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SummaryEmotional events comprise our strongest and most valuable memories, yet it is unknown how the brain prioritizes emotional information for storage. Here, we examined the neural basis of this prioritization using direct brain recording, deep brain stimulation, and psychometric assessment, with human subjects performing an episodic memory task in which they showed improved performance for emotional stimuli. During the task, high-frequency activity (HFA), a correlate of neuronal spiking activity, increased in both the hippocampus and amygdala when subjects successfully encoded emotionally arousing stimuli. Applying inhibitory electrical stimulation to these regions decreased HFA and specifically reversed the enhancement of memory for emotional stimuli, indicating that neuronal activity in the amygdalohippocampal circuit has a direct role in prioritizing emotional memories. Finally, we found abnormal patterns of amygdalohippocampal HFA in depressed individuals which correlated with a bias for negative memories in these subjects. Going forward, targeted modulation that upregulates neuronal excitation in the amygdalohippocampal circuit may have a causal and translational role in modulating emotional memory.

Jonathan Corren,1 Sarbjit S Saini,2 Remi Gagnon,3 Mark H Moss,4 Gordon Sussman,5 Joshua Jacobs,6 Elizabeth Laws,7 Elinore S Chung,8 Tatiana Constant,8 Yiping Sun,8 Jennifer Maloney,8 Jennifer D Hamilton,8 Marcella Ruddy,8 Claire Q Wang,8 Meagan P O’Brien8 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Internal Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA; 3Clinique Spécialisée en Allergie de la Capitale, Québec, QC, Canada; 4Departments of Medicine and Pediatrics, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Allergy and Asthma Clinical Research, Inc, Walnut Creek, CA, USA; 7Sanofi, Bridgewater, NJ, USA; 8Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USACorrespondence: Meagan P O’BrienRegeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USATel +1 914 826-5271Email meagan.obrien@regeneron.comJonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USATel +1 310 312-5050, ext 250Email jcorren@ucla.eduBackground: Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.Objective: To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.Methods: This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0– 1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.Results: Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0– 1 h) following NAC at Week 17 vs SCIT (least squares mean − 56.76% vs − 52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.Conclusion: In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study Number: NCT03558997.Keywords: dupilumab, seasonal allergic rhinitis, subcutaneous immunotherapy, nasal allergen responses

Karna Gendo, Tony Orden, Allyson Tevrizian, Joshua Jacobs, Nancy Mozelsio, Katherine Gilbert, Matthew Lodewick Allergy and Asthma Medical Group of the Bay Area, Walnut Creek, CA, 94598, USACorrespondence: Karna GendoAllergy and Asthma Medical Group of the Bay Area, Walnut Creek, CA, 94598, USATel +1 925 935-6252Fax +1 925 930-0942Email kbgendo@mac.comAbstract: Food SLIT (sublingual immunotherapy) is a food desensitization method with a daily maintenance dose of < 10 mg for up to 5 years. Many protocols use commercially available skin test extracts. Oral immunotherapy (OIT) treatment solutions have consistent protein concentrations, are comparatively cheaper and customizable and therefore were adapted for use in a published SLIT dosing schedule.Keywords: food allergy, immunotherapy, pharmacoeconomics, food allergy treatments, sublingual immunotherapy, desensitization

Significance Time cells are neurons in the hippocampus and entorhinal cortex that fire at specific moments within a cognitive task or experience. While many prominent theories of memory encoding offer time cells as the source of the temporal component to memory, they have never been observed in human recordings. We identify time cell populations in the medial temporal lobe of humans during memory encoding and retrieval. Further, we demonstrate that the stability of the time signal provided by time cells during encoding influences the ability to temporally order memories at time of retrieval., The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of “time cells” in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of retrieved memory items. We also uncover evidence of ramping cell activity in humans, which represents a complementary type of temporal information. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.

Background Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. Objective The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain. Methods To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. Results Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. Conclusion By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

The COVID-19 pandemic has disrupted every aspect of society in a way never previously experienced by our nation's orthopaedic surgeons. In response to the challenges the American Board of Orthopaedic Surgery has taken steps to adapt our Board Certification and Continuous Certification processes. These changes were made to provide flexibility for as many Candidates and Diplomates as possible to participate while maintaining our high standards. The American Board of Orthopaedic Surgery is first and foremost committed to the safety and well-being of our patients, physicians, and families while striving to remain responsive to the changing circumstances affecting our Candidates and Diplomates.

Adverse local tissue reactions (ALTRs) were first associated with patients with failed metal-on-metal surface replacements and total hip arthroplasty (THA). However, an increasing number of cases of ALTR in metal-on-polyethylene (MOP) THA patients is being reported. Clinically, ALTR appears as benign, aseptic masses or bursae in the periprosthetic tissues. Histopathologically, ALTRs are distinguished by an intense lymphocyte infiltrate, destruction of the synovial surfaces, widespread necrosis, and fibrin exudate. Tribocorrosion of modular junctions appears to be the cause of ALTR in MOP patients. The various tribocorrosion damage modes occurring at modular junctions produce metal ions and a diversity of particulates in relation to size, chemical composition, and structure. The mechanisms by which these various products of tribocorrosion lead to ALTR are still a matter of considerable research. This review clarifies what constitutes ALTR, its relationship to implant factors, and highlights current methods for diagnosis and management of patients with ALTR in the setting of MOP THA.

The purpose of this retrieval study was to determine the effect of implant positioning on wear, taking patient-related factors into account. Therefore, the volumetric material loss of 59 retrieved tibial liners was quantitatively determined using a coordinate measuring-machine. All retrievals were made of the same polyethylene and design by a single manufacturer. Using time in-situ and linear regression, a wear rate for each liner was determined and corrected for bedding-in. Backside damage was qualitatively scored. The following implant positioning parameters were obtained from radiographs: anatomical lateral-distal femoral angle, anatomical medial-proximal tibial angle, femoral tilt angle and posterior tibial slope. The patella position was assessed by the Blackburne-Peel Index and the Insall-Salvati Ratio. Unlike the Insall-Salvati Ratio, the Blackburne-Peel Index is known to detect surgical joint line elevation. Using general linear modeling the most impactful factors on wear rate and backside damage was determined, thereby taking patient demographic factors into account. The mean volumetric wear rate was 11.6 mm(3)/yr. Wear decreased with older age (p=0.021) and female sex (p=0.001). The wear rate increased with joint line elevation as indicated from a decreased Blackburne-Peel Index (p=0.019), and increased with increased posterior tibial slope (p = 0.026). The backside damage score also increased with joint line elevation (p=0.036). A Blackburne-Peel Index decrease of 0.1, signifying joint line elevation, was found to increase the wear rate by 1.8 mm(3)/yr and increase back-sided wear. A high tibial slope (>7°) led to a 9.3 mm(3)/yr increase in wear rate compared with a low tibial slope (

The aim of this study was to determine the effect of two in-vivo-determined gait patterns, one with low and one with high anteroposterior (AP) motion, on total and backside polyethylene insert wear in comparison with the ISO (International Organization for Standardization) standard 14243-3. In order to differentiate and accurately quantify topside and backside wear, a novel technique was employed where different lanthanide tracers were incorporated into the polyethylene during manufacture. Wear particle analysis was conducted following established protocols. For all tested liners and motion protocols, the chemically calculated wear rates correlated closely with gravimetrically determined wear. Both in vivo motion groups displayed higher wear rates than the ISO group following the order of the AP motion amplitudes. Backside wear for ISO constituted 2.76% ± 0.90% (mean ± SE) of the total wear, increasing significantly to 15.8% ± 3.2% for the low AP and further increasing to 19.3% ± 0.95% for the high AP motion protocol. The mean wear particle sizes were under 200 nm for all three motion patterns, being largest for the protocol with high AP motion. Particle release from the low and high AP gait patterns was 1.9 to 2.8 times that from the ISO protocol. Testing for the proportion of backside wear across various activities of daily living should be an important consideration in evaluating knee prostheses wear.

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 examine 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 observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does 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-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes., We show that the human hippocampus exhibits two distinct theta oscillations during spatial navigation with the faster oscillation in posterior regions showing movement modulation. This result suggests a distinct feature of the human hippocampus compared to rodents, which generally show a single 8 Hz rhythm.

Recognizing and adopting standardized terms for adverse local tissue reaction associated with tribocorrosion in total hip arthroplasty are essential for clear scientific discourse and clinical communication. Our goal was to develop terms that can be broadly applied to characterize the local tissue response to tribocorrosion debris, based on current evidence regarding the etiology of this failure mode and its consequences. The proposed standardized terms will improve the understanding and interpretation of analytical tests, advance diagnostic and treatment algorithms, and reduce confusion in research by maintaining consistent nomenclature.

The medial temporal lobe is critical for both spatial navigation and memory. Although single neurons in the medial temporal lobe activate to represent locations in the environment during navigation, how this spatial tuning relates to memory for events involving those locations remains unclear. We examined memory-related changes in spatial tuning by recording single-neuron activity from neurosurgical patients performing a virtual-reality object-location memory task. We identified 'memory-trace cells' with activity that was spatially tuned to the retrieved location of the specific object that participants were cued to remember. Memory-trace cells in the entorhinal cortex, in particular, encoded discriminable representations of different memories through a memory-specific rate code. These findings indicate that single neurons in the human entorhinal cortex change their spatial tuning to target relevant memories for retrieval.

Ti6Al4V is the most common titanium alloy within the biomaterial field. While material standards for different variations of this alloy exist, there are only minimal requirements with respect to its microstructure which is directly related to the alloy's properties. Thus, a better understanding of the Ti6Al4V microstructure of common contemporary implant components and its effect on the electrochemical behavior is needed; including additively manufactured (AM) devices. Therefore, this study aimed at characterizing the microstructures of conventional and AM total joint replacement components, and to identify the effect of microstructure on the electrochemical behavior. Thus, 22 components from conventional (surgically retrieved cast and wrought implants) and AM implants (not previously implanted) were analysed to characterize microstructure by means of electron backscatter diffraction (EBSD) and energy dispersive X-Ray spectroscopy (EDS), and tested to determine its electrochemical behavior (potentiodynamic polarization and EIS). The microstructure of the conventional implants varied broadly but could be categorized into four groups as to their grain size and shape: fine equiaxed, coarse equiaxed, bimodal, and lamellar. The AM components exhibited a fifth category: lath-type. The AM components had a network of β-phase along the α-phase grain boundaries, prior β-grains, and manufacturing voids. Finally, the electrochemical study showed that the equiaxed coarse grains and lath-type grains (AM components) had inferior electrochemical behavior, whereas cast alloys had superior electrochemical behaviour; fine-grained wrought alloys likely provide the best compromise between electrochemical and mechanical properties.

Currently, preclinical mechanical wear testing of total knee replacements (TKRs) is done using ideally aligned components using standardized TKR level walking under either force or displacement-control regimes. To understand the influence of implant alignment and testing control regime, we studied the effect of nine component alignment parameters on TKR volumetric wear in silico. We used a computational framework combining Latin Hypercube sampling design of experiments, finite element analysis, and a numerical model of polyethylene wear, to create a predictive model of how component alignment affects wear rate for each control regime. Nine component alignment parameters were investigated, five femoral variables and four tibial variables. To investigate perturbations of the nine implant alignment variables, two separate 300-point designs were executed, one for each control regime. The results were then used to generate surrogate statistical models using stepwise multiple linear regression. Wear at the neutral position was 4.5mm(3)/million cycle and 8.6mm(3)/million cycle for displacement and force-control, respectively. Stepwise multiple linear regression surrogate models were highly significant for each control regime, but force-control generated a stronger predictive model, with a higher R(2), more included terms, and a lower RMSE. Both models predicted transverse plane rotational mismatch can lead to large changes in predicted wear; a transverse plane alignment mismatch of 15° can elicit a change in wear of up to 5mm(3)/million cycle, almost double that of neutral alignment. Therefore, transverse plane alignment is particularly important when considering failure of the implant due to wear.

Adapting the subcutaneous immunotherapy methods and schedule for use in oral immunotherapy eases the implementation of oral immunotherapy by simplifying the solution creation process and potentially improves safety with dosing transparency.

Background Recent studies indicate that, in addition to antibody production, lymphocyte responses to SARS-CoV-2 may play an important role in protective immunity to COVID-19 and a percentage of the general population may exhibit lymphocyte memory due to unknown/asymptomatic exposure to SARS-CoV-2 or cross-reactivity to other more common coronaviruses pre-vaccination. Total joint replacement (TJR) candidates returning to elective surgeries (median age 68 years) may exhibit similar lymphocyte and/or antibody protection to COVID-19 prior to vaccination Methods In this retrospective study, we analyzed antibody titters, lymphocyte memory, and inflammatory biomarkers specific for the Spike and Nucleocapsid proteins of the SARS-CoV-2 virus in a cohort of n=73 returning TJR candidates (knees and/or hips) pre-operatively. Results Peripheral blood serum of TJR candidate patients exhibited a positivity rate of 18.4% and 4% for IgG antibodies specific for SARS-CoV-2 nucleocapsid and spike proteins, respectively. 13.5% of TJR candidates exhibited positive lymphocyte reactivity (SI > 2) to the SARS-CoV-2 nucleocapsid protein and 38% to the spike protein. SARS-CoV-2 reactive lymphocytes exhibited a higher production of inflammatory biomarkers (i.e., IL-1β, IL-6, TNFα, and IL-1RA) compared to non-reactive lymphocytes. Conclusions A percentage of TJR candidates returning for elective surgeries exhibit pre-vaccination positive SARS-CoV-2 antibodies and T cell memory responses with associated pro-inflammatory biomarkers. This is an important parameter for understanding immunity, risk profiles, and may aid pre-operative planning. Trial registration Retrospectively registered.

Knowing where we are, where we have been, and where we are going is critical to many behaviors, including navigation and memory. One potential neuronal mechanism underlying this ability is phase precession, in which spatially tuned neurons represent sequences of positions by activating at progressively earlier phases of local network theta (~5–10 Hz) oscillations. Phase precession may be a general neural pattern for representing sequential events for learning and memory. However, phase precession has never been observed in humans. By recording human single-neuron activity during spatial navigation, we show that spatially tuned neurons in the human hippocampus and entorhinal cortex exhibit phase precession. Furthermore, beyond the neural representation of locations, we show evidence for phase precession related to specific goal-states. Our findings thus extend theta phase precession to humans and suggest that this phenomenon has a broad functional role for the neural representation of both spatial and non-spatial information.

Summary ParagraphEpisodic memories, or consciously accessible memories of unique events, represent a key aspect of human cognition. Evidence from rodent models suggests that the neural representation of these complex memories requires cooperative firing of groups of neurons on short time scales1, organized by gamma oscillations2, 3. These co-firing groups, termed “neuronal assemblies,”4 represent a fundamental neurophysiological unit supporting memory. Using microelectrode data from neurosurgical patients5, we identify neuronal assemblies in the human MTL and show that they exhibit consistent organization in their firing pattern based on gamma phase information. We connect these properties to memory performance across recording sessions. Finally, we describe how human neuronal assemblies flexibly adjust6-9 over longer time scales. Our findings provide key evidence linking assemblies to human episodic memory for the first time.

The majority of angioedema cases encountered in clinical practice are histamine-mediated (allergic); however, some cases are bradykinin-related (non-allergic) and do not respond to standard anti-allergy medications. Among bradykinin-related angioedema, hereditary angioedema (HAE) is a rare, but chronic and debilitating condition. The majority of HAE is caused by deficiency (type 1) or abnormal function (type 2) of the naturally occurring protein, C1-inhibitor (C1-INH)-a major inhibitor of proteases in the contact (kallikrein-bradykinin cascade), fibrinolytic pathway, and complement systems. Failure to recognize HAE and initiate appropriate intervention can lead to years of pain, disability, impaired quality of life (QoL) and, in cases of laryngeal involvement, it can be life-threatening. HAE must be considered in the differential diagnosis of non-urticarial angioedema, particularly for patients with a history of recurrent angioedema attacks, family history of HAE, symptom onset in childhood/adolescence, prodromal signs/symptoms before swellings, recurrent/painful abdominal symptoms, and upper airway edema. Management strategies for HAE include on-demand treatment for acute attacks, short-term prophylaxis prior to attack-triggering events/procedures, and long-term or routine prophylaxis for attack prevention. Patients should be evaluated at least annually to assess need for routine prophylaxis. HAE specific medications like plasma-derived and recombinant C1-INH products, kallikrein inhibitors, and bradykinin B2 receptor antagonists, have improved management of HAE. While the introduction of intravenous C1-INH represented a major breakthrough in routine HAE prophylaxis, some patients fail to achieve adequate control and others have psychological barriers or experience complications related to intravenous administration. Subcutaneous (SC) C1-INH, SC monoclonal antibody (mAb)-based therapies, and an oral kallikrein inhibitor offer effective alternatives for HAE attack prevention and may facilitate self-administration. HAE management should be individualized, with QoL improvement being a key goal. This can be achieved with broader availability of existing options for routine prophylaxis, including greater global availability of C1-INH(SC), mAb-based therapy, oral treatments, and multiple on-demand therapies.

Background A battlefield-related injury results in increased local and systemic innate immune inflammatory responses, resulting in wound-specific complications and an increased incidence of osteoarthritis. However, little is known about whether severe injuries affect long-term systemic homeostasis, for example, immune function. Moreover, it also remains unknown whether battlefield-acquired metal fragments retained over the long term result in residual systemic effects such as altered immune reactivity to metals. Questions/purposes Does a retained metal fragment from a battlefield injury contribute to increased (1) adaptive metal-specific immune responses, (2) systemically elevated metal ion serum levels, and (3) serum immunoglobulin levels compared with combat injuries that did not result in a retained metal fragment? Methods In this pilot study, we analyzed metal-immunogenicity in injured military personnel and noninjured control participants using lymphocyte transformation testing (LTT, lymphocyte proliferation responses to cobalt, chromium and nickel challenge at 0.001, 0.01 and 0.1-mM concentrations in triplicate for each participant), serum metal ion analysis (ICP-mass spectroscopy), and serum immunoglobulin analysis (IgE, IgG, IgA, and IgM ). Military personnel with a battlefield-sustained injury self-recruited without any exclusion for sex, age, degree of injury. Those with battlefield injury resulting in retained metal fragments (INJ-FRAG, n = 20 male, mean time since injury ± SD was 12 ± 10 years) were compared with those with a battlefield injury but without retained metal fragments (INJ-NO-FRAG, n = 12 male, mean time since injury ± SD was 13 ± 12 years). A control group comprised of male noninjured participants was used to compare measured immunogenicity metrics (n = 11, males were selected to match battlefield injury group demographics). Results Military participants with sustained metal fragments had increased levels of metal-induced lymphocyte responses. The lymphocyte stimulation index among military participants with metal fragments was higher than in those with nonretained metal fragments (stimulation index = 4.2 ± 6.0 versus stimulation index = 2.1 ± 1.2 (mean difference 2.1 ± 1.4 [95% confidence interval 5.1 to 0.8]; p = 0.07) and an average stimulation index = 2 ± 1 in noninjured controls. Four of 20 participants injured with retained fragments had a lymphocyte proliferation index greater than 2 to cobalt compared with 0 in the group without a retained metal fragment or 0 in the control participants. However, with the numbers available, military personnel with retained metal fragments did not have higher serum metal ion levels than military participants without retained metal fragment-related injuries or control participants. Military personnel with retained metal fragments had lower serum immunoglobulin levels (IgG, IgA, and IgM) than military personnel without retained metal fragments and noninjured controls, except for IgE. Individuals who were metal-reactive positive (that is, a stimulation index > 2) with retained metal fragments had higher median IgE serum levels than participants who metal-reactive with nonmetal injuries (1198 ± 383 IU/mL versus 171 ± 67 IU/mL, mean difference 1027 ± 477 IU/mL [95% CI 2029 to 25]; p = 0.02). Conclusions We found that males with retained metal fragments after a battlefield-related injury had altered adaptive immune responses compared with battlefield-injured military personnel without indwelling metal fragments. Military participants with a retained metal fragment had an increased proportion of group members and increased average lymphocyte reactivity to common implant metals such as nickel and cobalt. Further studies are needed to determine a causal association between exposure to amounts of retained metal fragments, type of injury, personnel demographics and general immune function/reactivity that may affect personal health or future metal implant performance. Level of evidence Level IV, therapeutic study.

Recent evidence suggests that mesoscopic neural oscillations measured via intracranial electroencephalography exhibit spatial representations, which were previously only observed at the micro- and macroscopic level of brain organization. Specifically, theta (and gamma) oscillations correlate with movement, speed, distance, specific locations, and goal proximity to boundaries. In entorhinal cortex (EC), they exhibit hexadirectional modulation, which is putatively linked to grid cell activity. Understanding this mesoscopic neural code is crucial because information represented by oscillatory power and phase may complement the information content at other levels of brain organization. Mesoscopic neural oscillations help bridge the gap between single-neuron and macroscopic brain signals of spatial navigation and may provide a mechanistic basis for novel biomarkers and therapeutic targets to treat diseases causing spatial disorientation.

Background Modular femoral trunnions enable the surgeon to independently adjust offset, leg length, and anteversion in total hip arthroplasty (THA). However, modularity may result in an increased risk of fretting and corrosion along with a higher risk of implant dissociation or fracture. The purpose of this study is to evaluate mid-term survivorship of THAs using a cementless modular system. Methods A consecutive series of 221 patients who underwent a primary THA using the ALFA II modular stem by a single surgeon between 2002 and 2004 were reviewed. Survivorship of the ALFA II modular hip system was evaluated at a minimum of 5 years postoperatively. Results Of the 221 patients, 28 (12.7%) died from causes unrelated to the surgery before adequate follow-up, and 64 (29.0%) patients were lost to follow-up. The remaining 129 patients had a mean 6.5-year (range: 5-8 years) follow-up. All-cause survivorship of the modular stem system was 81% (95% confidence interval = 69-90) at a mean 6.5-year follow-up. Of the 25 (19.4%) cases requiring revision surgery, 52.0% was for dissociation of the modular components, 32.0% was for fracture of the prosthesis, 12.0% was for instability/multiple dislocations, and 4.0% was for chronic septic THA. Body mass index (odds ratio = 1.080) and offset (odds ratio = 1.254) were independent risk factors for mechanical failures of the modular stem system. Conclusion The modular stem hip system of interest in this study demonstrates a high failure rate at mid-term follow-up, and we caution against the use of similar designs in primary THAs.

A man in his late 30s developed non-ischaemic cardiomyopathy due to systemic cobalt toxicity associated with accelerated bearing surface wear from metal-on-metal hip resurfacing implanted in the previous 6 years. Following revision arthroplasty, the patient regained baseline cardiac function. Cobalt-induced cardiomyopathy is a grave condition that deserves early consideration due to potentially irreversible morbidity. We present this case to increase awareness, facilitate early detection and emphasise the need for research into the diagnosis and management of at-risk patients.

Spatial navigation and memory rely on neural systems that encode places, distances, and directions in relation to the external world or relative to the navigating organism. Place, grid, and head-direction cells form key units of world-referenced, allocentric cognitive maps, but the neural basis of self-centered, egocentric representations remains poorly understood. Here, we used human single-neuron recordings during virtual spatial navigation tasks to identify neurons providing a neural code for egocentric spatial maps in the human brain. Consistent with previous observations in rodents, these neurons represented egocentric bearings towards reference points positioned throughout the environment. Egocentric bearing cells were abundant in the parahippocampal cortex and supported vectorial representations of egocentric space by also encoding distances towards reference points. Beyond navigation, the observed neurons showed activity increases during spatial and episodic memory recall, suggesting that egocentric bearing cells are not only relevant for navigation but also play a role in human memory.

It is widely recognized that innate macrophage immune reactions to implant debris are central to the inflammatory responses that drive biologic implant failure over the long term. Less common, adaptive lymphocyte immune reactions to implant debris, such as delayed type hypersensitivity (DTH), can also affect implant performance. It is unknown which key patient factors, if any, mediate these adaptive immune responses that potentiate particle/macrophage mediated osteolysis. The objective of this investigation was to determine to what degree known adaptive immune responses to metal implant debris can affect particle-induced osteolysis (PIO); and if this pathomechanism is dependent on: 1) innate immune danger signaling, i.e., NLRP3 inflammasome activity, 2) sex, and/or 3) age. We used an established murine calvaria model of PIO using male and female wild-type C57BL/6 vs. Caspase-1 deficient mice as well as young (12–16 weeks old) vs. aged (18–24 months old) female and male C57BL/6 mice. After induction of metal-DTH, and Cobalt-alloy particle (ASTM F-75, 0.4um median diameter) calvaria challenge, bone resorption was assessed using quantitative micro-computed tomography (micro-CT) analysis and immune responses were assessed by measuring paw inflammation, lymphocyte transformation test (LTT) reactivity and adaptive immune cytokines IFN-gamma and IL-17 (ELISA). Younger aged C57BL/6 female mice exhibited the highest rate and severity of metal sensitivity lymphocyte responses that also translated into higher PIO compared to any other experimental group. The absence of inflammasome/caspase-1 activity significantly suppressed DTH metal-reactivity and osteolysis in both male and female Caspase-1 deficient mice. These murine model results indicate that young female mice are more predisposed to metal-DTH augmented inflammatory responses to wear debris, which is highly influenced by active NLRP3 inflammasome/caspase-1 danger signaling. If these results are clinically meaningful for orthopedic patients, then younger female individuals should be appropriately assessed and followed for DTH derived peri-implant complications.

Augmented reality (AR) technology enhances a user's perception through the superimposition of digital information on physical images while still allowing for interaction with the physical world. The tracking, data processing, and display technology of traditional computer-assisted surgery (CAS) navigation have the potential to be consolidated to an AR headset equipped with high-fidelity cameras, microcomputers, and optical see-through lenses that create digital holographic images. This article evaluates AR applications specific to total knee arthroplasty, total hip arthroplasty, and the opportunities for AR to enhance arthroplasty education and professional development.

BACKGROUND: Fretting and corrosion in metal-on-polyethylene total hip arthoplasty (THA) modular junctions can cause adverse tissue reactions that are responsible for 2% to 5% of revision surgeries. Damage within cobalt-chromium-molybdenum (CoCrMo) alloy femoral heads can progress chemically and mechanically, leading to damage modes such as column damage, imprinting, and uniform fretting damage. At present, it is unclear which of these damage modes are most detrimental and how they may be linked to implant alloy metallurgy. The alloy microstructure exhibits microstructural features such as grain boundaries, hard phases, and segregation bands, which may enable different damage modes, higher material loss, and the potential risk of adverse local tissue reactions. QUESTIONS/PURPOSES: In this study, we asked: (1) How prevalent is chemically dominated column damage compared with mechanically dominated damage modes in severely damaged metal-on-polyethylene THA femoral heads made from wrought CoCrMo alloy? (2) Is material loss greater in femoral heads that underwent column damage? (3) Do material loss and the presence of column damage depend on alloy microstructure as characterized by grain size, hard phase content, and/or banding? METHODS: Surgically retrieved wrought CoCrMo modular femoral heads removed between June 2004 and June 2019 were scored using a modified version of the Goldberg visually based scoring system. Of the total 1002 heads retrieved over this period, 19% (190 of 1002) were identified as severely damaged, exhibiting large areas of fretting scars, black debris, pits, and/or etch marks. Of these, 43% (81 of 190) were excluded for metal-on-metal articulations, alternate designs (such as bipolar, dual-mobility, hemiarthroplasty, metal adaptor sleeves), or previous sectioning of the implant for past studies. One sample was excluded retroactively as metallurgical analysis revealed that it was made of cast alloy, yielding a total of 108 for further analysis. Information on patient age (57 ± 11 years) and sex (56% [61 of 108] were males), reason for removal, implant time in situ (99 ± 78 months), implant manufacturer, head size, and the CoCrMo or titanium-based stem alloy pairing were collected. Damage modes and volumetric material loss within the head tapers were identified using an optical coordinate measuring machine. Samples were categorized by damage mode groups by column damage, imprinting, a combination of column damage and imprinting, or uniform fretting. Metallurgical samples were processed to identify microstructural characteristics of grain size, hard phase content, and banding. Nonparametric Mann-Whitney U and Kruskal-Wallis statistical tests were used to examine volumetric material loss compared with damage mode and microstructural features, and linear regression was performed to correlate patient- and manufacturer-specific factors with volumetric material loss. RESULTS: Chemically driven column damage was seen in 48% (52 of 108) of femoral heads, with 34% (37 of 108) exhibiting a combination of column damage and imprinting, 12% (13 of 108) of heads displaying column damage and uniform fretting, and 2% (2 of 108) exhibiting such widespread column damage that potentially underlying mechanical damage modes could not be verified. Implants with column damage showed greater material loss than those with mechanically driven damage alone, with median (range) values of 1.2 mm(3) (0.2 to 11.7) versus 0.6 mm(3) (0 to 20.7; p = 0.03). Median (range) volume loss across all femoral heads was 0.9 mm(3) (0 to 20.7). Time in situ, contact area, patient age, sex, head size, manufacturer, and stem alloy type were not associated with volumetric material loss. Banding of the alloy microstructure, with a median (range) material loss of 1.1 mm(3) (0 to 20.7), was associated with five times higher material loss compared with those with a homogeneous microstructure, which had a volume loss of 0.2 mm(3) (0 to 4.1; p = 0.02). Hard phase content and grain size showed no correlation with material loss. CONCLUSION: Chemically dominated column damage was a clear indicator of greater volume loss in this study sample of 108 severely damaged heads. Volumetric material loss strongly depended on banding (microstructural segregations) within the alloy. Banding of the wrought CoCrMo microstructure should be avoided during the manufacturing process to reduce volumetric material loss and the release of corrosion products to the periprosthetic tissue. CLINICAL RELEVANCE: Approximately 30% of THAs rely on wrought CoCrMo femoral heads. Most femoral heads in this study exhibited a banded microstructure that was associated with larger material loss and the occurrence of chemically dominated column damage. This study suggests that elimination of banding from the alloy could substantially reduce the release of implant debris in vivo, which could potentially also reduce the risk of adverse local tissue reactions to implant debris.

Aims The aim of this study was to develop a novel computational model for estimating head/stem taper mechanics during different simulated assembly conditions. Methods Finite element models of generic cobalt-chromium (CoCr) heads on a titanium stem taper were developed and driven using dynamic assembly loads collected from clinicians. To verify contact mechanics at the taper interface, comparisons of deformed microgroove characteristics (height and width of microgrooves) were made between model estimates with those measured from five retrieved implants. Additionally, these models were used to assess the role of assembly technique—one-hit versus three-hits—on the taper interlock mechanical behaviour. Results The model compared well to deformed microgrooves from the retrieved implants, predicting changes in microgroove height (mean 1.1 μm (0.2 to 1.3)) and width (mean 7.5 μm (1.0 to 18.5)) within the range of measured changes in height (mean 1.4 μm (0.4 to 2.3); p = 0.109) and width (mean 12.0 μm (1.5 to 25.4); p = 0.470). Consistent with benchtop studies, our model found that increasing assembly load magnitude led to increased taper engagement, contact pressure, and permanent deformation of the stem taper microgrooves. Interestingly, our model found assemblies using three hits at low loads (4 kN) led to decreased taper engagement, contact pressures and microgroove deformations throughout the stem taper compared with tapers assembled with one hit at the same magnitude. Conclusion These findings suggest additional assembly hits at low loads lead to inferior taper interlock strength compared with one firm hit, which may be influenced by loading rate or material strain hardening. These unique models can estimate microgroove deformations representative of real contact mechanics seen on retrievals, which will enable us to better understand how both surgeon assembly techniques and implant design affect taper interlock strength. Cite this article: Bone Joint J 2020;102-B(7 Supple B):33–40.

Background Matched serum and urine samples from patients who had total hip replacement were used to assess serum-validated immunoassay reagents for use in urine. Methods Samples were evaluated by an automated electrochemiluminescent immunoassay (cobas e411; Roche Diagnostics) for C-terminal telopeptide of type I collagen isoform β (β-Crosslaps), osteocalcin N-terminal midfragment (N-MID OC), N-terminal propeptide of type I collagen (PINP), and interleukin 6 (IL-6). Spike and recovery experiments were utilized to assess urinary matrix effects. Correlations between serum and both raw and creatinine-corrected urinary measures were assessed. Short-term precision was assessed. Results Spike and recovery experiments indicated minimal matrix effects of urine for the β-Crosslaps assay. Potential matrix effects were observed for the other analytes because N-MID OC and IL-6 tended to be slightly overrecovered, whereas PINP was underrecovered. There were strong correlations between serum β-Crosslaps and raw (Spearman ρ [rs] = 0.725, P < 0.0001) and creatinine-corrected (rs = 0.793, P < 0.0001) urinary measures and moderate correlations between serum N-MID OC and raw (rs = 0.582, P < 0.0001) and creatinine-corrected (rs = 0.482, P < 0.0001) urinary measures. PINP was not detected in urine, and no significant serum–urine correlations were found for IL-6. Short-term precision for urinary levels of β-Crosslaps, N-MID OC, and IL-6 were 1.6%, 6.3% and 14.4%, respectively. Conclusions Urinary measurements of β-Crosslaps and N-MID OC assays were correlated with serum measurements and had good short-term precision. Urinary PINP was not detectable. IL-6 can be measured in urine using this technology, but the levels did not correlate with serum levels, and the short-term precision was variable.

Aims A retrospective longitudinal study was conducted to compare directly volumetric wear of retrieved polyethylene inserts to predicted volumetric wear modelled from individual gait mechanics of total knee arthroplasty (TKA) patients. Methods In total, 11 retrieved polyethylene tibial inserts were matched with gait analysis testing performed on those patients. Volumetric wear on the articular surfaces was measured using a laser coordinate measure machine and autonomous reconstruction. Knee kinematics and kinetics from individual gait trials drove computational models to calculate medial and lateral tibiofemoral contact paths and forces. Sliding distance along the contact path, normal forces and implantation time were used as inputs to Archard’s equation of wear to predict volumetric wear from gait mechanics. Measured and modelled wear were compared for each component. Results Volumetric wear rates on eight non-delaminated components measured 15.9 mm3/year (standard error (SE) ± 7.7) on the total part, 11.4 mm3/year (SE ± 6.4) on the medial side and 4.4 (SE ± 2.6) mm3/year on the lateral side. Volumetric wear rates modelled from patient gait mechanics predicted 16.4 mm3/year (SE 2.4) on the total part, 11.7 mm3/year (SE 2.1) on the medial side and 4.7 mm3/year (SE 0.4) on the lateral side. Measured and modelled wear volumes correlated significantly on the total part (p = 0.017) and the medial side (p = 0.012) but not on the lateral side (p = 0.154). Conclusion In the absence of delamination, patient-specific knee mechanics during gait directly affect wear of the tibial component in TKA. Cite this article: Bone Joint J 2020;102-B(6 Supple A):129–137.

Background The purpose of this study is to determine if there is a difference in echocardiographic results between patients with metal-on-metal (MoM) vs non-MoM total hip arthroplasty (THA) and to determine if a correlation exists between serum metal levels and echocardiographic outcomes. Methods Seventy-five patients with the same modular THA enrolled in this prospective cohort study, and 49 had MoM bearings. All patients had serum cobalt, chromium, and titanium levels drawn at 2 study visits with a transthoracic echocardiogram at the second visit. Serum metal concentrations and echocardiographic parameters were compared with 2-way t-tests. Multiple linear regression analyses identified any significant predictors of echocardiographic outcomes. Results Mean serum cobalt and chromium levels were significantly greater in the MoM group at both time-points (P .05). MoM patients had significantly lower global longitudinal strain compared with the non-MoM group (18.4% vs 20.2%; P = .026). Serum cobalt concentration was found to be an independent predictor of tricuspid annular plane systolic excursion (P = .02). Conclusion MoM THA bearings are associated with increased serum cobalt and chromium levels. Patients with MoM THAs had decreased global longitudinal strain, a measure of left ventricular function, but both groups remained within normal range. The clinical impact of the positive association between serum cobalt concentration and tricuspid annular plane systolic excursion, a marker of right ventricular function, deserves further study. These findings can reassure physicians and patients that metal-induced cardiomyopathy is not typical in the setting of MoM THA. Level of Evidence Level II, Prospective Cohort Study.

SummarySpatial navigation relies on neural systems that encode information about places, distances, and directions in relation to the external world or relative to the navigating organism. Since the proposal of cognitive maps, the neuroscience of navigation has focused on allocentric (world-referenced) neural representations including place, grid, and head-direction cells. Here, using single-neuron recordings during virtual navigation, we identify “anchor cells” in the human brain as a neural code for egocentric (self-centered) spatial maps: Anchor cells represent egocentric directions towards “anchor points” located in the environmental center or periphery. Anchor cells were abundant in parahippocampal cortex, supported full vectorial representations of egocentric space, and were integrated into a neural memory network. Neurons encoding allocentric direction complemented anchor-cell activity, potentially assisting anchor cells in transforming percepts into allocentric representations. Anchor cells may facilitate egocentric navigation strategies, may support route planning from egocentric viewpoints, and may underlie the first-person perspective in episodic memories.

Modern navigation aids revolutionized human navigation, but are also criticized for potential negative effects on human spatial memory. However, previous tests focused on spatial skills such as environment learning and mental rotations rather then on spatial memory directly. Here, we test directly the effect of a simple navigational aid – an augmented arrow pointing towards the next target – on users’ spatial memory. We find that performance was significantly more efficient with these guiding arrows, but with no significant decrease in spatial memory performance. This suggests negative effects may stem from other features such as attention, and tempers the media’s over-alarmist view.

Background Mechanically assisted crevice corrosion (MACC) at modular junctions can cause a spectrum of adverse local tissue reactions (ALTRs) in patients who have undergone total hip arthroplasty (THA). The purpose of this study is to describe the presentation, treatments, and related complications of a cohort of patients presenting with late instability following metal-on-polyethylene THA due to underlying MACC and ALTR. Methods This multicenter retrospective case series presents 17 patients (12 women, mean age 62.6, range 42-73) presenting with late instability secondary to ALTR and MACC. All patients had a metal (Cobalt Chrome)-on-polyethylene bearing surface. Patients experienced a mean 2.7 dislocations (range 1-6) at mean 4.3 years (range 0.4-17.0) following their index surgery. Serum metal levels (n = 12) demonstrated a greater elevation of cobalt (mean 6.9, range 0.13-20.88 ng/mL) than chromium (mean 1.9, range 0.13-3.23 ng/mL). Results Patients were revised for instability at a mean of 6.8 years (range 2.1-19.4) following their index surgery. ALTR was encountered in every case and the modular head-neck junction demonstrated visible corrosion. An exchange of the CoCr head to a ceramic head with a titanium sleeve and placement of a constrained liner was performed for a majority of patients (n = 15, 88.2%). Five patients (29.4%) had complications postoperatively including peroneal palsy (n = 2), periprosthetic joint infection (n = 2), and ALTR recurrence (n = 1). Conclusion Recurrent instability in the setting of otherwise well-positioned THA components and without another obvious cause should raise concern for ALTR as a potential underlying etiology.

Recurrent hemarthrosis is a burdensome complication following TKA, characterized by repeated episodes of intra-articular bleeding that cause effusions and reduced range of motion, and is readily confirmed on aspiration. Coagulopathies should be ruled out first. Excluding patients with coagulopathy, impingement of hypertrophied synovium is typically the most common cause of bleeding. Pseudoaneurysms represent another important cause. Diagnosis relies on angiography to identify offending vessels or arthroscopic/open visualization. Treatment is straightforward and begins with conservative modalities with concurrent evaluation to detect an underlying coagulopathy. If these measures fail, more aggressive treatments may be required.

Adverse local tissue reactions to corrosion products can lead to total hip arthroplasty failure. Although this problem has been well known for more than 25 years, it has seemingly increased in frequency over the recent years. The occurrence of corrosion is multifactorial—depending on implant, patient, and surgeon factors. As of now, there is no “one-size-fits-all” solution to prevent corrosion in total hip arthroplasty devices. Thus, it is imperative to fully understand the exact mechanisms of modular junction corrosion to prevent premature implant failure. This review highlights a few key concepts that need to be explored to minimize the impact of corrosion. The key concepts include (1) the prevention of micromotion, (2) the role of implant alloy metallurgy in the corrosion process, (3) the in vivo generation of a corrosive environment, and (4) potential unanticipated problems.

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) 1-mutant tumors. The unique metabolomic profile of IDH1-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 IDH1-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 and 72h post treatment with temozolomide, an oral alkylating agent used to treat IDH1-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). Tumor specific metabolites such as carnitine and pyruvic acid were detected in microdialysate from tumor bearing mice compared to non-tumor bearing mice. Microdialysis is a feasible technology to identify metabolomics-based biomarker in IDH1-mutant PDX. This work is complemented by parallel analysis of non-IDH1-mutant and TMZ resistant xenografts to yield predictive in vivo tissue biomarkers of drug responsiveness translatable to clinical practice.

Peri-implant osteolysis is commonly diagnosed after substantial bone loss has occurred, making revision surgery more challenging. The goal of the current study was to identify urinary biomarkers that differentiate total hip replacement patients who eventually develop osteolysis from patients who do not. We used a repository of 24-h urine samples collected prior to surgery and annually thereafter in 26 patients, 16 who developed osteolysis, and 10 who did not. We examined the markers at radiographic diagnosis, annually for 6 years preceding diagnosis, at the first post-operative sampling point, and pre-operatively. Patients in the osteolysis and non-osteolysis groups were matched according to time post-surgery and did not differ in the male:female ratio or age at surgery. Seven candidate biomarkers were measured, including free deoxypyridinoline (DPD), cross-linked N-telopeptides (NTX), interleukin-6 (IL-6), interleukin-8 (IL-8), osteoprotegerin (OPG), α-crosslaps (α-CTX), and β-crosslaps (β-CTX). As an individual biomarker, DPD demonstrated the highest ability to predict osteolysis, with an area under the curve (AUC) in Receiver Operating Characteristic (ROC) analyses of 0.844 at 6 years prior to diagnosis. A panel of α-CTX and IL-6 was able to identify at-risk patients with an AUC of 0.941 or greater at all post-operative time points and an AUC of 1.000 pre-operatively. The results demonstrate the potential of using non-invasive biomarkers to identify patients at risk for peri-implant osteolysis long before the emergence of radiographic signs. Further, the high accuracy of the pre-operative biomarker levels demonstrates the potential importance of pre-existing, patient-specific factors driving subsequent osteolysis. Study Design © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2754-2761, 2018.

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.