Search

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

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 (

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.