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The calcium-sensing receptor (CaSR) plays a key role in calcium homeostasis, and small-molecule and peptide positive allosteric modulators (PAMs) of CaSR, so-called calcimimetics, are used in the treatment of hyperparathyroidism and hypocalcemic disorders. In this study, four monovalent nanobodies - representing four distinct nanobody families with CaSR PAM activity - were subjected to elaborate pharmacological profiling at the receptor. While Nb5 displayed negligible PAM activity at CaSR in all assays, Nb4, Nb10 and Nb45 all potently potentiated Ca 2+ -evoked signalling through a myc epitope-tagged CaSR expressed in HEK293 or HEK293T cells in Gα q and Gα i1 protein activation assays and in a Ca 2+ /Fluo-4 assay. Nb4 and Nb10 also displayed comparable PAM properties at a stable CaSR-HEK293 cell line in a Ca 2+ /Fura-2 imaging assay, but surprisingly Nb45 was completely inactive at this cell line in both the Ca 2+ /Fura-2 and Ca 2+ /Fluo-4 assays. Investigations into this binary difference in Nb45 activity revealed that the nanobody only possesses modulatory activity at CaSRs tagged N-terminally with various epitopes (myc, HA, Flag-SNAP), whereas it is inactive at the untagged wild-type receptor. In conclusion, overall each of the four nanobodies exhibit similar CaSR PAM properties in a range of assays, and thus none of them display pathway bias as modulators. However, of the four nanobodies Nb4 and Nb10 would be applicable as pharmacological tools for the wild-type CaSR, whereas the complete inactivity of Nb45 at the untagged CaSR serves as an reminder that epitope-tagging of a receptor, even if deemed functionally silent, can have profound implications for ligand discovery efforts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In the era of value-based care, pressures lead to cherry-picking healthier patients and lemon-dropping riskier patients to higher levels-of-care. This study examined whether "lemon-dropped" primary total joint arthroplasty (pTJA) patients require increased health care resources and experience worse outcomes., Methods: This was a retrospective cohort study of all pTJAs at one tertiary care center in 2022, excluding bilaterals, acute fractures, oncologic cases, and conversion hips. Patients were classified via referral pattern as simple or complex (referred for medical or surgical complexity). Primary outcomes were implant costs and any emergency department visit, readmission, reoperation, or complication within 90 days. Secondary outcomes were distance traveled to the hospital, anesthesia type, estimated blood loss, case duration, time in the recovery unit, length of stay, and discharge disposition. Outcomes were assessed via electronic medical record review and analyzed via Fisher's exact and unpaired Welch's t-tests., Results: In total 641 pTJAs (322 hips, 319 knees) met inclusion criteria; 10.3% were complex referrals. Complex patients were younger (59 versus 66 years, P < .05) and more often non-White (41 versus 31%, P < .001), non-English speaking (11 versus 7%, P < .001), and had nonprimary osteoarthritis as a surgical indication (59 versus 12%, P < .001), but had similar Charlson Comorbidity Index and American Society of Anesthesiologists scores. Complex patients had increased odds of 90-day emergency department visits (OR [odds ratio] = 2.11, P = .04), 90-day complications (OR = 2.63, P < .001), and non-home discharge (OR = 2.60, P = .006); higher mean relative implant costs (1.31x, P < .001); longer time in the operating room (181 versus 158 minutes P < .001), time in surgery (125 versus 105 minutes, P < .001), and length of stay (3.2 versus 1.7 days, P = .005)., Conclusions: "Lemon-dropped" pTJAs had worse early clinical outcomes and higher health care utilization, despite a control group with patients ill enough to utilize a tertiary care center as their medical home. Reimbursement models and evaluation metrics must account for these differences., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Sex disparities in presentation of osteoarthritis and utilization of joint replacement surgery (JRS) have been demonstrated. The role of patients' unique perspectives on JRS on their treatment decisions is poorly understood., Methods: JRS candidates who were offered JRS but declined surgical treatment completed this survey. Survey questions included demographic information, patient experiences and current opinions around JRS, patient experiences with providers, goals and concerns, and barriers to JRS., Results: More women experience barriers to undergoing JRS compared with men (53% versus 16%; P = 0.014). While both men and women indicated pain relief as their primary goal for treatment, women were significantly more likely to prioritize regaining the ability to complete daily tasks and responsibilities when compared with men (P = 0.007). Both men and women indicated that low symptom severity and nonsurgical treatment options were the reasons for not undergoing JRS (P = 0.455). Compared with men, women trended toward feeling that they were not sufficiently educated about JRS (P = 0.051)., Conclusion: Women have unique perspectives and goals for JRS that may pose sex-specific barriers to care. A better understanding of how patients' gendered experiences affect their decision making is necessary to improve treatment of osteoarthritis and decrease disparities in care., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Introduction: Studies show that females have a higher prevalence of osteoarthritis, worse symptoms, but lower rates of joint replacement surgery (JRS). The reason for this remains unknown., Methods: A database of JRS candidates was created for patients seen in 2019 at an academic center. Demographics, Kellgren-Lawrence grades, symptom duration, visual analogue pain score, Charlson Comorbidity Index, and nonsurgical treatments were collected. Patients who were offered but declined surgery were invited to focus groups. Two independent sample t-tests, Mann-Whitney U tests, and chi-square tests were used for continuous, scored, and categorical variables, respectively, with two-tailed significance <0.05. Qualitative, code-based analysis was performed for the focus groups., Results: The cohort included 321 patients (81 shoulder, 59 hip, and 181 knee) including 199 females (62.0%). There were no differences in proportions of females versus males who underwent JRS or in nonsurgical treatments. Female shoulder arthritis patients were older, had a higher visual analogue pain score, and had a higher Charlson Comorbidity Index. In focus groups, males prioritized waiting for technology advancements to return to an active lifestyle, whereas females experienced negative provider interactions, self-advocated for treatment, concerned about pain, and believed that their sex affected their treatment., Discussion: We found equal utilization of JRS at our institution. However, female patients experienced unique barriers to surgery., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: While racial and ethnic disparities are well documented in access to total joint arthroplasty (TJA), little is known about the association between having limited English proficiency (LEP) and postoperative care access. This study seeks to correlate LEP status with rates of revision surgery after hip and knee arthroplasty., Methods: This was a retrospective cohort study of patients aged ≥ 18 years who underwent either total hip or total knee arthroplasty between January 2013 and December 2021 at a single academic medical center. The predictor variable was English proficiency status, where LEP was defined as having a primary language that was not English. Multivariable regressions controlling for potential demographic and clinical confounders were used to calculate adjusted odds ratios of undergoing revision surgery within 1 and 2 years after primary arthroplasty for patients who have LEP, compared to English proficient patients., Results: A total of 7,985 hip and knee arthroplasty surgeries were included in the analysis. There were 577 (7.2%) patients who were classified as having LEP. Patients who have LEP were less likely to undergo revision surgeries within 1 year (1.4% versus 3.2%, P = .01) and 2 years (1.7% versus 3.9%, P = .006) of primary TJA. Patients who have LEP had adjusted odds ratios of 0.45 (confidence interval: 0.22-0.92, P = .03) and 0.44 (confidence interval: 0.23-0.85, P = .01) of receiving revision surgery within 1 and 2 years, respectively., Conclusion: Patients who have LEP, compared to English proficient patients, were less likely to undergo revision surgeries at the same institution up to 2 years after hip and knee arthroplasty. These findings suggest that patients who have LEP may face barriers in accessing postoperative care., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Disparities exist and affect outcomes after anterior cruciate ligament (ACL) injury. The purpose of this study was to investigate the association between race, ethnicity, and insurance type on the incidence of ACL reconstruction in the United States., Methods: The Healthcare Cost and Utilization Project database was used to determine demographics and insurance types for those undergoing elective ACL reconstruction from 2016 to 2017. The US Census Bureau was used to obtain demographic and insurance data for the general population., Results: Non-White patients undergoing ACL reconstruction with commercial insurance were more likely to be younger, male, less burdened with comorbidities including diabetes, and less likely to smoke. When we compared Medicaid patients who had undergone ACL reconstruction with all Medicaid recipients, there was an under-representation of Black patients and a similar percentage of White patients undergoing ACL reconstruction (P < 0.001)., Discussion: This study suggests ongoing healthcare disparities with lower rates of ACL reconstruction for non-White patients and those with public insurance. Equal proportions of patients identifying as Black undergoing ACL reconstruction as compared with the underlying general population suggests a possible narrowing in disparities. More data are needed at numerous points of care between injury, surgery, and recovery to identify and address disparities., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: Recent advances in high-throughput DNA sequencing technologies have made it possible to characterize the microbial profile in anatomical sites previously assumed to be sterile. We used this approach to explore the microbial composition within joints of osteoarthritic patients., Methods: This prospective multicenter study recruited 113 patients undergoing hip or knee arthroplasty between 2017 and 2019. Demographics and prior intra-articular injections were noted. Matched synovial fluid, tissue, and swab specimens were obtained and shipped to a centralized laboratory for testing. Following DNA extraction, microbial 16S-rRNA sequencing was performed., Results: Comparisons of paired specimens indicated that each was a comparable measure for microbiological sampling of the joint. Swab specimens were modestly different in bacterial composition from synovial fluid and tissue. The 5 most abundant genera were Escherichia, Cutibacterium, Staphylococcus, Acinetobacter, and Pseudomonas. Although sample size varied, the hospital of origin explained a significant portion (18.5%) of the variance in the microbial composition of the joint, and corticosteroid injection within 6 months before arthroplasty was associated with elevated abundance of several lineages., Conclusions: The findings revealed that prior intra-articular injection and the operative hospital environment may influence the microbial composition of the joint. Furthermore, the most common species observed in this study were not among the most common in previous skin microbiome studies, suggesting that the microbial profiles detected are not likely explained solely by skin contamination. Further research is needed to determine the relationship between the hospital and a "closed" microbiome environment. These findings contribute to establishing the baseline microbial signal and identifying contributing variables in the osteoarthritic joint, which will be valuable as a comparator in the contexts of infection and long-term arthroplasty success., Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/H489)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

As both a sensor of extracellular calcium (Ca 2+ o ) concentration and a key controller of Ca 2+ o homeostasis, one of the most interesting properties of the calcium-sensing receptor (CaR) is its sensitivity to, and modulation by, ions and small ligands other than Ca 2+ . There is emerging evidence that extracellular phosphate can act as a partial, non-competitive CaR antagonist to modulate parathyroid hormone (PTH) secretion, thus permitting the CaR to integrate mineral homeostasis more broadly. Interestingly, phosphorylation of certain intracellular CaR residues can also inhibit CaR responsiveness. Thus, negatively charged phosphate can decrease CaR activity both extracellularly ( via association with arginine) and intracellularly ( via covalent phosphorylation)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Centeno, Binmahfouz, Alghamdi and Ward.)

Background: The challenges of culture-negative periprosthetic joint infection (PJI) have led to the emergence of molecular methods of pathogen identification, including next-generation sequencing (NGS). While its increased sensitivity compared with traditional culture techniques is well documented, it is not fully known which organisms could be expected to be detected with use of NGS. The aim of this study was to describe the NGS profile of culture-negative PJI., Methods: Patients undergoing revision hip or knee arthroplasty from June 2016 to August 2020 at 14 institutions were prospectively recruited. Patients meeting International Consensus Meeting (ICM) criteria for PJI were included in this study. Intraoperative samples were obtained and concurrently sent for both routine culture and NGS. Patients for whom NGS was positive and standard culture was negative were included in our analysis., Results: The overall cohort included 301 patients who met the ICM criteria for PJI. Of these patients, 85 (28.2%) were culture-negative. A pathogen could be identified by NGS in 56 (65.9%) of these culture-negative patients. Seventeen species were identified as common based on a study-wide incidence threshold of 5%. NGS revealed a polymicrobial infection in 91.1% of culture-negative PJI cases, with the set of common species contributing to 82.4% of polymicrobial profiles. Escherichia coli, Cutibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus ranked highest in terms of incidence and study-wide mean relative abundance and were most frequently the dominant organism when occurring in polymicrobial infections., Conclusions: NGS provides a more comprehensive picture of the microbial profile of infection that is often missed by traditional culture. Examining the profile of PJI in a multicenter cohort using NGS, this study demonstrated that approximately two-thirds of culture-negative PJIs had identifiable opportunistically pathogenic organisms, and furthermore, the majority of infections were polymicrobial., Level of Evidence: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H102 )., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Patients with limited English proficiency (LEP) face difficulties in access to postoperative follow-up care, including post-discharge medication refills. However, prior studies have not examined how utilization of prescription pain medications after discharge from joint replacement surgeries differs between English proficient (EP) and LEP patients., Objective: This study explored the relationship between English language proficiency and opioid prescription refill requests after hospital discharge for total knee arthroplasty (TKA)., Methods: This was an observational cohort study of patients ≥18 years of age who underwent TKA between January 2015 and December 2019 at a single academic center. LEP status was defined as not having English as the primary language and requesting an interpreter. Primary outcome variables included opioid pain medication refill requests between 0 and 90 days from discharge. Multivariable logistic regression modeling calculated the odds ratios of requesting an opioid refill., Results: A total of 2148 patients underwent TKA, and 9.8% had LEP. Postoperative pain levels and rates of prior opioid use did not differ between LEP and EP patients. LEP patients were less likely to request an opioid prescription refill within 30 days (35.3% vs 52.4%, p < 0.001), 60 days (48.7% vs 61.0%, p = 0.004), and 90 days (54.0% vs 62.9%, p = 0.041) after discharge. In multivariable analysis, LEP patients had an odds ratio of 0.61 of requesting an opioid refill (95% CI, 0.41-0.92, p = 0.019) within 30 days of discharge. Having Medicare insurance and longer lengths of hospitalization were correlated with lower odds of 0-30 days opioid refills, while prior opioid use and being discharged home were associated with higher odds of opioid refill requests 0-30 days after discharge for TKA., Conclusions: Language barriers may contribute to poorer access to postoperative care, including prescription medication refills. Barriers to postoperative care may exist at multiple levels for LEP patients undergoing surgical procedures., Competing Interests: Dr. Ward has received consulting stipends from Depuy (Johnson & Johnson) and there are no other conflicts to report., (© 2022 The Authors.)

Introduction: Morbidity and mortality benefits have been associated with prompt surgical treatment of geriatric hip fractures. The purpose of this study was to evaluate the impact of early (≤24 hr) vs delayed (>24 hr) time to operating room (TTOR) on 1) hospital length of stay and 2) total and post-operative opiate use in geriatric hip fractures., Materials and Methods: This study was a retrospective review of patients ≥65 years-old at the time of admission for surgery for hip fracture at a Level II academic trauma center. Outcome measures were length of stay (LOS), oral morphine equivalents (OME) throughout hospitalization. Patients were stratified into early and delayed TTOR groups and comparisons were made between groups., Results: Between the early (n = 75, 80.6%) and late (n = 18, 19.4%) groups, there were no differences in age, fracture pattern, type of treatment, preoperative opiate use, and perioperative non-oral pain management. The early group trended toward shorter total LOS (108.0 ± 67.2 hours vs 144.8 ± 103.7 hours, P = .066), but not post-operative LOS. Total OME usage was less in the early intervention group (92.5 ± 188.0 vs 230.2 ± 296.7, P = .015), in addition to reduced post-operative OME (81.3 ± 174.9 vs 213.3 ± 271.3, P = .012). There were no differences in evaluated potential delay sources such as primary language, use of surrogate decision makers, or need for advanced imaging., Discussion: Surgical treatment of geriatric hip/femur fractures in ≤24 hours from presentation is achievable and may be associated with reduced total inpatient opiate use, although daily use did not differ., Conclusion: Establishing institutional TTOR goals as part of an interdisciplinary hip fracture co-management clinical pathway can facilitate prompt care and contribute to recovery and less opiate use in these patients with highly morbid injuries., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Derek T. Ward serves as a consultant for DePuy. Sachin Allahabadi, Mohammad Roostan, Erika Roddy, Stephanie Rogers, and Candace Kim declare that they each have no conflict of interest., (© The Author(s) 2022.)

Background: Interdisciplinary standardized protocols for the care of patients with hip fractures have been shown to improve outcomes. A hip fracture protocol was implemented at our institution to standardize care, focusing on emergency care, pre-operative medical management, operative timing, and geriatrics co-management. The aim of this study was to evaluate the efficacy of this protocol., Methods: We conducted a retrospective review of adult patients admitted to a single tertiary care institution who underwent operative management of a hip fracture between July 2012 and March 2020. Comparison of patient characteristics, hospitalization characteristics, and outcomes were performed between patients admitted before and after protocol implementation in 2017., Results: A total of 517 patients treated for hip fracture were identified: 313 before and 204 after protocol implementation. Average age, average Charlson Comorbidity Index, percent female gender, and distribution of hip fracture diagnosis did not vary significantly between groups. There was a significant reduction in time from admission to surgical management, from 37.0 ± 47.7 to 28.5 ± 27.1 h (p = 0.0016), and in the length of hospital stay, from 6.3 ± 6.5 to 5.4 ± 4.0 days (p = 0.0013). The percentage of patients whose surgeries were performed under spinal anesthesia increased from 12.5 to 26.5% (p = 0.016). There was no difference in 90-day readmission rate or mortality at 30 days, 90 days, or 1 year between groups., Conclusion: With the implementation of an interdisciplinary hip fracture protocol, we observed significant and sustained reductions in time to surgery and hospital length of stay, important metrics in hip fracture management, without increased readmission or mortality. This has implications to minimize health care costs and improve outcomes for our aging population., Level of Evidence: III, therapeutic., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Impaired mineral ion metabolism is a hallmark of CKD-metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR., Methods: To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox )., Results: Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D 3 ), and parathyroid hormone levels. Renal tubular α -Klotho protein expression was increased in KO mice but vascular α -Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice., Conclusions: These results suggest that, in addition to CaSR's established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis., (Copyright © 2022 by the American Society of Nephrology.)

Background: Waste is endemic in the U.S. health care system. Operating rooms are a source of significant solid waste. Surgeons are integral to many decisions in the operating room., Method: Online survey of surgeons at 2 major academic centers in the United States assessing perspectives on intraoperative waste and willingness to work to actively reduce intraoperative waste., Results: We received responses from 219 surgeons: 90% agreed or strongly agreed that waste of sterile surgical items is an issue, and 95% agreed or strongly agreed to a willingness to change the operating room workflow to reduce waste. Surgeons estimated 26% of single-use, sterile supplies opened for surgery were unused at the end of the case. The barriers to waste reduction cited most frequently were: (1) lack of awareness of waste, (2) lack of concern for waste, and (3) lack of time to address the waste., Conclusion: Surgeons understand there is significant waste in the operating room and are willing to change their workflow to reduce waste. Changes in operating room practices that reduce waste will be beneficial to health systems' finances and their efforts to improve population health through a reduction in consumption and pollution. Efforts should be directed toward reducing operating room waste with an initial focus on the elimination of unnecessary waste of sterile surgical supplies. Further work is needed to determine the precise sources of perioperative waste and what initiatives can be implemented to reduce this burden while maintaining high-value patient care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The efficacy of virtual reality (VR) as a teaching augment for arthroplasty has not been well examined for unfamiliar multistep procedures such as unicompartmental knee arthroplasty (UKA). This study sought to determine whether VR improves surgical competence over traditional procedural preparation when performing a UKA., Methods: Twenty-two orthopaedic surgery trainees were randomized to two surgical preparation cohorts: (1) "Guide" group (control) with access to manufacture's technique guide and surgical video and (2) "VR" group with access to an immersive commercially available VR learning module. Surgical performance of UKA on a SawBone model was assessed through time and the Objective Structured Assessment of Technical Skills (OSATS) validated rating system., Results: Participants were equally distributed among all training levels and previous exposure to UKA. No difference in mean surgical times was observed between Guide and VR groups (Guide = 42.4 minutes versus VR = 43.0 minutes; P = 0.9) or mean total OSATS (Guide = 15.7 versus VR = 14.2; P = 0.59). Most trainees felt VR would be a useful tool for resident education (77%) and would use VR for case preparation if available (86.4%)., Conclusion: In a randomized controlled trial of trainees at a single, large academic center performing a complex, multistep, unfamiliar procedure (UKA), VR training demonstrated equivalent surgical competence compared with the use of traditional technique guides, as measured by surgical time and OSATS scores. Most of the trainees found the VR technology beneficial. This study suggests that VR technology may be considered as an adjunct to traditional surgical preparation/training methods., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

Background: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro . Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels., Methods: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia., Results: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds., Conclusions: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus., (Copyright © 2022 by the American Society of Nephrology.)

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Surgical-site delivery of local anesthetics decreases pain and opioid consumption after total knee arthroplasty (TKA). The optimal route of administration is unknown. We compared local anesthetic delivery using periarticular soft-tissue infiltration to delivery using a combination of preimplantation immersion and intra-articular injection (combination treatment). The records of patients who underwent unilateral, cemented, primary TKA with spinal anesthesia and adductor canal blocks at a single Veterans Affairs Medical Center were retrospectively reviewed. Three subgroups were compared, including controls who did not receive additional local anesthetics, patients who received periarticular infiltration, and patients who received combination treatment. Mean daily pain scores and mean 24-hour opioid consumption on postoperative days (PODs) 0 and 1 were calculated, and analysis of variance was used to assess for significant differences. Factors that were associated with lower pain scores and opioid consumption were then identified using multivariate stepwise regression. There were 26 controls, 25 periarticular infiltration patients, and 39 combination patients. The periarticular infiltration cohort had significantly lower mean pain scores and opioid consumption than controls on POD 0, but not on POD 1. The combination cohort had significantly lower mean pain scores and opioid consumption than controls on PODs 0 and 1. There were no significant differences between the infiltration and combination groups on either day. Multivariate regression analysis showed that infiltration was associated with significantly decreased opioid consumption on both days and decreased pain on POD 0. Combination treatment was associated with significantly decreased pain and opioid consumption on both days. Both local anesthetic periarticular infiltration and combination treatment are associated with decreased pain and opioid consumption after TKA. The stronger effects of the combination treatment compared with periarticular infiltration on POD 1 suggests that combination delivery may have a longer duration of action., Competing Interests: None declared., (Thieme. All rights reserved.)

Skeletal muscle has an outstanding capacity for regeneration in response to injuries, but there are disorders in which this process is seriously impaired, such as sarcopenia. Pharmacological treatments to restore muscle trophism are not available, therefore, the identification of suitable therapeutic targets that could be useful for the treatment of skeletal reduced myogenesis is highly desirable. In this in vitro study, we explored the expression and function of the calcium-sensing receptor (CaSR) in human skeletal muscle tissues and their derived satellite cells. The results obtained from analyses with various techniques of gene and protein CaSR expression and of its secondary messengers in response to calcium (Ca 2+ ) and CaSR drugs have demonstrated that this receptor is not present in human skeletal muscle tissues, neither in the established satellite cells, nor during in vitro myogenic differentiation. Taken together, our data suggest that, although CaSR is a very important drug target in physiology and pathology, this receptor probably does not have any physiological role in skeletal muscle in normal conditions.

25-hydroxyvitamin D 1α-hydroxylase (encoded by CYP27B1 ), which catalyzes the synthesis of 1,25-dihydroxyvitamin D 3 , is subject to negative or positive modulation by extracellular Ca 2+ (Ca 2+ o ) depending on the tissue. However, the Ca 2+ sensors and underlying mechanisms are unidentified. We tested whether calcium-sensing receptors (CaSRs) mediate Ca 2+ o -dependent control of 1α-hydroxylase using HEK-293 cells stably expressing the CaSR (HEK-CaSR cells). In HEK-CaSR cells, but not control HEK-293 cells, cotransfected with reporter genes for CYP27B1- Photinus pyralis (firefly) luciferase and control Renilla luciferase, an increase in Ca 2+ o from 0.5mM to 3.0mM induced a 2- to 3-fold increase in firefly luciferase activity as well as mRNA and protein levels. Surprisingly, firefly luciferase was specifically suppressed at Ca 2+ o ≥ 5.0mM, demonstrating biphasic Ca 2+ o control. Both phases were mediated by CaSRs as revealed by positive and negative modulators. However, Ca 2+ o induced simple monotonic increases in firefly luciferase and endogenous CYP27B1 mRNA levels, indicating that the inhibitory effect of high Ca 2+ o was posttranscriptional. Studies with inhibitors and the CaSR C-terminal mutant T888A identified roles for protein kinase C (PKC), phosphorylation of T888, and extracellular regulated protein kinase (ERK) 1/2 in high Ca 2+ o -dependent suppression of firefly luciferase. Blockade of both PKC and ERK 1/2 abolished Ca 2+ o -stimulated firefly luciferase, demonstrating that either PKC or ERK 1/2 is sufficient to stimulate the CYP27B1 promoter. A key CCAAT box (-74 bp to -68 bp), which is regulated downstream of PKC and ERK 1/2 , was required for both basal transcription and Ca 2+ o -mediated transcriptional upregulation. The CaSR mediates Ca 2+ o -dependent transcriptional upregulation of 1α-hydroxylase and an additional CaSR-mediated mechanism is identified by which Ca 2+ o can promote luciferase and possibly 1α-hydroxylase breakdown., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: It is controversial whether the use of antibiotic-laden bone cement (ALBC) in primary total knee arthroplasty (TKA) affects periprosthetic joint infection (PJI) or revision rates. The impact of ALBC on outcomes of primary TKA have not been previously investigated in U.S. veterans, to our knowledge. The purposes of this study were to quantify utilization of ALBC among U.S. veterans undergoing primary TKA and to determine if ALBC usage is associated with differences in revision TKA rates., Methods: Patients who had TKA with cement from 2007 to 2015 at U.S. Veterans Health Administration (VHA) hospitals with at least 2 years of follow-up were retrospectively identified. Patients who received high-viscosity Palacos bone cement with or without gentamicin were selected as the final study cohort. Patient demographic and comorbidity data were collected. Revision TKA was the primary outcome. All-cause revisions and revisions for PJI were identified from both VHA and non-VHA hospitals. Unadjusted and adjusted regression analyses were performed to identify variables that were associated with increased revision rates., Results: The study included 15,972 patients who had primary TKA with Palacos bone cement at VHA hospitals from 2007 to 2015. Plain bone cement was used for 4,741 patients and ALBC was used for 11,231 patients. Utilization of ALBC increased from 50.6% in 2007 to 69.4% in 2015. At a mean follow-up of 5 years, TKAs with ALBC had a lower all-cause revision rate than those with plain bone cement (5.3% versus 6.7%; p = 0.0009) and a lower rate of revision for PJI (1.9% versus 2.6%; p = 0.005). On multivariable regression, ALBC use was associated with a lower risk of all-cause revision compared with plain bone cement (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68 to 0.92; p = 0.0019). Seventy-one primary TKAs needed to be implanted with ALBC to avoid 1 revision TKA., Conclusions: The utilization of ALBC for primary TKAs performed at VHA hospitals has increased over time and was associated with a lower all-cause revision rate and a lower rate of revision for PJI., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, γ -glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o ) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. SIGNIFICANCE STATEMENT: The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Although obesity is a risk factor for periprosthetic joint infection (PJI) after total knee arthroplasty (TKA), the role of soft tissue thickness (STT) at the surgical site has not been well studied. This study examined if increased STT in the medial and anterior aspects of the knee are independent risk factors for PJI., Methods: A retrospective study was conducted on 206 patients who underwent 2-stage exchange arthroplasty for PJI from 2000 to 2015. They were matched 1:3 to a control group of primary, noninfected TKA patients with minimum 2 years infection-free survival by age, gender, age-adjusted Charlson Comorbidity Index, date of surgery, and body mass index (BMI). Two blinded orthopedic surgeons measured the medial STT from the medial aspect of the knee at the level of the joint line on an anteroposterior radiograph, and anterior STT 8 cm above the joint line on a lateral radiograph from the skin to the quadriceps tendon., Results: Increased STT was significantly associated with a higher risk for PJI. The mean anterior STT was 29.74 ± 13.76 mm in the PJI group and 24.88 ± 9.76 mm in the control group. The mean medial STT was 42.42 ± 14.66 mm for PJI and 37.27 ± 12.51 mm for control. Both STT measurements were significantly higher in PJI cases with BMI <30 kg/m 2 vs control patients with BMI <30 kg/m 2 ., Conclusion: Anterior and medial knee STT was an independent risk factor for PJI after primary TKA and represents a simple radiographic method to assess postoperative infection risk. Excess adipose tissue around the surgical site can predispose patients to PJI after TKA regardless of BMI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: As the demand for knee arthroplasty increases, risk assessment and counseling are critical for optimal patient outcomes perioperatively. The purpose of this study was to determine if specific complications occurring after unilateral knee replacement predict the risk of recurrence after a staged replacement of the contralateral knee for patients with bilateral symptomatic disease., Methods: Linked, nationwide data from the U.S. Hospital Cost and Utilization Project from 2005 to 2014 were used to measure the occurrence of complications after the first and second procedures in staged bilateral total knee arthroplasties (TKAs). Odds ratios (ORs) and conditional probabilities were determined to assess whether having a specific complication after the first TKA increased the chance that the same complication occurred after the second procedure., Results: A total of 36,278 patients who underwent staged bilateral TKAs were analyzed. All complications occurring after the first arthroplasty were associated with both a significantly increased probability and odds of recurrence following the second arthroplasty. These included myocardial infarction (OR, 56.63 [95% confidence interval (CI), 18.04 to 155.44]; p < 0.001), ischemic stroke (OR, 41.38 [95% CI, 1.98 to 275.82]; p = 0.03), other cardiac complications (OR, 7.73 [95% CI, 4.24 to 14.11]; p < 0.001), respiratory complications (OR, 8.58 [95% CI, 2.85 to 23.17]; p = 0.002), urinary complications (OR, 11.19 [95% CI, 5.44 to 22.25]; p = 0.001), hematoma (OR, 15.05 [95% CI, 7.90 to 27.27]; p < 0.001), deep vein thrombosis (OR, 7.40 [95% CI, 5.37 to 10.08]; p < 0.001), and pulmonary embolism (OR, 11.00 [95% CI, 5.01 to 23.92]; p < 0.001)., Conclusions: Medical complications that occur postoperatively after TKA are associated with a significantly increased risk of recurrence of these complications after staged replacement of the contralateral knee. Although overall complication rates remain low, patients who develop these medical complications after the first replacement should be counseled on their increased risk profile prior to the contralateral surgical procedure., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a key role in calcium homeostasis, by sensing free calcium levels in blood and regulating parathyroid hormone secretion in response. The CaSR is highly expressed in parathyroid gland and kidney where its role is well characterised, but also in other tissues where its function remains to be determined. The CaSR can be activated by a variety of endogenous ligands, as well as by synthetic modulators such as Cinacalcet, used in the clinic to treat secondary hyperparathyroidism in patients with chronic kidney disease. The CaSR couples to multiple G proteins, in a tissue-specific manner, activating several signalling pathways and thus regulating diverse intracellular events. The multifaceted nature of this receptor makes it a valuable therapeutic target for calciotropic and non-calciotropic diseases. It is therefore essential to understand the complexity behind the pharmacology, trafficking, and signalling characteristics of this receptor. This review provides an overview of the latest knowledge about the CaSR and discusses future hot topics in this field.

Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD). The calcium-sensing receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism. Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR. Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a receptor-mediated action. The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion.

Background: Currently, the decision to resurface the patella is often made irrespective of the presence of patellar arthritis. The purpose of this study is to utilize the existing literature to assess cost-utility of routinely vs selectively resurfacing the patella., Methods: Prospective randomized studies of patella resurfacing vs non-resurfacing in total knee arthroplasty (TKA) were identified through literature review. Data from these studies represented probabilities of varied outcomes following TKA dependent upon patella resurfacing. Using previously validated utility scores from the McKnee modified Health Utilities Index, endpoint utility values were provided for each potential outcome., Results: Literature review yielded a total of 14 studies with 3,562 patients receiving 3,823 TKAs, of which 1,873 (49.0%) patellae were resurfaced. Persistent postoperative anterior knee pain occurred in 20.9% vs 13.2% (P < .001) and patella reoperation was performed in 3.7% vs 1.6% (P < .001) of unresurfaced and resurfaced patella, respectively. In studies excluding those with arthritic patellae, the incidence of anterior knee pain was equivalent between groups and reoperation decreased to 1.2% vs 0% (P = .06). Patella resurfacing provided marginally improved quality-adjusted life-years (QALY) for both selective and indiscriminate patella resurfacing. When including all studies, the incremental cost per QALY was $3,032. However, when analyzing only those studies with nonarthritic patellae, the incremental cost per QALY to resurface the patella increased to $183,584., Conclusion: Patellar resurfacing remains a controversial issue in TKA. Utilizing data from new prospective randomized studies, this analysis finds that routinely resurfacing arthritis-free patellae in TKA are not cost-effective., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain-of-function mutations of the calcium-sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca 2+ i ), and ERK and p38 MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation. NPSP795 was generally safe and well-tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half-maximally activated (EC 50 ) at lower concentrations of extracellular calcium (Ca 2+ o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC 50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

The calcium-sensing receptor (CaS) is the principal controller of extracellular calcium (Ca 2+ o ) homeostasis and is inhibited in vitro and in vivo by protein kinase C (PKC)-mediated phosphorylation at CaS T888 However, PKC inhibition enhances signaling even in CaSs lacking Thr-888, suggesting that an additional inhibitory site exists. An apparently equivalent PKC regulatory site in metabotropic glutamate receptor 5 (Ser-839) aligns not with CaS T888 but instead with CaS S875 , which was not previously considered to be a PKC site. CaS S875A (nonphosphorylatable) exhibited significantly enhanced Ca 2+ o sensitivity of both intracellular Ca 2+ mobilization and extracellular signal-regulated kinase 1/2 activation, whereas the phosphomimetic CaS S875D mutant exhibited a loss of function. The CaS S875A/T888A double mutant exhibited even greater Ca 2+ o sensitivity than CaS T888A alone, a response no longer enhanced by PKC inhibition. Finally, when expressed in CaS lacking its extracellular domain, the CaS S875A/T888A double mutation elicited maximal activation even under control conditions, but remained sensitive to negative allosteric modulation [ N -(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine] or Ca 2+ o removal. Therefore, we have now identified CaS S875 as the missing PKC phosphorylation site that, together with CaS T888 , shapes the CaS signaling that underpins Ca 2+ o homeostasis. Together with the inactive form of the CaS extracellular domain, these sites attenuate Ca 2+ o sensitivity to attain appropriate physiologic Ca 2+ o sensing. SIGNIFICANCE STATEMENT: Serine-875 represents the missing inhibitory PKC phosphorlyation site in CaS that in tandem with Thr-888 controls receptor activity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Aims: Increasingly, patients with bilateral hip arthritis wish to undergo staged total hip arthroplasty (THA). With the rise in demand for arthroplasty, perioperative risk assessment and counselling is crucial for shared decision making. However, it is unknown if complications that occur after a unilateral hip arthroplasty predict complications following surgery of the contralateral hip., Patients and Methods: We used nationwide linked discharge data from the Healthcare Cost and Utilization Project between 2005 and 2014 to analyze the incidence and recurrence of complications following the first- and second-stage operations in staged bilateral total hip arthroplasty (BTHAs). Complications included perioperative medical adverse events within 30 to 60 days, and infection and mechanical complications within one year. Conditional probabilities and odds ratios (ORs) were calculated to determine whether experiencing a complication after the first stage of surgery increased the risk of developing the same complication after the second stage., Results: A total of 13 829 patients (5790 men and 8039 women) who underwent staged BTHAs were analyzed. The mean age at first operation was 62.9 years (14 to 95). For eight of the 12 outcomes evaluated, patients who experienced the outcome following the first arthroplasty had a significantly increased probability and odds of developing that same complication following the second arthroplasty, compared with those who did not experience the complication after the first surgery. This was true for digestive complications (OR 25.67, 95% confidence interval (CI) 13.86 to 46.08; p < 0.001), urinary complications (OR 6.48, 95% CI 1.7 to 20.73; p = 0.01), haematoma (OR 12.17, 95% CI 4.55 to 31.14; p < 0.001), deep vein thrombosis (OR 4.82, 95% CI 2.34 to 9.65; p < 0.001), pulmonary embolism (OR 12.03, 95% CI 2.02 to 46.77; p = 0.01), deep hip infection (OR 534.21, 95% CI 314.96 to 909.25; p < 0.001), superficial hip infection (OR 1574.99, 95% CI 269.83 to 9291.81; p < 0.001), and mechanical malfunction (OR 117.49, 95% CI 91.55 to 150.34; p < 0.001)., Conclusion: The occurrence of certain complications after unilateral THA is associated with an increased risk of the same complication occurring after staged arthroplasty of the contralateral hip. Patients who experience these complications after unilateral hip arthroplasty should be appropriately counselled regarding their risk profile prior to undergoing staged contralateral hip arthroplasty. Cite this article: Bone Joint J 2019;101-B(6 Supple B):77-83.

Background: The purpose of this study is to determine whether episode Target Prices in the Bundled Payment for Care Improvement (BPCI) initiative sufficiently match the complexities and expenses expected for patients undergoing hip arthroplasty for femoral neck fracture (FNF) as compared to hip degenerative joint disease (DJD)., Methods: Claims data under BPCI Model 2 were collected for patients undergoing hip arthroplasty at a single institution over a 2-year period. Payments from the index hospitalization to 90 days postoperatively were aggregated by Medicare Severity Diagnosis-Related Group (469 or 470), indication (DJD vs FNF), and categorized as index procedure, postacute services, and related hospital readmissions. Actual episode costs and Target Prices were compared in both the FNF and DJD cohorts undergoing hip arthroplasty to gauge the cost discrepancy in each group., Results: A total of 183 patients were analyzed (31 with FNFs, 152 with DJD). In total, the FNF cohort incurred a $415,950 loss under the current episode Target Prices, whereas the DJD cohort incurred a $172,448 gain. Episode Target Prices were significantly higher than actual episode prices for the DJD cohort ($32,573 vs $24,776, P < .001). However, Target Prices were significantly lower than actual episode prices for the FNF cohort ($32,672 vs $49,755, P = .021)., Conclusion: Episode Target Prices in the current BPCI model fall dramatically short of the actual expenses incurred by FNF patients undergoing hip arthroplasty. Better risk-adjusting Target Prices for this fragile population should be considered to avoid disincentives and delays in care., (Copyright © 2018 Elsevier Inc. All rights reserved.)