Khanh Ly - Academia.edu (original) (raw)

Papers by Khanh Ly

Drug and Alcohol Dependence, 2020

Background: Many people who need specialty treatment for substance use disorders (SUDs) do not re... more Background: Many people who need specialty treatment for substance use disorders (SUDs) do not receive it. Clinical interventions could increase treatment utilization but are not routinely used. This systematic review aimed to describe clinical interventions that may increase SUD specialty treatment utilization (i.e., treatment initiation, attendance, meaningful engagement) and to determine which intervention(s) most consistently increase treatment utilization. Methods: We conducted a systematic review of clinical intervention studies (published in English between 2000 and 2017) reporting outcomes relevant to specialty SUD treatment utilization. Outcomes were treatment initiation, attendance, and meaningful engagement. Risk of bias was assessed using Cochrane guidelines and randomized controlled trials (RCTs) with bias scores < 3 were included in a synthesis of results. Proportions of positive to negative utilization outcomes were calculated for each low-bias RCT; studies with 50% positive outcomes or more were considered "majority-positive". Studies were categorized by theory-based approach. Results: Twenty-three RCTs had low risk of bias and were synthesized. Among intervention types with two or more studies, cognitive-behavioral (100% majority-positive) and coordinated care (67% majority-positive) interventions were most likely to increase treatment initiation, while 12-step promotion interventions were most likely to increase treatment attendance (50% majority-positive). One study (12-step promotion) measured meaningful engagement, with majority-positive outcomes. Conclusions: A systematic review and narrative synthesis of clinical interventions promoting specialty SUD treatment utilization provided preliminary evidence that cognitive-behavioral and coordinated care interventions may increase treatment initiation, while 12-step promotion interventions may promote treatment attendance. More quality studies and greater consistency in treatment utilization measurement are needed.

Substance Abuse, 2019

Background: Adherence to clinical practice guidelines for alcohol and drug screening, brief inter... more Background: Adherence to clinical practice guidelines for alcohol and drug screening, brief intervention, and referral to treatment (SBIRT) is often inadequate. Mobile apps developed as clinical translation tools could improve the delivery of high fidelity SBIRT. Methods: This study tested the effectiveness of an SBIRT mobile app conceptually aligned with the Theory of Planned Behavior (TPB) to support SBIRT delivery by health care trainees (nursing, social work, internal medicine, psychiatry, and psychology) working in clinical settings (N = 101). Bivariate analyses examined the rate of SBIRT delivery between trainees assigned to the experimental (app) and control (no app) study conditions; as well as the relationship between TPB-based constructs, intention to deliver SBIRT, and screening rates. Results: No significant differences were identified between the study conditions in SBIRT delivery. Significant correlations were found between intent to screen and TPB variables including attitudes/behavioral beliefs concerning substance use treatment (r = .49, p = .01); confidence in clinical skills (r = .36, p = .01); subjective norms (r = .54, p = .01) and perceived behavioral control over appointment time constraints (r = .42, p = .01). Also significant were correlations between percent of patients screened and confidence (r = .24, p = .05); subjective norms (r = .22, p = .05) and perceived behavioral control (r = .28, p = .01). Conclusions: The negative results of the study condition comparisons indicate the need for further investigation of strategies to optimize mobile app utilization, engagement, and effectiveness as a clinical translation tool. Findings of significant correlations between substance use screening rates and both norms and confidence support the potential value of the TPB model in explaining behavior of health care learners in SBIRT delivery.

Journal of the American Association of Nurse Practitioners, 2019

Background and purpose: Screening, brief Intervention, and referral to treatment (SBIRT) is a wid... more Background and purpose: Screening, brief Intervention, and referral to treatment (SBIRT) is a widely trained evidence-based strategy to identify and address alcohol and drug use problems. The purpose of this qualitative study was to explore the experience of family nurse practitioner (FNP) learners in the implementation of SBIRT and the perceived clinical utility of an SBIRT mobile app. Methods: Twenty-two FNP learners completed didactic SBIRT training and orientation to an SBIRT mobile app. At the conclusion of the study, participant focus groups explored overall SBIRT delivery (N = 19) and SBIRT mobile app utilization (N = 14). Focus group data were analyzed within a Theory of Planned Behavior framework. Results: Participants indicated that the mobile app was useful in the ongoing development of SBIRT knowledge, skill confidence, and motivation. Learners identified the clinical context as a major factor in facilitating the delivery of SBIRT overall. Participants who did not deliver SBIRT indicated that the most significant barriers to SBIRT implementation were lack of support from clinical preceptors and health systems. Conclusions: Findings suggest that a mobile app is an acceptable and feasible tool to improve the delivery of SBIRT. However, collaboration with preceptors and clinical training organizations is essential to optimize clinical translation.

JMIR research protocols, Jan 18, 2017

Translation of knowledge and skills from classroom settings to clinical practice is a major chall... more Translation of knowledge and skills from classroom settings to clinical practice is a major challenge in healthcare training, especially for behavioral interventions. For example, screening, brief intervention, and referral to treatment (SBIRT) is a highly-promoted approach to identifying and treating individuals at risk for alcohol or drug problems, yet effective, routine use of SBIRT has lagged. The objective of this paper is to describe the development, pilot testing, and trial protocol of a mobile app based on the theory of planned behavior (TPB) to promote SBIRT skill translation and application. Intended for use after classroom training occurs, the mobile app has three primary functions designed to increase behavioral intent to deliver SBIRT: (1) review skills (ie, address knowledge and beliefs about SBIRT), (2) apply skills with patients (ie, build confidence and perceived behavioral control), and (3) report performance data (ie, increase accountability and social norms and/o...

Journal of Orthopaedic Research, 2008

Aseptic loosening is the most critical problem in total hip arthroplasty. It can occur in even a ... more Aseptic loosening is the most critical problem in total hip arthroplasty. It can occur in even a technically well-inserted prosthesis. Although many reports have been published on the pathogenesis of loosening, the precise mechanism of loosening has not been elucidated 1,2. In animal models proinflammatory cytokines have been proposed to have an important role 3. However, this has not been proved in human tissue. The current study was designed to determine the cellular the cytokine and chemokine network from periprosthetic tissues of loose hips joints and from synovium in hips with osteoarthritis. Materials and Methods. Interface tissues between bone and prosthesis were collected from 15 cases of aseptic loose artificial hip joint at revision. Synovial tissue samples were collected from 14 patients with hip osteoarthritis at primary surgery Table I. The samples were retrieved fresh, using a sterile technique, and immediately were placed in stabilizing solution (RNA later, QIAGEN) and stored at-20 0 C. Total RNA was isolated (Trizol) and the quality was confirmed by aragose gel electrophoresis. Real-time RT-PCR was carried out using iQ TM SYBR ® green supermix reagent (Bio-RAD, CA), and mRNA amounts were normalized relative to control gene HPRT. Generation of only the correct amplification products confirmed by melting curve analysis of the products. The Mann-Whitney test was applied to detect significant differences in the expression levels for each mRNA between the two groups. Results. Relative mRNA expression levels, fold increase or decrease in osteolysis patients compared to controls, and p values are shown in Table II. Osteoclastogenesis. Osteoclast markers (Cath K, TRAP, MMP9, DC-STAMP) were significantly higher in osteolysis patients. Osteoprotegerin was low in osteolysis while RANKL was not significantly different in two groups. Macrophage activation. There was no difference in levels of the pro-inflammatory cytokines TNFa and IL-6. However, the alternative macrophage activation markers chitinase and CCL18 were 66 and 3 fold more in osteolysis, respectively. BCL2A1, an antiapoptotic macrophage protein was 16 fold more abundant in osteolysis patients. Chemokines. IL-8 and MIP1A were significant higher in osteolysis Osteogenesis. BMP4 and FGF18 were significantly lower in osteolysis patients than controls. Discussion The data from this in vivo study show that proinflammatory cytokines are not expressed at significantly elevated levels in end stage osteolysis patients. Proinflammatory cytokines signaling is prominently involved in animal models of osteolysis, and may be involved in the early stages of osteolysis. However, our data showed a different pathogenesis during the chronic stage of osteolysis. Rather, an alternative activation of macrophages characterized by increased levels of markers as Chit-1, CCL18 and BCL2A1 is evident. Elevated expression of chemokines and decreased OPG (but unchanged RANKL expression) contributes to the increased osteoclastogenesis associated with this disease. In addition, this study shows an impairment of osteoblastic bone formation indicated by decreased BMP4 and FGF18

Journal of Orthopaedic Research, 2006

The ability of prosthetic wear debris to induce pro-inflammatory responses in macrophages is wide... more The ability of prosthetic wear debris to induce pro-inflammatory responses in macrophages is widely appreciated, but little is known about the molecular mechanisms involved in particle recognition. Specifically, the nature of the cell surface receptors that interact with wear debris is poorly understood. Elucidating the identities of these receptors and how they interact with different types of wear debris are critical to understanding how wear debris initiates periprosthetic osteolysis. We examined the involvement of opsonization, complement receptor 3 (CR3), and scavenger receptor A (SRA), in responses to polymethylmethacrylate (PMMA) and titanium wear particles. Serum dependence of pro-inflammatory responses to PMMA and titanium was tested, and serum proteins that adhered to these two types of particles were identified. Several serum proteins, including known opsonins such as C3bi and fibronectin, adhered to PMMA but not titanium, and serum was required for pro-inflammatory signaling induced by PMMA, but not by titanium. Phagocytosis of PMMA and titanium by macrophages was demonstrated by flow cytometry. Blocking CR3 specifically inhibited phagocytosis of PMMA by macrophages, whereas blocking SRA specifically inhibited titanium uptake. Direct involvement of CR3 and SRA in cell-particle interaction was assessed by expression of these receptors in nonphagocytic HEK293 cells. CR3 specifically induced cell binding to PMMA particles and adhesion to PMMA-coated plates, while SRA specifically induced binding to titanium particles and adhesion to titanium-coated plates. Taken together, these results suggest involvement of opsonization, complement, and integrin receptors, including CR3 and fibronectin receptors, in PMMA action, and an involvement of scavenger receptors in responses to titanium.

The Journal of Bone & Joint Surgery, 2006

Background: Wear debris challenge of macrophages provokes the generation of proinflammatory cytok... more Background: Wear debris challenge of macrophages provokes the generation of proinflammatory cytokines, which contribute to periprosthetic osteolysis. However, it is not known whether this effect is accompanied by reprogramming of other cytokines present within the periprosthetic tissue that may be involved in anti-osteoclastogenic activities. In the present study, we examined the ability of wear debris particles to inhibit the signaling of two such cytokines, interleukin-6 and interferon-γ. Methods: Human osteoclast precursor cells were challenged with particles of titanium or polymethylmethacrylate bone cement prior to the addition of the cytokines interleukin-6 or interferon-γ. Interleukin-6 signaling was determined by measuring the activation of STAT3 signal transduction with use of immunoblotting and electrophoretic mobility shift assays. Interferon-γ signaling was determined by measuring the activation of STAT1 with use of immunoblotting and electrophoretic mobility shift assays and by measuring the expression of interferon-γ-inducible genes with use of realtime reverse transcription-polymerase chain reaction assays. Involvement of mitogen-activated protein kinases in cytokine signaling was assessed by including mitogen-activated protein kinase inhibitors in these assays and also by means of immunoblot assessment of mitogen-activated protein kinase activation by wear debris particles. Wear debris modulation of expression of the cytokine suppressors SOCS1 and SOCS3 (as well as pro-inflammatory mediators) was assessed with use of real-time reverse transcription-polymerase chain reaction assays. Results: Both titanium and polymethylmethacrylate particles potently inhibited interleukin-6-induced STAT3 activation in human osteoclast precursor cells. Inhibition of p38 mitogen-activated protein kinase, which is activated by titanium and polymethylmethacrylate, reversed the inhibitory effects of these particles on interleukin-6 signaling, whereas inhibition of ERK and JNK mitogen-activated protein kinases (which are also activated by both types of wear debris) had no effect. Titanium and polymethylmethacrylate also both induced expression of SOCS3, an inhibitor of interleukin-6 signaling. In addition to its effects on interleukin-6 signaling, titanium also profoundly inhibited the interferon-γinduced activation of STAT1 and the expression of interferon-γ-inducible genes, whereas polymethylmethacrylate had no effect on interferon-γ signaling. Conclusions: Titanium inhibits both interferon-γ and interleukin-6 signaling in human osteoclast precursor cells, whereas polymethylmethacrylate bone cement inhibits only the latter. Wear particle inhibition of interleukin-6 specifically involves the activation of p38 mitogen-activated protein kinase and is accompanied by substantial induction of SOCS3, an inhibitor of interleukin-6 signaling. In contrast, titanium inhibition of interferon-γ signaling is not dependent on mitogen-activated protein kinase activation and is accompanied by only modest induction of the interferon-γ inhibitor SOCS1. Clinical Relevance: The critical role of wear debris in the development of periprosthetic osteolysis likely involves the inhibition of anti-inflammatory/anti-osteoclastogenic cytokine signaling in addition to the well-established induction of pro-inflammatory mediators. Strategies to augment these "protective" signaling pathways may therefore have therapeutic potential for the treatment of periprosthetic osteolysis.

Drug and Alcohol Dependence, 2020

Background: Many people who need specialty treatment for substance use disorders (SUDs) do not re... more Background: Many people who need specialty treatment for substance use disorders (SUDs) do not receive it. Clinical interventions could increase treatment utilization but are not routinely used. This systematic review aimed to describe clinical interventions that may increase SUD specialty treatment utilization (i.e., treatment initiation, attendance, meaningful engagement) and to determine which intervention(s) most consistently increase treatment utilization. Methods: We conducted a systematic review of clinical intervention studies (published in English between 2000 and 2017) reporting outcomes relevant to specialty SUD treatment utilization. Outcomes were treatment initiation, attendance, and meaningful engagement. Risk of bias was assessed using Cochrane guidelines and randomized controlled trials (RCTs) with bias scores < 3 were included in a synthesis of results. Proportions of positive to negative utilization outcomes were calculated for each low-bias RCT; studies with 50% positive outcomes or more were considered "majority-positive". Studies were categorized by theory-based approach. Results: Twenty-three RCTs had low risk of bias and were synthesized. Among intervention types with two or more studies, cognitive-behavioral (100% majority-positive) and coordinated care (67% majority-positive) interventions were most likely to increase treatment initiation, while 12-step promotion interventions were most likely to increase treatment attendance (50% majority-positive). One study (12-step promotion) measured meaningful engagement, with majority-positive outcomes. Conclusions: A systematic review and narrative synthesis of clinical interventions promoting specialty SUD treatment utilization provided preliminary evidence that cognitive-behavioral and coordinated care interventions may increase treatment initiation, while 12-step promotion interventions may promote treatment attendance. More quality studies and greater consistency in treatment utilization measurement are needed.

Substance Abuse, 2019

Background: Adherence to clinical practice guidelines for alcohol and drug screening, brief inter... more Background: Adherence to clinical practice guidelines for alcohol and drug screening, brief intervention, and referral to treatment (SBIRT) is often inadequate. Mobile apps developed as clinical translation tools could improve the delivery of high fidelity SBIRT. Methods: This study tested the effectiveness of an SBIRT mobile app conceptually aligned with the Theory of Planned Behavior (TPB) to support SBIRT delivery by health care trainees (nursing, social work, internal medicine, psychiatry, and psychology) working in clinical settings (N = 101). Bivariate analyses examined the rate of SBIRT delivery between trainees assigned to the experimental (app) and control (no app) study conditions; as well as the relationship between TPB-based constructs, intention to deliver SBIRT, and screening rates. Results: No significant differences were identified between the study conditions in SBIRT delivery. Significant correlations were found between intent to screen and TPB variables including attitudes/behavioral beliefs concerning substance use treatment (r = .49, p = .01); confidence in clinical skills (r = .36, p = .01); subjective norms (r = .54, p = .01) and perceived behavioral control over appointment time constraints (r = .42, p = .01). Also significant were correlations between percent of patients screened and confidence (r = .24, p = .05); subjective norms (r = .22, p = .05) and perceived behavioral control (r = .28, p = .01). Conclusions: The negative results of the study condition comparisons indicate the need for further investigation of strategies to optimize mobile app utilization, engagement, and effectiveness as a clinical translation tool. Findings of significant correlations between substance use screening rates and both norms and confidence support the potential value of the TPB model in explaining behavior of health care learners in SBIRT delivery.

Journal of the American Association of Nurse Practitioners, 2019

Background and purpose: Screening, brief Intervention, and referral to treatment (SBIRT) is a wid... more Background and purpose: Screening, brief Intervention, and referral to treatment (SBIRT) is a widely trained evidence-based strategy to identify and address alcohol and drug use problems. The purpose of this qualitative study was to explore the experience of family nurse practitioner (FNP) learners in the implementation of SBIRT and the perceived clinical utility of an SBIRT mobile app. Methods: Twenty-two FNP learners completed didactic SBIRT training and orientation to an SBIRT mobile app. At the conclusion of the study, participant focus groups explored overall SBIRT delivery (N = 19) and SBIRT mobile app utilization (N = 14). Focus group data were analyzed within a Theory of Planned Behavior framework. Results: Participants indicated that the mobile app was useful in the ongoing development of SBIRT knowledge, skill confidence, and motivation. Learners identified the clinical context as a major factor in facilitating the delivery of SBIRT overall. Participants who did not deliver SBIRT indicated that the most significant barriers to SBIRT implementation were lack of support from clinical preceptors and health systems. Conclusions: Findings suggest that a mobile app is an acceptable and feasible tool to improve the delivery of SBIRT. However, collaboration with preceptors and clinical training organizations is essential to optimize clinical translation.

JMIR research protocols, Jan 18, 2017

Translation of knowledge and skills from classroom settings to clinical practice is a major chall... more Translation of knowledge and skills from classroom settings to clinical practice is a major challenge in healthcare training, especially for behavioral interventions. For example, screening, brief intervention, and referral to treatment (SBIRT) is a highly-promoted approach to identifying and treating individuals at risk for alcohol or drug problems, yet effective, routine use of SBIRT has lagged. The objective of this paper is to describe the development, pilot testing, and trial protocol of a mobile app based on the theory of planned behavior (TPB) to promote SBIRT skill translation and application. Intended for use after classroom training occurs, the mobile app has three primary functions designed to increase behavioral intent to deliver SBIRT: (1) review skills (ie, address knowledge and beliefs about SBIRT), (2) apply skills with patients (ie, build confidence and perceived behavioral control), and (3) report performance data (ie, increase accountability and social norms and/o...

Journal of Orthopaedic Research, 2008

Aseptic loosening is the most critical problem in total hip arthroplasty. It can occur in even a ... more Aseptic loosening is the most critical problem in total hip arthroplasty. It can occur in even a technically well-inserted prosthesis. Although many reports have been published on the pathogenesis of loosening, the precise mechanism of loosening has not been elucidated 1,2. In animal models proinflammatory cytokines have been proposed to have an important role 3. However, this has not been proved in human tissue. The current study was designed to determine the cellular the cytokine and chemokine network from periprosthetic tissues of loose hips joints and from synovium in hips with osteoarthritis. Materials and Methods. Interface tissues between bone and prosthesis were collected from 15 cases of aseptic loose artificial hip joint at revision. Synovial tissue samples were collected from 14 patients with hip osteoarthritis at primary surgery Table I. The samples were retrieved fresh, using a sterile technique, and immediately were placed in stabilizing solution (RNA later, QIAGEN) and stored at-20 0 C. Total RNA was isolated (Trizol) and the quality was confirmed by aragose gel electrophoresis. Real-time RT-PCR was carried out using iQ TM SYBR ® green supermix reagent (Bio-RAD, CA), and mRNA amounts were normalized relative to control gene HPRT. Generation of only the correct amplification products confirmed by melting curve analysis of the products. The Mann-Whitney test was applied to detect significant differences in the expression levels for each mRNA between the two groups. Results. Relative mRNA expression levels, fold increase or decrease in osteolysis patients compared to controls, and p values are shown in Table II. Osteoclastogenesis. Osteoclast markers (Cath K, TRAP, MMP9, DC-STAMP) were significantly higher in osteolysis patients. Osteoprotegerin was low in osteolysis while RANKL was not significantly different in two groups. Macrophage activation. There was no difference in levels of the pro-inflammatory cytokines TNFa and IL-6. However, the alternative macrophage activation markers chitinase and CCL18 were 66 and 3 fold more in osteolysis, respectively. BCL2A1, an antiapoptotic macrophage protein was 16 fold more abundant in osteolysis patients. Chemokines. IL-8 and MIP1A were significant higher in osteolysis Osteogenesis. BMP4 and FGF18 were significantly lower in osteolysis patients than controls. Discussion The data from this in vivo study show that proinflammatory cytokines are not expressed at significantly elevated levels in end stage osteolysis patients. Proinflammatory cytokines signaling is prominently involved in animal models of osteolysis, and may be involved in the early stages of osteolysis. However, our data showed a different pathogenesis during the chronic stage of osteolysis. Rather, an alternative activation of macrophages characterized by increased levels of markers as Chit-1, CCL18 and BCL2A1 is evident. Elevated expression of chemokines and decreased OPG (but unchanged RANKL expression) contributes to the increased osteoclastogenesis associated with this disease. In addition, this study shows an impairment of osteoblastic bone formation indicated by decreased BMP4 and FGF18

Journal of Orthopaedic Research, 2006

The ability of prosthetic wear debris to induce pro-inflammatory responses in macrophages is wide... more The ability of prosthetic wear debris to induce pro-inflammatory responses in macrophages is widely appreciated, but little is known about the molecular mechanisms involved in particle recognition. Specifically, the nature of the cell surface receptors that interact with wear debris is poorly understood. Elucidating the identities of these receptors and how they interact with different types of wear debris are critical to understanding how wear debris initiates periprosthetic osteolysis. We examined the involvement of opsonization, complement receptor 3 (CR3), and scavenger receptor A (SRA), in responses to polymethylmethacrylate (PMMA) and titanium wear particles. Serum dependence of pro-inflammatory responses to PMMA and titanium was tested, and serum proteins that adhered to these two types of particles were identified. Several serum proteins, including known opsonins such as C3bi and fibronectin, adhered to PMMA but not titanium, and serum was required for pro-inflammatory signaling induced by PMMA, but not by titanium. Phagocytosis of PMMA and titanium by macrophages was demonstrated by flow cytometry. Blocking CR3 specifically inhibited phagocytosis of PMMA by macrophages, whereas blocking SRA specifically inhibited titanium uptake. Direct involvement of CR3 and SRA in cell-particle interaction was assessed by expression of these receptors in nonphagocytic HEK293 cells. CR3 specifically induced cell binding to PMMA particles and adhesion to PMMA-coated plates, while SRA specifically induced binding to titanium particles and adhesion to titanium-coated plates. Taken together, these results suggest involvement of opsonization, complement, and integrin receptors, including CR3 and fibronectin receptors, in PMMA action, and an involvement of scavenger receptors in responses to titanium.

The Journal of Bone & Joint Surgery, 2006

Background: Wear debris challenge of macrophages provokes the generation of proinflammatory cytok... more Background: Wear debris challenge of macrophages provokes the generation of proinflammatory cytokines, which contribute to periprosthetic osteolysis. However, it is not known whether this effect is accompanied by reprogramming of other cytokines present within the periprosthetic tissue that may be involved in anti-osteoclastogenic activities. In the present study, we examined the ability of wear debris particles to inhibit the signaling of two such cytokines, interleukin-6 and interferon-γ. Methods: Human osteoclast precursor cells were challenged with particles of titanium or polymethylmethacrylate bone cement prior to the addition of the cytokines interleukin-6 or interferon-γ. Interleukin-6 signaling was determined by measuring the activation of STAT3 signal transduction with use of immunoblotting and electrophoretic mobility shift assays. Interferon-γ signaling was determined by measuring the activation of STAT1 with use of immunoblotting and electrophoretic mobility shift assays and by measuring the expression of interferon-γ-inducible genes with use of realtime reverse transcription-polymerase chain reaction assays. Involvement of mitogen-activated protein kinases in cytokine signaling was assessed by including mitogen-activated protein kinase inhibitors in these assays and also by means of immunoblot assessment of mitogen-activated protein kinase activation by wear debris particles. Wear debris modulation of expression of the cytokine suppressors SOCS1 and SOCS3 (as well as pro-inflammatory mediators) was assessed with use of real-time reverse transcription-polymerase chain reaction assays. Results: Both titanium and polymethylmethacrylate particles potently inhibited interleukin-6-induced STAT3 activation in human osteoclast precursor cells. Inhibition of p38 mitogen-activated protein kinase, which is activated by titanium and polymethylmethacrylate, reversed the inhibitory effects of these particles on interleukin-6 signaling, whereas inhibition of ERK and JNK mitogen-activated protein kinases (which are also activated by both types of wear debris) had no effect. Titanium and polymethylmethacrylate also both induced expression of SOCS3, an inhibitor of interleukin-6 signaling. In addition to its effects on interleukin-6 signaling, titanium also profoundly inhibited the interferon-γinduced activation of STAT1 and the expression of interferon-γ-inducible genes, whereas polymethylmethacrylate had no effect on interferon-γ signaling. Conclusions: Titanium inhibits both interferon-γ and interleukin-6 signaling in human osteoclast precursor cells, whereas polymethylmethacrylate bone cement inhibits only the latter. Wear particle inhibition of interleukin-6 specifically involves the activation of p38 mitogen-activated protein kinase and is accompanied by substantial induction of SOCS3, an inhibitor of interleukin-6 signaling. In contrast, titanium inhibition of interferon-γ signaling is not dependent on mitogen-activated protein kinase activation and is accompanied by only modest induction of the interferon-γ inhibitor SOCS1. Clinical Relevance: The critical role of wear debris in the development of periprosthetic osteolysis likely involves the inhibition of anti-inflammatory/anti-osteoclastogenic cytokine signaling in addition to the well-established induction of pro-inflammatory mediators. Strategies to augment these "protective" signaling pathways may therefore have therapeutic potential for the treatment of periprosthetic osteolysis.