made setup was used to evaluate the fretting corrosion behavior of hip implant modular junctions. A Newborn calf serum solution (30 g/L protein content) was used to simulate the synovial fluid environment. A sinusoidal fretting motion, with a displacement amplitude of +50 µm, was applied to the Ti alloy rod. The effects of pathology driven, periprosthetic pH variation were simulated at four different pH levels (3.0, 4.5, 6.0 and 7.6). Electrochemical and mechanical properties were evaluated before, during, and after the applied fretting motion. Results The impedance of the system was increased in response to the fretting motion. The hysteresis tangential load/displacement behavior was not affected by pH level. The worn surfaces of CoCrMo pins exhibited the presence of tribolayer or organic deposits, in the pH 4.5 group, which may explain the lower drop in potential and mass loss observed in that group. Mechanically dominated wear mechanisms, namely, adhesive wear was shown in the pH 7.6 group, which may account for a higher potential drop and metal content loss. Conclusions This study suggests that the fretting-corrosion mechanisms in hip implant are affected by the pH levels of the surrounding environment and patient-specific factors.

In orthopedic healthcare, Total Hip Replacement (THR) is a common and effective solution to hip-related bone and joint diseases/fracture; however, corrosion of the hip implant and the release of degradation metal ions/particles can lead to early implant failure and pose potential toxicity risk for the surrounding tissues. The main objective of this work was to investigate the potential role of Vitamin E to minimize corrosion-related concerns from CoCrMo hip implants. The study focused on two questions (i) Can Vitamin E inhibit CoCrMo corrosion? and (ii) Does Vitamin E moderate the toxicity associated with the CoCrMo implant particles? In the study (i) the electrochemical experiments (ASTM G61 ) with different concentrations of Vitamin E (1, 2, 3 mg/ml against the control) were performed using normal saline and simulated synovial fluid (Bovine calf serum-BCS, 30 g/L protein, pH 7.4) as electrolytes. The polished CoCrMo disc (Ra 50 nm) was the working electrode. The findings suggested that both Vitamin E-Saline (45 ± 0.9%) and Vitamin E-BCS (91 ± 3%) solutions protected against implant corrosion at a Vitamin E concentration of 3 mg/ml, but Vitamin E-BCS showed protection at all Vitamin E (1-3 mg/ml) concentration levels. These results suggested that the Vitamin E and the protein present in the BCS imparted additive effects towards the electrochemical inhibition. In the study (ii) the role of Vitamin E in cytotoxicity inhibition was studied using a mouse neuroblastoma cell line (N2a) for CoCrMo particles and Cr ions separately. The CoCrMo particles were generated from a custom-built hip simulator. The alamarBlue assay results suggested that Vitamin E provides significant protection (85% and 75% proliferation) to N2a cells against CoCrMo particles and Cr ions, respectively at 1 μg/ml concentration, as compared to the control group. However, the results obtained from ROS expression and DNA fiber staining suggest that Vitamin E is only effective against CoCrMo degradation particles and not against Cr ions. In summary, the findings show that Vitamin E can minimize the corrosion processes and play a role in minimizing the potential toxicity associated with implants.

Adverse local tissue reactions (ALTRs) triggered by corrosion products from modular taper junctions are a known cause of premature THA failure. CoCrMo devices are of particular concern because cobalt ions and chromium-orthophosphates were shown to be linked to ALTRs, even in metal-on-polyethylene THAs. The most common categories of CoCrMo alloy are cast and wrought alloy, which exhibit fundamental microstructural differences in terms of grain size and hard phases. The impact of implant alloy microstructure on the occurring modes of corrosion and subsequent metal ion release is not well understood. The purpose of this study was to determine whether (1) the microstructure of cast CoCrMo alloy varies broadly between manufacturers and can dictate specific corrosion modes; and whether (2) the microstructure of wrought CoCrMo alloy is more consistent between manufacturers and has low implications on the alloy’s corrosion behavior. The alloy microstructure of four femoral-stem and three femoral-head designs from four manufacturers was metallographically and electrochemically characterized. Three stem designs were made from cast alloy; all three head designs and one stem design were made from wrought alloy. Alloy samples were sectioned from retrieved components and then polished and etched to visualize grain structure and hard phases such as carbides (eg, M23C6) or intermetallic phases (eg, σ phase). Potentiodynamic polarization (PDP) tests were conducted to determine the corrosion potential (Ecorr), corrosion current density (Icorr), and pitting potential (Epit) for each alloy. Four devices were tested within each group, and each measurement was repeated three times to ensure repeatable results. Differences in PDP metrics between manufacturers and between alloys with different hard phase contents were compared using one-way analysis of variance and independent-sample t-tests. Microstructural features such as twin boundaries and slip bands as well as corrosion damage features were viewed and qualitatively assessed in a scanning electron microscope. We found broad variability in implant alloy microstructure for both cast and wrought alloy between manufacturers, but also within the same implant design. In cast alloys, there was no difference in PDP metrics between manufacturers. However, coarse hard phases and clusters of hard phases (mainly intermetallic phases) were associated with severe phase boundary corrosion and pitting corrosion. Furthermore, cast alloys with hard phases had a lower Epit than those without (0.46 V, SD 0.042; 0.53 V, SD 0.03, respectively; p = 0.015). Wrought alloys exhibited either no hard phases or numerous carbides (M23C6). However, the corrosion behavior was mainly affected by lattice defects and banded structures indicative of segregations that appear to be introduced during bar stock manufacturing. Alloys with banding had a lower Ecorr (p = 0.008) and higher Icorr (p = 0.028) than alloys without banding (−0.76 V, SD 0.003; −0.73 V, SD 0.009; and 1.14 × 10−4 mA/cm2, SD 1.47 × 10−5; 5.2 × 10−5 mA/cm2, SD 2.57 × 10−5, respectively). Alloys with carbides had a slightly higher Ecorr (p = 0.046) than those without (−0.755 V, SD 0.005; −0.761 V, SD 0.004); however, alloys with carbides exhibited more severe corrosion damage as a result of phase boundary corrosion, hard phase detachment, and subsequent local crevice corrosion. The observed variability in CoCrMo alloy microstructure of both cast and wrought components in this study appears to be an important issue to address, perhaps through better standards, to minimize in vivo corrosion. The finding of the banded structures within wrought alloys is especially concerning because it unfavorably influences the corrosion behavior independent of the manufacturer. The findings suggest that a homogeneous alloy microstructure with a minimal hard phase fraction exhibits more favorable corrosion behavior within the in vivo environment of modular taper junctions, thus lowering metal ion release and subsequently the risk of ALTRs to corrosion products. Also, the question arises if hard phases fulfill a useful purpose in metal-on-polyethylene bearings, because they may come with a higher risk of phase boundary corrosion and pitting corrosion and the benefit they provide by adding strength is not needed (unlike in metal-on-metal bearings). Implant failure resulting from corrosion processes within modular junctions is a major concern in THA. Our results suggest that implant alloy microstructure is not sufficiently standardized and may also dictate specific corrosion modes and subsequent metal ion release.

Biotribology is one of the key branches in the field of artificial joint development. Wear and corrosion are among fundamental processes which cause material loss in a joint biotribological system; the characteristics of wear and corrosion debris are central to determining the in vivo bioreactivity. Much effort has been made elucidating the debris-induced tissue responses. However, due to the complexity of the biological environment of the artificial joint, as well as a lack of effective imaging tools, there is still very little understanding of the size, composition, and concentration of the particles needed to trigger adverse local tissue reactions, including periprosthetic osteolysis. Fourier transform infrared spectroscopic imaging (FTIR-I) provides fast biochemical composition analysis in the direct context of underlying physiological conditions with micron-level spatial resolution, and minimal additional sample preparation in conjunction with the standard histopathological analysis workflow. In this study, we have demonstrated that FTIR-I can be utilized to accurately identify fine polyethylene debris accumulation in macrophages that is not achievable using conventional or polarized light microscope with histological staining. Further, a major tribocorrosion product, chromium phosphate, can be characterized within its histological milieu, while simultaneously identifying the involved immune cell such as macrophages and lymphocytes. In addition, we have shown the different spectral features of particle-laden macrophages through image clustering analysis. The presence of particle composition variance inside macrophages could shed light on debris evolution after detachment from the implant surface. The success of applying FTIR-I in the characterization of prosthetic debris within their biological context may very well open a new avenue of research in the orthopedics community.

Contemporary hip implants feature a modular design. Increased reported failure rates associated with the utilization of modular junctions have raised many clinical concerns. Typically, these modular interfaces contain circumferential machining marks (threads or microgrooves), but the effect of the machining marks on the fretting-corrosion behavior of total hip implant materials is unknown. This study reports the effects of microgrooves on the fretting-corrosion behavior of hip implant materials. The flat portions of two cylindrical, polished, CrCrMo alloy pins were loaded horizontally against one rectangular Ti alloy rod. Two surface preparation groups were used for the Ti6Al4V rod (polished and machined). The polished group was prepared using the same methods as the CoCrMo pins. The machined samples were prepared by creating parallel lines on the rod surfaces to represent microgrooves present on the stem tapers of head-neck modular junctions. Newborn calf serum (30 g/L protein content; 37 °C) at pH of levels of 7.6 and 3.0 were used to simulate the normal joint fluid and a lowered pH within a crevice, respectively. The samples were tested in a fretting corrosion apparatus under a 200N normal force and a 1Hz sinusoidal fretting motion with a displacement amplitude of 25 μm. All electrochemical measurements were performed with a potentiostat in a three-electrode configuration. The results show significant differences between machined samples and polished samples in both electrochemical and mechanical responses. In all cases, the magnitude of the drop in potential was greater in the machined group compared to the polished group. The machined group showed a lower total dissipated friction energy for the entire test compared to the polished group. Additionally, the potentiostatic test measurements revealed a higher evolved charge in the machined group compared to the polished group at both pH conditions (pH 7.6 and 3.0). The machined surfaces lowered the overall dissipated friction energy at pH 7.6 compared to pH 3.0, but also compromised electrochemical performance in the tested conditions. Therefore, the role of synergistic interaction of wear and corrosion with surface topographical changes is evident from the outcome of the study. Despite the shift towards higher electrochemical destabilization in the machined group, both polished and machined groups still exhibited a mechanically dominated degradation.

Background Recently, corrosion at the head-neck junction in metal-on-polyethylene bearing surface total hip arthroplasty (THA) has been recognized as a cause of adverse local tissue reactions (ALTRs). Serum metal levels have been advocated as a tool for the diagnosis of ALTR; however, no prior studies have specifically examined their utility. The purpose of this study was to determine the optimal cutoff values for serum cobalt and chromium levels in diagnosing ALTR after metal-on-polyethylene bearing surface THA. Methods We reviewed 447 consecutive patients with serum metal levels tested at our institution and identified 64 patients with a metal-on-polyethylene bearing who had axial imaging or underwent reoperation to confirm the presence or absence of ALTR. Receiver-operating characteristic curves were produced to identify cutoff thresholds to optimize sensitivity, and diagnostic test performance was characterized. Results Forty-four of the 64 patients (69%) were positive for an ALTR. The best test for the diagnosis of ALTR was the serum cobalt level (area under the curve [AUC] = 99%). A threshold cutoff of ≥1.0 ng/mL had a sensitivity of 100%, specificity of 90%, positive predictive value (PPV) of 96%, and negative predictive value (NPV) of 100%. Serum chromium levels were also diagnostic (AUC = 87%). A threshold cutoff of ≥0.15 ng/mL had a sensitivity of 100%, specificity of 50%, PPV of 81%, and NPV of 100%. Finally, serum cobalt-to-chromium ratio was also helpful for diagnosis (AUC = 90%). A threshold cutoff value of 1.4 for the cobalt-to-chromium ratio offered a sensitivity of 93%, specificity of 70%, PPV of 87%, and NPV of 82%. Conclusion Measurement of serum cobalt level with a threshold value of 1.0 ng/mL in our experience is the best test for identifying the presence of ALTR in patients with a metal-on-polyethylene THA. Measurement of chromium level and the ratio of cobalt-to-chromium levels are also of value.

Total hip replacement (THR) failure due to mechanically assisted crevice corrosion within modular head-neck taper junctions remains a major concern. Several processes leading to the generation of detrimental corrosion products have been reported in first generation modular devices. Contemporary junctions differ in their geometries, surface finishes, and head alloy. This study specifically provides an overview for CoCrMo/CoCrMo and CoCrMo/Ti6Al4V head-neck contemporary junctions. A retrieval study of 364 retrieved THRs was conducted which included visual examination and determination of damage scores, as well as the examination of damage features using scanning electron microscopy. Different separately occurring or overlapping damage modes were identified that appeared to be either mechanically or chemically dominated. Mechanically dominated damage features included plastic deformation, fretting, and material transfer, whereas chemically dominate damage included pitting corrosion, etching, intergranular corrosion, phase boundary corrosion, and column damage. Etching associated cellular activity was also observed. Furthermore, fretting corrosion, formation of thick oxide films, and imprinting were observed which appeared to be the result of both mechanical and chemical processes. The occurrence and extent of damage caused by different modes was shown to depend on the material, the material couple, and alloy microstructure. In order to minimize THR failure due to material degradation within modular junctions, it is important to distinguish different damage modes, determine their cause, and identify appropriate counter measures, which may differ depending on the material, specific microstructural alloy features, and design factors such as surface topography. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1672-1685, 2018.

There is controversy regarding the clinical significance of metal hypersensitivity in total knee arthroplasty (TKA). Given the current state of the art, metal hypersensitivity, if it exists at all, is a diagnosis of exclusion. Clinical presentation may involve a cutaneous response, but current diagnostic methods do not have robust clinical validation and should be used with caution. The two most commonly used tests include cutaneous patch testing and in vitro lymphocyte transformation testing. Initially, conservative management is indicated and other more common causes of a symptomatic total knee replacement should be fully explored. In rare cases, device removal may be undertaken but this should be considered a last resort. Pre-operative testing prior to a primary total joint replacement may be helpful when there′s a patient-reported history of intolerance to jewelry or of an allergic reaction to a prior metal implant, but routine lab screening is not supported by the literature.

BACKGROUND Recent studies indicate that females demonstrate an increased risk of experiencing adverse local tissue reactions, aseptic loosening, and revision after primary metal-on-metal hip resurfacing arthroplasty compared with males; the underlying biological mechanisms responsible for sex discrepancies in implant failure remain unclear. In addition to anatomical and biomechanical sex differences, there may be inherent immunological disparities that predispose females to more aggressive adaptive immune reactivity to implant debris, i.e., metal sensitivity. METHODS In this retrospective study, we analyzed sex-associated rates and levels of metal sensitization in 1,038 male and 1,575 female subjects with idiopathic joint pain following total joint arthroplasty (TJA) who were referred for in vitro metal-sensitivity testing. RESULTS Females demonstrated a significantly higher rate and severity of metal sensitization compared with males. The median lymphocyte stimulation index (SI) among males was 2.8 (mean, 5.4; 95% confidence interval [CI], 4.9 to 6.0) compared with 3.5 (mean, 8.2; 95% CI, 7.4 to 9.0) among females (p < 0.05). Forty-nine percent of females had an SI of ≥4 (reactive) compared with 38% of males, and the implant-related level of pain was also significantly (p < 0.0001) higher among females (mean, 6.8; 95% CI, 6.6 to 6.9) compared with males (mean, 6.1; 95% CI, 6.0 to 6.3). CONCLUSIONS In a select group of patients who had joint pain following TJA and no evidence of infection and who were referred for metal-sensitivity testing, females exhibited a higher level of pain and demonstrated a higher rate and severity (as measured by lymphocyte SI) of metal sensitization compared with males. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Failed metal-on-metal (MoM) bearings are being increasingly encountered with little information to guide evaluation for aseptic lymphocytic-dominated vasculitis-associated lesions (ALVAL). It is often assumed that elevated metal ion levels correlate with the occurrence of ALVAL. Our purpose was to determine the utility of the erythrocyte sedimentation rate, C-reactive protein, synovial white blood cell count, differential (%PMN), and serum metal ion levels in diagnosing ALVAL. Methods We identified 80-failed MoM total hip arthroplasties. Tissue was examined under light microscopy and graded on a scale of ALVAL severity. Mean laboratory values were compared between groups and receiver operating curves generated with an area under the curve to determine test performance and optimal cutoffs. Results ALVAL scores were graded as low in 30 (37.5%), moderate in 39 (49%), and severe in 8 (10%), with 3 being unreadable. No clear cutoff values for erythrocyte sedimentation rate, C-reactive protein, or synovial white blood cell count could be determined to reliably diagnose moderate or severe ALVAL. Furthermore, serum metal levels had no correlation with ALVAL score. The best test to diagnose ALVAL was the synovial fluid monocyte percentage with an optimal cutoff value of 39% and area under the curve of 69% (moderate testing performance). Conclusion The diagnosis of ALVAL remains challenging, with most of the screening tests being unreliable. Although serum metal ion levels are typically elevated in failed MoM bearings, higher levels do not appear to correlate with ALVAL grade. Elevated synovial fluid monocytes may provide diagnostic utility for ALVAL, suggesting a possible delayed-type hypersensitivity reaction.

Study design Prospective longitudinal study. Objective The serum titanium (Ti) concentrations were examined in patients implanted with a PRESTIGE LP Cervical Disc System (Medtronic, Inc., Memphis, TN). The metal-on-metal disc with ball-in-trough articulation is made of titanium alloy/titanium carbide composite (Ti-6Al-4 V/TiC). Summary of background data Cervical disc arthroplasty provides a motion-preserving treatment alternative to anterior cervical discectomy and fusion for degenerative cervical disc disease. The articulating surfaces have a tendency to generate in vivo wear in the form of insoluble particulates (debris) and soluble metal ions. Not much information is available on the long-term metal concentrations observed in cervical disc arthroplasty and how these compare with the metal concentrations in Ti-based posterior fixation devices and other joint replacement implants. Methods Thirty patients were enrolled after strict exclusion criteria that included no previous permanent metal implants and no professional exposure to metal particles. High-resolution inductively coupled plasma-mass spectrometry was used to assay blood serum titanium concentrations preoperatively and at 3, 6, 12, 24, 36, 60, and 84 months after surgery. The detection limit for Ti was 0.2 ng/mL. The Friedman test was used to make longitudinal statistical comparisons. Results The median serum Ti concentrations determined preoperatively, and at 3, 6, 12, 24, 36, 60, and 84 months were 0.10, 1.22, 1.15, 1.27, 1.21, 1.46, 1.34, and 1.42 ng/mL, respectively. The serum Ti concentrations at all postoperative time points were significantly higher than that at the preoperative time point (Friedman P Conclusion The long-term postoperative serum Ti concentrations were significantly higher than the preoperative concentrations. The observed serum Ti concentrations in this study are lower than the reported concentrations in patients receiving posterior spinal instrumentation and metal or ceramic-on-polyethylene hip prostheses with Ti-alloy based stems and acetabular components. Level of evidence 3.

Deep brain stimulation (DBS) has shown promise for treating a range of brain disorders and neurological conditions. One recent study showed that DBS in the entorhinal region improved the accuracy of human spatial memory. Based on this line of work, we performed a series of experiments to more fully characterize the effects of DBS in the medial temporal lobe on human memory. Neurosurgical patients with implanted electrodes performed spatial and verbal-episodic memory tasks. During the encoding periods of both tasks, subjects received electrical stimulation at 50 Hz. In contrast to earlier work, electrical stimulation impaired memory performance significantly in both spatial and verbal tasks. Stimulation in both the entorhinal region and hippocampus caused decreased memory performance. These findings indicate that the entorhinal region and hippocampus are causally involved in human memory and suggest that refined methods are needed to use DBS in these regions to improve memory.

Spatial memory is a crucial part of our lives. Spatial memory research and rehabilitation in humans is typically performed either in real environments, which is challenging practically, or in Virtual Reality (VR), which has limited realism. Here we explored the use of Augmented Reality (AR) for studying spatial cognition. AR combines the best features of real and VR paradigms by allowing subjects to learn spatial information in a flexible fashion while walking through a real-world environment. To compare these methods, we had subjects perform the same spatial memory task in VR and AR settings. Although subjects showed good performance in both, subjects reported that the AR task version was significantly easier, more immersive, and more fun than VR. Importantly, memory performance was significantly better in AR compared to VR. Our findings validate that integrating AR can lead to improved techniques for spatial memory research and suggest their potential for rehabilitation.HighlightsWe built matching spatial memory tasks in VR and ARSubjectively, subjects find the AR easier, more immersive and more funObjectively, subjects are significantly more accurate in AR compared to VRPointing based tasks did not fully show the same advantagesOnly AR walking significantly correlated with SBSoD, suggesting mobile AR better captures more natural spatial performance

Prior studies have documented racial and ethnic disparities in total hip arthroplasty (THA) outcomes in the U.S. The purpose of this study was to assess whether racial/ethnic disparities in THA outcomes persist in a universally insured population of patients enrolled in an integrated health-care system.A U.S. health-care system total joint replacement registry was used to identify patients who underwent elective primary THA between 2001 and 2016. Data on patient demographics, surgical procedures, implant characteristics, and outcomes were obtained from the registry. The outcomes analyzed were lifetime revision (all-cause, aseptic, and septic) and 90-day postoperative events (infection, venous thromboembolism, emergency department [ED] visits, readmission, and mortality). Racial/ethnic differences in outcomes were analyzed with use of multiple regression with adjustment for socioeconomic status and other potential confounders.Of 72,755 patients in the study, 79.1% were white, 8.2% were black, 8.5% were Hispanic, and 4.2% were Asian. Compared with white patients, lifetime all-cause revision was lower for black (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.94; p = 0.007), Hispanic (adjusted HR, 0.73; 95% CI, 0.61 to 0.87; p = 0.002), and Asian (adjusted HR, 0.49; 95% CI, 0.37 to 0.66; p0.001) patients. Ninety-day ED visits were more common among black (adjusted odds ratio [OR], 1.15; 95% CI, 1.05 to 1.25; p = 0.002) and Hispanic patients (adjusted OR, 1.18; 95% CI, 1.08 to 1.28; p0.001). For all other postoperative events, minority patients had similar or lower rates compared with white patients.In contrast to prior research, we found that minority patients enrolled in a managed health-care system had rates of lifetime reoperation and 90-day postoperative events that were generally similar to or lower than those of white patients, findings that may be related to the equal access and/or standardized protocols associated with treatment in the managed care system. However, black and Hispanic patients still had higher rates of 90-day ED visits. Further research is required to determine the reasons for this finding and to identify interventions that could reduce unnecessary ED visits.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Spatial memory is a critical function. Without it, we cannot understand our environment, situate ourselves within it, or remember where items are located. Most research on the neural basis of spatial memory is conducted either with invasive brain recordings from animals or with non-invasive imaging in humans. An emerging way to link these areas is by studying rare invasive recordings from the human brain, which can be obtained from epilepsy patients who have electrodes surgically implanted for seizure mapping. In recent years this invasive method has expanded our understanding of how the human brain represents space and has also suggested methods for modulating and potentially rehabilitating memory. However, it is unclear whether these results from epilepsy patients generalize to the non-epileptic population, and from testing in hospital rooms to more immersive and comfortable setups. Here, groups of epilepsy patients (n=69) and healthy participants (n=17) performed the same virtual spatial memory task, enabling us to compare their spatial memory performance. Moreover, we compared spatial memory performance between a standard computer screen versus a head-mounted display. We found that the spatial memory performance of epilepsy patients performing our task in a hospital was similar to that of matched healthy participants performing the task in the lab. Furthermore, actual spatial memory performance was similar on the group level irrespective of the interface used, despite the fact that subjects reported higher immersion with the head mounted display. By showing consistent spatial memory performance with a single paradigm across epilepsy patients and healthy participants, as well as with the use of different display modalities, our results provide a baseline for evaluating findings regarding the neural basis of spatial memory and neuromodulation for rehabilitation. More broadly, these results demonstrate that findings from neurosurgical patients are comparable to the wider population.

Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2).Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2).Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies.Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy.Teva Branded Pharmaceutical Products RD.

Background For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). Objective To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Methods Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). Results A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. Conclusions In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4–10-Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta’s function. To characterize human hippocampal theta, we examined the properties of theta oscillations throughout the anterior–posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observed hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displayed oscillations at ~8-Hz and the precise frequency of these oscillations correlated with the speed of movement, implicating these signals in spatial navigation. We also observed slower ~3-Hz oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency did not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.

Wear particles generated by hip and knee arthroplasties disseminate to the liver and spleen with the highest concentrations observed in subjects who have had a failed arthroplasty. We asked to what extent metallic particles could also disseminate to remote hematopoietic bone marrow. Cored samples of red marrow from the axial skeleton and proximal humerus were obtained postmortem from four males and two females aged 79-92 years. Seven to seventeen years prior to their demise, each subject had undergone successful revision of their arthroplasty for mechanical failure in which an unintended wear condition had generated a large volume of metal particles. The marrow samples were analyzed using stained histological sections and energy dispersive X-ray analysis. Intracellular metal alloy particles were detected in the bone marrow of the cranium, proximal humerus, sternum, ribs, lumbar vertebrae, and the iliac crest. The components previously revised for mechanical failure were confirmed to be the predominant source of the disseminated wear debris. Particles of either Ti, Ti6Al4V, CoCrMo, FeCrNi alloys, or BaSO4 were identified in 24 of the 25 marrow samples examined. The particles ranged in size from 50 nm (the limit of resolution of our technique) to 6 μm. Metallic wear particles generated by hip and knee arthroplasties can disseminate widely to hematopoietic bone marrow throughout the axial skeleton and proximal humerus, especially in cases with a history of severe wear. The hematopoietic microenvironment is potentially sensitive to metallic degradation products. However, actual medical sequelae from disseminated wear debris is a rare occurrence. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1930-1936, 2019.

Current treatments for long-term prophylaxis in hereditary angioedema have limitations.To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P .001); -1.44 (95% CI, -1.84 to -1.04; P .001); and -1.71 (95% CI, -2.09 to -1.33; P .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Ten percent of the population claims an allergy to penicillin, but 90% of these individuals are not allergic. Patients labeled as penicillin-allergic have higher medical costs, longer hospital stays, are more likely to be treated with broad-spectrum antibiotics, and develop drug-resistant bacterial infections. Most penicillin skin test reagents are not approved by the Food and drug Administration or readily available to evaluate patients labeled penicillin-allergic.To determine the negative predictive value (NPV) of the Penicillin Skin Test Kit containing the major allergenic determinant (penicilloyl polylysine), a minor determinant mixture (penicillin G, penicilloate, penilloate), and amoxicillin, produced according to Food and Drug Administration standards.This was a prospective, multicenter, open-label investigation of penicillin skin testing using the Penicillin Skin Test Kit. Skin test-negative subjects were challenged with 250 mg amoxicillin, whereas skin test-positive patients were not challenged. The primary end point was NPV of the Penicillin Skin Test Kit, defined as the percentage of subjects with negative skin test results who did not experience an IgE-dependent reaction within 72 hours of amoxicillin challenge.In total, 455 patients with a history of penicillin allergy underwent skin testing and 63 (13.8%) had 1 or more positive test results; 65% of the positive test results were to the minor determinant mixture and/or amoxicillin alone. In the per protocol group of 373 skin test-negative subjects, 8 developed potential IgE-dependent reactions following oral amoxicillin challenge, translating to an NPV of 97.9% (95% CI, 95.8-99.1; P.0001). All but 1 of the reactions was mild or moderate, and most subjects who required treatment received only antihistamines.The Penicillin Skin Test Kit, containing all relevant penicillin allergenic determinants, demonstrated very high NPV. Removal of a penicillin allergy label in a large majority of currently mislabeled patients has substantial personal and public health implications.

Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system (CNS), with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH)-mutant tumors. The unique metabolomic profile of IDH-mutant tumors may present opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from two patient-derived GBM lines harboring mutations in IDH1. Perfusates were collected from intra-cranial tumors in aythmic nude mice sampled at baseline, 24h and 72h time-points post treatment with temozolomide, an oral alkylating agent used to treat IDH-mutant gliomas, compared with vehicle treatment, and TMZ-treated non-tumor bearing animals. Perfusates were analyzed via unsupervised metabolomic profiling using both gas and liquid chromatography-mass spectrometry (GC/LC-MS). Results of metabolic signatures will be presented. This study aims to demonstrate proof-of-principle and the feasibility of using microdialysis as an approach to identify local tissue biomarkers of tumor response to drug therapy. This work will be complemented by parallel analysis of non-IDH-mutant and TMZ-resistant xenografts, as well as signatures of response to other therapies to yield predictive in vivo tissue biomarkers of drug responsiveness translatable to clinical practice.

Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system, with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH) 1-mutant tumors. The unique metabolomic profile of IDH1-mutant tumors presents opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH1-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from patient-derived xenografts (PDX) harboring mutant IDH-1 (R132H). Perfusates were collected from intra-cranial tumors in athymic nude mice sampled at baseline and 72h post treatment with temozolomide (TMZ), an oral alkylating agent used to treat IDH1-mutant gliomas, compared with vehicle treatment. Perfusates were analyzed via untargeted metabolomic profiling using liquid chromatography-mass spectrometry. Tumor specific metabolites such as (D)-2 hydroxyglutarate, were detected in microdialysate from IDH-1 mutant tumor bearing mice compared to non-tumor bearing mice. We also found high levels of metabolites such as 5-methylthioadenosine, and dimethylarginine and wide range of amino acids in microdialysate from IDH-1 mutant tumor bearing mice. TMZ treatment induced changes to metabolites in creatine and histidine metabolism. Our results indicate that microdialysis is a feasible technology to identify metabolomics-based biomarkers in IDH1-mutant gliomas and their response to therapy. We suggest that in vivo intratumoral microdialysis over several days could yield metabolic pharmacodynamic biomarkers of value to therapeutic translation for IDH-mutant gliomas.

Adverse local tissue reactions (ALTRs) were initially reported as complications associated with metal-on-metal (MoM) bearings; however, there is increasing concern regarding the occurrence of adverse local tissue reactions from mechanically assisted crevice corrosion (MACC) at the femoral head-neck junction or between other modular junctions of the implant containing cobalt chromium parts in patients with metal-on-polyethylene (MoP) bearings. ALTR due to MACC at the head-neck junction has primarily been reported in association with cobalt chromium alloy femoral heads. As pain following total hip arthroplasty may have various intrinsic and extrinsic causes, a systematic approach to evaluation (risk stratification algorithm) based on the currently available data is recommended to optimize patient management. Evaluation should begin by ruling out common causes of pain, including component loosening and periprosthetic joint infection. While specialized tests such as blood metal analysis and metal artifact reduction sequence magnetic resonance imaging (MARS MRI) are useful modalities in evaluating for ALTRs, over-reliance on any single investigative tool in the clinical decision-making process should be avoided. There should be a low threshold to perform a systematic evaluation for ALTR due to MACC in patients with metal-on-polyethylene total hip arthroplasty as early recognition and diagnosis is critical, as delays in appropriate treatment initiation may result in soft-tissue damage, which complicates surgical treatment and is associated with a higher risk of complications and poorer patient outcomes.

Background There are increasing reports of total hip arthroplasty failure subsequent to modular taper junction corrosion. The surfaces of tapers are machined to have circumferential machining marks, resulting in a surface topography of alternating peaks and valleys on the scale of micrometers. It is unclear if the geometry of this machined surface topography influences the degree of fretting and corrosion damage present on modular taper junctions or if there are differences between modular taper junction material couples.

Background Recently, there has been increasing concern in the orthopedic community over the use of hip implant modular devices due to an increasing number of reports of early failure, failure that has been attributed to fretting-corrosion at modular interfaces. Much is still unknown about the electrochemical and mechanical degradation mechanisms associated with the use of such devices. Purpose Accordingly, the purpose of our study was to develop a methodology for testing the fretting-corrosion behavior of modular junctions. Methods A fretting-corrosion apparatus was used to simulate the fretting-corrosion conditions of a CoCrMo hip implant head on a Ti6Al4V hip implant stem. The device features two perpendicularly-loaded CoCrMo pins that articulated against a Ti6Al4V rod. A sinusoidal fretting motion was applied to the rod at various displacement amplitudes (25, 50, 100, 150 and 200 μm) at a constant load of 200 N. Bovine calf serum at two different pH levels (3.0 and 7.6) was used to simulate the fluid environment around the joint. Experiments were conducted in two modes of electrochemical control – free-potential and potentiostatic. Electrochemical impedance spectroscopy tests were done before and after the fretting motion to assess changes in corrosion kinetics. Results In free potential mode, differences were seen in change in potential as a function of displacement amplitude. In general, V Drop (the drop in potential at the onset of fretting), V Fretting, (the average potential during fretting), Δ V Fretting (the change in potential from the onset of fretting to its termination) and V Recovery (the change in potential from the termination of fretting until stabilization) appeared linear at both pH levels, but showed drastic deviation from linearity at 100 μm displacement amplitude. Subsequent EDS analysis revealed a large number of Ti deposits on the CoCrMo pin surfaces. Potentiostatic tests at both pH levels generally showed increasing current with increasing displacement amplitude. Electrochemical impedance spectroscopy measurements from free potential and potentiostatic tests indicated increased levels of resistance of the system after induction of the fretting motion. In free potential tests, the largest increase in impedance was found for the 100 μm group. Conclusions We conclude that the 100 µm group exhibits deviations from linearity for several parameters, and this was most likely due to adhesive wear between Ti6Al4V and CoCrMo surfaces. Overall, the degradation of the system was dominated by wear at all pH levels, and displacement amplitudes.

Innate immune reactions to orthopedic implant debris are the primary cause of total joint replacement (TJR) failure over the long term (15-20 years). The role of pathogen associated pattern recognition receptors (i.e., TLRs) in regulating immune reactivity to metal implant particles remains controversial. Do different TLRs (i.e., TLR2 vs. TLR4) activated by their respective ligands in concert with metal implant debris elicit equivalent innate immune responses? In this investigation, our in vitro and in vivo data indicate that Gram-negative PAMPs are more pro-inflammatory than Gram-positive PAMPs. In vitro results indicated TLR4 activation in concert with CoCrMo orthopedic implant debris (CoCrMo/LPS+) challenged primary macrophages resulted in significantly greater inflammatory responses than CoCrMo/PAM3CSK+ (TLR2). Similarly, in vivo results indicated CoCrMo/LPS+ TLR4 challenge induced a twofold increase in inflammation-induced bone resorption (osteolysis) than CoCrMo/PAM3CSK+ (p

Metal hypersensitivity in patients with a total knee arthroplasty (TKA) is a controversial topic. The diagnosis is difficult, given the lack of robust clinical validation of the utility of cutaneous and in vitro testing. Metal hypersensitivity after TKA is quite rare and should be considered after eliminating other causes of pain and swelling, such as low-grade infection, instability, component loosening or malrotation, referred pain, and chronic regional pain syndrome. Anecdotal observations suggest that two clinical presentations of metal hypersensitivity may occur after TKA: dermatitis or a persistent painful synovitis of the knee. Patients may or may not have a history of intolerance to metal jewelry. Laboratory studies, including erythrocyte sedimentation rate, C-reactive protein level, and knee joint aspiration, are usually negative. Cutaneous and in vitro testing have been reported to be positive, but the sensitivity and specificity of such testing has not been defined. Anecdotal reports suggest that, if metal hypersensitivity is suspected and nonsurgical measures have failed, then revision to components fabricated of titanium alloy or zirconium coating can be successful in relieving symptoms. Revision should be considered as a last resort, however, and patients should be informed that no evidence-based medicine is available to guide the management of these conditions, particularly for decisions regarding revision. Given the limitations of current testing methods, the widespread screening of patients for metal allergies before TKA is not warranted.

We reviewed 27 patients who underwent revision for an adverse local tissue reaction (ALTR) secondary to corrosion at the head-neck junction with MoP bearings. Serum cobalt and chromium levels were elevated in all cases, with a mean cobalt of 11.2 ppb and chromium of 2.2 ppb. Patients underwent modular bearing exchange, including a ceramic head with a titanium sleeve in 23 of 27 cases with only one recurrence of ALTR in one of the four patients not treated with a ceramic head. The diagnosis of ALTR secondary to corrosion is associated with cobalt levels of >1 ppb with cobalt levels elevated above chromium. Retention of a well-fixed stem and modular exchange to a ceramic head leads to resolution of symptoms and decreases in metal levels.

Modern hip prostheses feature a modular implant design with at least one tapered junction. This design can lead to several complications due to the introduction of additional interfaces, which are subjected to various loading conditions and micromotion. The main objective of current study is to develop a fretting corrosion apparatus, which is able characterize the mechanical and electrochemical behaviour of various existing metal alloy couples during fretting motion. This study describes the design and the main considerations during the development of a novel fretting corrosion apparatus, as well as determination of the machine compliance and the initial testing results. Machine compliance considerations and frictional interactions of the couples are discussed in detail. For the preliminary tests, metal alloy pins, made of Ti6Al4V and wrought high-carbon CoCrMo were mechanically polished to a surface roughness of less than 20nm. 2 pins (Diameter = 11mm) of either Ti6Al4V or CoCrMo were loaded onto a Ti6Al4V alloy rod at a normal force of 200N. The interface types included: Ti6Al4V-Ti6Al4V-Ti6Al4V, Ti6Al4V-Ti6Al4V-CoCrMo, and CoCrMo-Ti6Al4V-CoCrMo. The Ti6Al4V rod articulated against the metal alloy pins in a sinusoidal fretting motion with a displacement amplitude of ±50μm. Bovine calf serum (30g/L of protein content) was selected as a lubricant and tested at 2 different pH levels (pH 3.0 and 7.6). In all cases, current and friction energy were monitored during the fretting process. The results indicated distinct, material-specific current evolutions and friction energies. No significant differences were observed in electrochemical or mechanical behaviour in response to pH change. In general, Ti6Al4V-Ti6Al4V-Ti6Al4V couples displayed the earliest passivation and superior electrochemical behaviour compared to Ti6Al4V-Ti6Al4V-CoCrMo and CoCrMo-Ti6Al4V-CoCrMo under fretting conditions. In addition, fluctuations in current were observed in specific regions at all instances where Ti6Al4V was coupled with Ti6Al4V. These fluctuations were not observed in instances where Ti6Al4V was coupled with CoCrMo. These findings suggest transitions in the degradation mechanisms at the modular junction as a function of material couples/contacts. The findings may assist in improving the current hip modular junctions.

SummaryThe hippocampus and surrounding medial-temporal-lobe (MTL) structures are critical for both memory and spatial navigation, but we do not fully understand the neuronal representations used to support these behaviors. Much research has examined how the MTL neurally represents spatial information, such as with “place cells” that represent the current location or “head-direction cells” that code for the current heading. In addition to behaviors that require an animal to attend to the current spatial location, navigating to remote destinations is a common part of daily life. To examine the neural basis of these behaviors we recorded single-neuron activity from neurosurgical patients playing Treasure Hunt, a virtual-reality spatial-memory task. By analyzing how the activity of these neurons related to behavior in Treasure Hunt, we found that the firing rates of many MTL neurons during navigation significantly changed depending on the position of the current spatial target. In addition, we observed neurons whose firing rates during navigation were tuned to specific heading directions in the environment, and others whose activity changed depending on the timing within the trial. By showing that neurons in our task represent remote locations rather than the subject’s own position, our results suggest that the human MTL can represent remote spatial information according to task demands.

Metal ion release from the orthopedic implants is a great concern for the clinicians and patients. Currently, the inductive coupled plasma-mass spectroscopy (ICP-MS) technique is used to detect and estimate the metal ions in the blood or synovial fluid, which is expensive and needs technical assistance. Hence, the aim of the current work is to develop a biosensor based on the electrochemistry to measure the metal release to the body fluids (blood or synovial fluid) from the implants. This will work very similar to a glucometer (by function), as a patient-driven technique, if it is optimized for the blood samples, and for clinical purpose, in case of the synovial fluid estimation. As a proof of concept effort, the present study has two objectives: (1) To study the effectiveness of using a micro-chip biosensor as a diagnostic technique for the early detection of the released metal particles in the synovial fluid solution (study 1), and (2) to investigate the corrosion kinetics of CoCrMo alloy in the presence of metal particles in synovial fluid solution (study 2). A series of tests were done with biosensor prototype with increasing concentration of metal release (particles and ions), which is generated from a hip simulator (study 1). The impedance variation (delta Z) shows a very close correlation with increased amount of metal release (particles and ions) level (study 2). Although the study has several limitations, the initial findings indicate that a biosensor could be developed as a diagnostic tool to detect the metal release (particles and ions) levels.

The entorhinal cortex (EC) is known to play a key role in both memory and spatial navigation. Despite this overlap in spatial and mnemonic circuits, it is unknown how spatially responsive neurons contribute to our ability to represent and distinguish past experiences. Recording from medial temporal lobe (MTL) neurons in subjects performing cued recall of object–location memories in a virtual-reality environment, we identified “trace cells” in the EC that remap their spatial fields to locations subjects were cued to recall on each trial. In addition to shifting its firing field according to the memory cue, this neuronal activity exhibited a firing rate predictive of the cued memory’s content. Critically, this memory-specific neuronal activity re-emerged when subjects were cued for recall without entering the environment, indicating that trace-cell memory representations generalized beyond navigation. These findings suggest a general mechanism for memory retrieval via trace-cell activity and remapping in the EC.

The entorhinal cortex contains a network of grid cells that play a fundamental part in the brain's spatial system, supporting tasks such as path integration and spatial memory. In rodents, grid cells are thought to rely on network theta oscillations, but such signals are not evident in all species, challenging our understanding of the physiological basis of the grid network. We analyzed intracranial recordings from neurosurgical patients during virtual navigation to identify oscillatory characteristics of the human entorhinal grid network. The power of entorhinal theta oscillations showed six-fold modulation according to the virtual heading during navigation, which is a hypothesized signature of grid representations. Furthermore, modulation strength correlated with spatial memory performance. These results demonstrate the connection between theta oscillations and the human entorhinal grid network and show that features of grid-like neuronal representations can be identified from population electrophysiological recordings.

Implant debris generated by wear and corrosion is a prominent cause of joint replacement failure. This study utilized Fourier Transform InfraRed spectroscopic Imaging (FTIR-I) to gain a better understanding of the chemical structure of implant debris and its impact on the surrounding biological environment. Therefore, retrieved joint capsule tissue from five total hip replacement patients was analyzed. All five cases presented different implant designs and histopathological patterns. All tissue samples were formalin-fixed and paraffin-embedded. Unstained, 5μm thick sections were prepared. The unstained sections were placed on BaF(2) windows and deparaffinized with xylene prior to analysis. FTIR-I data were collected at a spectral resolution of 4 cm(−1) using an Agilent Cary 670 spectrometer coupled with Cary 620 FTIR microscope. The results of study demonstrated that FTIR-I is a powerful tool that can be used complimentary to the existing histopathological evaluation of tissue. FTIR-I was able to distinguish areas with different cell types (macrophages, lymphocytes). Small, but distinct differences could be detected depending on the state of cells (viable, necrotic) and depending on what type of debris was present (polyethylene (PE), suture material and metal oxides). Although, metal oxides were mainly below the measurable range of FTIR-I, the infrared spectra of tissues exhibited noticeable difference in their presence. Tens of micrometer sized polyethylene particles could be easily imaged, but also accumulations of submicron particles could be detected within macrophages. FTIR-I was also able to distinguish between PE debris, and other birefringent materials such as suture. Chromium-phosphate particles originating from corrosion processes within modular taper junctions of hip implants could be identified and easily distinguished from other phosphorous materials such as bone. In conclusion, this study successfully demonstrated that FTIR-I is a useful tool that can image and determine the biochemical information of retrieved tissue samples over tens of square millimeters in a completely label free, non-destructive, and objective manner. The resulting chemical images provide a deeper understanding of the chemical nature of implant debris and their impact on chemical changes of the tissue within which they are embedded.

In the 1990s, metal-on-metal (MoM) bearings were reintroduced in total hip arthroplasty (THA), having the proposed advantages of decreased wear and improved stability. However, catastrophic adverse local tissue reaction (ALTR) secondary to metal debris from both the bearing surface and the head–neck junction is a well-recognized complication. The measurement of metal ion levels in the serum is often a first-line test to identify failure of a MoM bearing. The authors describe a 70-year-old man who presented with a multiply revised MoM THA and a large periprosthetic fluid collection incidentally seen during computed tomography for renal nephrolithiasis. The patient reported painless, progressive swelling over the lateral aspect of the hip. An infectious workup including serum erythrocyte sedimentation rate, C-reactive protein, and intraarticular hip aspiration yielded negative results. Metal ion levels in the serum, including a minimally elevated cobalt level, were unremarkable, and metal-lymphocyte transformation testing yielded negative results. Radiographic imaging revealed progressive osteolysis around the proximal femur, and magnetic resonance imaging showed large fluid collections with irregular wall thickening surrounding the gluteal and iliopsoas musculature. At revision surgery, a large fluid collection and corrosion at the head–neck junction were present. Pathology specimens confirmed the presence of an ALTR. This report presents a previously undescribed case of an ALTR secondary to MoM THA in the absence of elevated serum metal ion levels. This indicates the necessity of considering all aspects of a patient's clinical presentation, imaging modalities, and laboratory testing in the evaluation and diagnosis of a symptomatic MoM THA. [ Orthopedics. 2018; 41(3):e438–e441.]