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Objectives: The purpose of this study is to evaluate the outcomes of a polyaxial locking plate utilizing locking-cap fixation for treatment of patients with displaced olecranon fractures., Methods: A retrospective review was performed for all consecutive patients at two institutions with displaced olecranon fractures treated with a polyaxial locking plate. Patients were required to have at least 1-year follow up. Clinical outcomes including the Disabilities of the Arm, Shoulder, and Hand (DASH) score, Single Assessment Numeric Evaluation (SANE), along with a Likert-scaled satisfaction survey ranging between 1-5 (1= very unsatisfied and 5= very satisfied) were collected., Results: The plate osteosynthesis was performed on 24 patients with displaced olecranon fractures. Functional outcome scores were collected on 19 (79.2%) patients. The mean age at the time of surgery was 57.9 years (range, 23 to 78) and mean clinical follow-up was 21.0 ± 6.6 months (range, 12-34 months). All patients achieved osseous union in an acceptable position. Four (16.7%) patients complained of plate related pain and 6 (25%) patients complained of postoperative stiffness. Complications were found in 3 (12.5 %) patients, which included two neuropathies and one hardware failure in which a patient presented following a fall with a broken screw. No patients required revision surgery nor removal of hardware. A total of 16 (84%) patients were somewhat to very satisfied. The mean SANE score was 87.8 ± 14.6 (range: 45-100) and the mean DASH score was 13.8 + 17.5 (range: 0-55.8). Seventeen (89%) patients rated their elbows as 75% or better on SANE assessment and 16 (84%) patients achieved DASH scores of less than 30., Conclusion: Polyaxial plate fixation utilizing locking-cap technology resulted in excellent short-term functional outcomes in patients with displaced olecranon fractures. Further follow-up is needed to determine the long-term outcomes of locking-cap constructs for olecranon fractures., Competing Interests: The authors and any research foundation with which they are affiliated did not receive any financial payments or other benefits for writing this manuscript. All authors significantly contributed to the document and have reviewed the final manuscript., (© 2025 Mashhad University of Medical Sciences.)

The incidence of ulnar collateral ligament injuries has increased over the past decade. As a result, the rate of ulnar collateral ligament reconstruction has increased dramatically at all levels of competition in overhead athletes. Currently, there is no consensus on milestones during rehabilitation or a largely agreed-upon structured throwing program after ulnar collateral ligament injuries. It is important to outline the criteria that should be met during rehabilitation and provide an evidence-based structured throwing program that can be implemented to improve and optimize an athlete's chances of returning to the same level of throwing. These guidelines may be used for rehabilitation after an injury is managed surgically or nonsurgically.

Study Design: Review article., Objective: To provide a comprehensive review and update on the evaluation and management of Hangman's fractures., Summary of Background Data: Hangman's fractures are the second most common fracture of the C2 vertebrae, and the prevalence is increasing with our aging population. Although these injuries are associated with good clinical outcomes and low rates of neurologic injury, they must be promptly recognized and treated according to patient and fracture factors., Methods: A review of the literature., Results: Neurologic injuries are uncommon in typical Hangman's fractures but are more of a concern in atypical Hangman's fractures due to lack of dissociation of the posterior ring of C2. The nonoperative treatment of stable type I, II, and atypical fractures with external immobilization leads to excellent long-term outcomes as does the operative treatment of unstable type IIa, III, and atypical fractures., Conclusions: Stable injury patterns can be treated with immobilization alone, whereas unstable injury patterns necessitate surgical treatment. Prompt diagnosis and treatment Hangman's fractures is paramount, and when managed properly, patients can have excellent clinical and neurologic outcomes., Competing Interests: B.L. reports participation in the Medtronic Biologics advisory board for spine related-fusion technologies. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The optimal surgical treatment of displaced proximal humerus fractures (PHFs) remains controversial. There are advocates for both open reduction and internal fixation with plate and screws (ORIF) and intramedullary nailing (IMN). The purpose this study was to evaluate the early-term clinical and radiographic outcomes of IMN for isolated, displaced 2-part surgical neck PHFs using a modern, straight nail system and to determine the effect of preoperative patient and fracture characteristics on outcome., Methods: This was a case series of 23 patients with displaced 2-part surgical neck PHFs who were treated with ORIF using a straight IMN with minimum follow-up of 1 year (mean 2.5 years [range, 1.1-4.6]). Patients were identified retrospectively and contacted for measurement of active range of motion (AROM) and patient reported outcome measures (PROMs) including the American Shoulder and Elbow Surgeons (ASES) score, Oxford Shoulder Score (OSS), and Single Assessment Numeric Evaluation (SANE), EuroQol-5D (EQ-5D), and Visual Analog Scale Pain score (VAS Pain). Plain radiographs were evaluated to assess the quality of the reduction and failure of fixation. Complications and reoperations were identified., Results: Reduction was anatomic in 12 (52%) patients, acceptable in 9 (39%), and 2 (9%) were malreduced. There were no differences in reduction quality based on sex (p = 0.37), age at surgery (p = 0.68), calcar comminution (p = 0.68), number of screws in the head (p = 0.99), or medial hinge disruption (p = 0.06). At final follow-up, the mean ASES score was 92 ± 10, OSS was 45 ± 4, SANE was 93 ± 7, EQ-5D of 0.85 ± 0.17, and VAS Pain was 0 ± 1. The mean active forward flexion was 143° ± 16°, active external rotation was 68° ± 20°, and internal rotation was T11 ± 4 vertebrae. Two (9%) patients underwent reoperation and 2 (9%) patients experienced clinical failure not requiring reoperation., Conclusions: Straight IMN is a reliable treatment for displaced 2-part surgical neck PHFs with excellent radiographic and clinical outcomes in early follow-up. The implant facilitated anatomic or acceptable alignment of the fracture in the vast majority of patients., Competing Interests: Conflicts of Interest and Source of Funding No outside funding or grant was received for the current study. AG receives royalties and consulting fees from DJO global, royalties from Wright/Tornier, royalties from Stryker, and payments from The Journal of Bone & Joint Surgery. ESP receives financial payments for consulting, service on advisory committees, and speakers’ bureau from the commercial entities Miami Device Solutions and Wright/Tornier. For the remaining authors none were declared., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Despite the large number of studies assessing adverse local tissue reaction (ALTR) in metal-on-metal (MoM) hip implants, there is still a lack of knowledge about the natural progression of ALTR. The aims of this study were to describe the natural course of changes in ALTR at mid- to long-term follow-up for patients treated with metal-on-metal hip arthroplasty and to determine possible risk factors associated with change in ALTR., Methods: A total of 158 patients (158 hips), 109 MoM hip resurfacing arthroplasties (HRAs) and 49 MoM total hip arthroplasties (THAs), with 2 clinical follow-ups including MARS-MRIs were included. The mean time from index operation to the first visit was 7.6 years (range 3.4-11.4 years), and the mean time between the 2 visits was 1.0 year (range 0.7-1.6 years)., Results: The proportion of patients with moderate or severe ALTR did not increase significantly between the first and second visit for the MoM HRA group (14.7-15.6%; p =  0.850) or the MoM THA group (32.7-36.7%; p =  0.671). 8 (7.3%) HRA patients and 9 (18.4%) THA patients progressed in ALTR grade. None of the collected clinical variables was sensitive or specific in identifying patients with ALTR progression., Conclusions: Although ALTR prevalence was high in our cohort, clinically significant ALTR progression was rare. We were unable to find any predictors associated with ALTR change. This indicates that MARS-MRI remains a valuable tool in the follow-up of patients treated with MoM hip devices in identifying patients who may need revision surgery.

Introduction: Our first aim was to report the longitudinal clinical performance of patients treated with the ASR Hip System, a metal-on-metal (MoM) device, in their mid- to late-term follow-up. Secondly, we sought to report on the reasons and risk factors for mid- to late-term implant failure., Methods: A total of 1721 ASR patients (1933 hips) from 16 centres in 6 countries were enrolled to a prospective, post-recall study. The average time to enrollment was 7.4 years from index surgery. Data from 3 follow-up visits over 2 years were analysed. Implant performance, based on ion levels and PROMs, was determined at each clinical visit., Results: The proportion of those exhibiting good performance decreased over time for hip resurfacing (ASR HRA) and total hip arthroplasty (ASR XL) patients. ASR XL patients were likely to exhibit longitudinal blood metal ion increases regardless of symptom state. ASR HRA patients were more likely to present with and maintain good performance over time, especially males with high general health indicators. 6% of ASR HRA and 14% of ASR XL patients were revised throughout the study period., Discussion: ASR XL THA patients are likely to exhibit blood metal ion increases without accompanying changes in symptom state, and therefore should be followed with annual blood tests at minimum. While appropriately selected ASR HRA patients were the most likely to exhibit low blood metal ion levels and report no symptoms, we recommend vigilant follow-up of all ASR patients to ensure that worsening clinical outcomes and asymptomatic soft tissue damage are not missed.

Purpose: To determine the definitions for recurrence used in the literature, assess the consensus in using these definitions, and determine the impact of these definitions on recurrence rates., Methods: A literature search was performed in PubMed and EMBASE including studies from 2000 to 2020 reporting on recurrence rates after anterior arthroscopic shoulder instability surgery. Dislocation, apprehension, subluxation and recurrence rates were compared., Results: Ninety-one studies were included. In 68% of the eligible studies, recurrence rates are not well defined. Thirty (33%) studies did not report on dislocations, 45 (49%) did not report on subluxations, and 58 (64%) did not report on apprehension. Seventeen different definitions for recurrence of instability, 4 definitions of dislocations, and 8 definitions of subluxation were used., Conclusion: Recurrence rates are poorly specified and likely underreported in the literature, hampering comparison with results of other studies. This highlights the need for a consensus on definition of recurrence across shoulder instability studies. We recommend not using the definition recurrence of instability anymore. We endorse defining dislocations as a radiographically confirmed dislocation or a dislocation that is manually reduced, subluxations as the feeling of a dislocation that can be (spontaneously) reduced without the need for a radiographically confirmed dislocation, and a positive apprehension sign as fear of imminent dislocation when placing the arm in abduction and external rotation during physical examination. Reporting on the events resulting in a dislocation or subluxation aids in making an estimation of the severity of instability., Level of Evidence: Level IV, systematic review., (© 2021 by the Arthroscopy Association of North America. Published by Elsevier Inc.)

Remotely sensed land cover datasets have been increasingly employed in studies of wildlife habitat use. However, meaningful interpretation of these datasets is dependent on how accurately they estimate habitat features that are important to wildlife. We evaluated the accuracy of the GAP dataset, which is commonly used to classify broad cover categories (e.g., vegetation communities) and LANDFIRE datasets, which classifies narrower cover categories (e.g., plant species) and structural features of vegetation. To evaluate accuracy, we compared classification of cover types and estimates of percent cover and height of sagebrush (Artemisia spp.) derived from GAP and LANDFIRE datasets to field-collected data in winter habitats used by greater sage-grouse (Centrocercus urophasianus). Accuracy was dependent on the type of dataset used as well as the spatial scale (point, 500-m, and 1-km) and biological level (community versus dominant species) investigated. GAP datasets had the highest overall classification accuracy of broad sagebrush cover types (49.8%) compared to LANDFIRE datasets for narrower cover types (39.1% community-level; 31.9% species-level). Percent cover and height were not accurately estimated in the LANDFIRE dataset. Our results suggest that researchers must be cautious when applying GAP or LANDFIRE datasets to classify narrow categories of land cover types or to predict percent cover or height of sagebrush within sagebrush-dominated landscapes. We conclude that ground-truthing is critical for successful application of land cover datasets in landscape-scale evaluations and management planning, particularly when wildlife use relatively rare habitat types compared to what is available., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Although TKA is a common and proven reliable procedure for treating end-stage knee osteoarthritis, a minority of patients still do not achieve satisfactory levels of pain relief and functional improvement. Even though several studies have attempted to identify patients at risk of having poor clinical outcomes, few have approached this issue by considering the outcome of the patient-acceptable symptom state (PASS), defined as the value on a patient-reported outcome measure scale above which the patient deems their current symptom state acceptable., Questions/purposes: (1) What is the proportion of patients who do not attain the PASS in pain and function at 1 year after TKA? (2) Which preoperative patient factors are associated with not achieving the PASS in pain at 1 year after TKA? (3) Which preoperative patient factors are associated with not achieving the PASS in function at 1 year after TKA?, Methods: This retrospective study is a secondary analysis of the 1-year follow-up data from a prospective, international, multicenter study of a single TKA system. Inclusion criteria for that study were patients diagnosed with primary osteoarthritis or post-traumatic arthritis and who were able to return for follow-up for 10 years; exclusion criteria were infection, osteomyelitis, and failure of a previous joint replacement. Between 2011 and 2014, 449 patients underwent TKA at 10 centers in five countries. At 1 year, 13% (58 of 449) were lost to follow-up, 2% could not be analyzed (eight of 449; missing 1-year KOOS), leaving 85% (383 of 449) for analysis here. The primary outcomes were not surpassing evidence-derived PASS thresholds in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Activities in Daily Living (ADL) sub-scores. Multivariate binary logistic regressions considering preoperative demographic, radiographic, and patient-reported outcome measure data were constructed using a forward stepwise elimination algorithm to reach the simplest best-fit regression models., Results: At 1 year after TKA, 38% of the patients (145 of 383) did not reach the PASS in KOOS Pain, 36% (139 of 383) did not reach the PASS in KOOS ADL, and 29% (110 of 383) did not achieve the PASS in either KOOS Pain or ADL. After controlling for potentially confounding variables such as gender, age, BMI, and comorbidity scores, we found that men (odds ratio 2.09; p = 0.01), and patients with less-than-advanced radiographic osteoarthritis (OR 2.09; p = 0.01) were strongly associated with not achieving the PASS in pain. After controlling for the same potentially confounding variables, we found that patients with less-than-advanced radiographic osteoarthritis (OR 2.09; p = 0.01) were also strongly associated with not achieving the PASS in function., Conclusions: We found that patients with less severe osteoarthritis were much less likely to attain the PASS in pain and function at 1 year after TKA, and that men were much less likely to achieve the PASS in pain at 1 year after TKA. Based on these findings, surgeons should strongly consider delaying surgery in patients who present with less-than-severe osteoarthritis, with increased caution in men. Surgeons should counsel their patients on their expectations and their chances of achieving meaningful levels of pain and functional improvement. Future regional and national registry studies should assess the true proportion of patients attaining PASS in pain and function after TKA and confirm if the preoperative factors identified in this study remain significant in larger, more diverse patient populations., Level of Evidence: Level III, therapeutic study.

Background: The primary aim is to identify the degree to which patient satisfaction with the outcome of total hip arthroplasty (THA) or total knee arthroplasty (TKA) changes between 1 and 3 years from the procedure. The secondary aim is to identify variables associated with satisfaction., Methods: Data were sourced from 2 prospective international, multicenter studies (919 THA and 450 TKA patients). Satisfaction was assessed by a 10-point numerical rating scale, at 1- and 3-year follow-up. Linear mixed-effects models were used to assess factors associated with satisfaction., Results: For the THA cohort, higher preoperative joint space width (odds ratio [OR] = 0.28; P = .004), pain from other joints (OR = 0.26; P = .033), and lower preoperative health state (OR = -0.02; P < .001) were associated with consistently lower levels of satisfaction. The model also showed that patients with preoperative anxiety/depression improved in satisfaction between 1 and 3 years (OR = -0.26; P = .031). For the TKA cohort, anterior (vs neutral or posterior) tibial component slope (OR = 0.90; P = .008), greater femoral component valgus angle (OR = 0.05; P = .012), less severe osteoarthritis (OR = -0.10; P < .001), and lower preoperative health state (OR = -0.02; P = .003) were associated with lower levels of satisfaction across the study period. In addition, patients with anterior tibial component slope improved in satisfaction level over time (OR = -0.33; P = .022)., Conclusion: Changes in satisfaction following THA and TKA are rare between 1- and 3-year follow-up. The findings of this study can be used to guide patient counseling preoperatively and to determine intervals of routine follow-up postoperatively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The Patient Acceptable Symptom State (PASS) represents the value on a patient-reported outcome measure scale beyond which patients consider themselves well or in a satisfactory state. The aim of this study is to define and validate the PASS threshold for the HHS at 3 months, 1, 3, 5, and 7 years after THA., Methods: A total of 976 patients from 14 centers in 7 countries were enrolled into a prospective study. Patients completed the HHS and a numerical rating scale for satisfaction at each follow-up. PASS thresholds for the HHS were calculated at each follow-up interval using the anchor-based, 80% specificity method. A bootstrapping method was used to internally validate the primary PASS thresholds. A patient sample sourced from an institutional registry was used for external validation., Results: The HHS was an excellent predictor of satisfaction at each time point (area under the curve > 0.8; P < .001). PASS thresholds for the HHS were 76 points at 3 months, 89 points at 1 year, 93 points at 3 years, 94 points at 5 years, and 93 points at 7 years. When applied to the internal and external validation cohorts, all PASS thresholds showed acceptable or excellent ability to predict satisfaction (area under the curve = 0.73-80; P < .001)., Conclusion: The present study is the first to present validated PASS thresholds for the HHS following THA. These findings will serve as a useful reference for future THA outcome studies and as benchmarks for surgeons in their assessment of their patients' clinical success., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The primary aim of the current study was to determine whether metal ion levels could identify well- from poorly-functioning implants in patients after undergoing bilateral Articular Surface Replacement (ASR) Hip System. The secondary aim was to establish threshold values for Co and Cr that could be used to predict clinical problems in these patients., Materials and Methods: The study included 125 patients treated with bilateral ASR hip resurfacing (HRA) and 93 patients treated with bilateral ASR XL total hip arthroplasty (THA) at a mean follow-up of 7.1 years post-surgery. Patients were labelled as well- or poorly-functioning based on strict criteria. We calculated the Co and Cr safe upper ion limits (SUL) for ASR HRA and ASR XL THA separately and assessed these cutoffs ability to predict clinical problems., Results: In patients with bilateral ASR HRA, the well-functioning group had lower ions than the poorly-functioning. In ASR THA patients, there was no difference in blood Co or Cr levels between well- and poorly-functioning implant groups ( p = 0.118 and p = 0.379, respectively). Both Co and Cr could effectively discriminate between well-functioning and poorly-functioning ASR HRA implants ( p < 0.001 and p < 0.001, respectively), but not for ASR THA implants ( p = 0.118 and p = 0.564, respectively). SULs of 4.0 ppb for Co and 4.0 ppb for Cr could differentiate between well- and poorly-functioning implants with high specificity., Conclusions: Metal ion levels are a more reliable tool in MoM HRA than THA when discriminating well- from poorly-functioning implants in bilateral patients. For patients treated with bilateral ASR HRA, ion levels above 4.0 ppb are highly specific for the detection of clinical problems.

Background: To facilitate the interpretation of numerical patient-reported outcome measure (PROM) scales, concepts such as the patient acceptable symptom state (PASS) have been introduced. Currently, no PASS thresholds have been established for the Knee injury and Osteoarthritis Outcome Score (KOOS) after total knee arthroplasty. The aims of the current study were to define PASS thresholds for the KOOS subscales and several other generic and knee-specific PROMs at 1 and 3 years after total knee arthroplasty using data from an international, multicenter clinical outcome study of a modern, well-performing implant system., Methods: The study cohort consisted of 499 patients undergoing total knee arthroplasty from an international, multicenter study. At 1 and 3 years after a total knee arthroplasty, patients completed the KOOS, EuroQoL 5-dimension 3-level (EQ-5D-3L), EuroQol visual analog scale (EQ-VAS), and numerical rating scales (NRS) for knee-related pain and satisfaction. PASS thresholds were calculated at each follow-up interval using 3 anchor-based approaches, using patient-reported satisfaction as the anchor., Results: According to our satisfaction anchor, 302 (78.9%) of 383 responding patients were satisfied at 1 year, and 242 (80.4%) of 301 responding patients were satisfied at 3 years. PASS thresholds were 84.5 points at 1 year and 87.5 points at 3 years for KOOS pain, 80.5 points at 1 year and 84.0 points at 3 years for KOOS symptoms, 83.0 points at 1 year and 87.5 points at 3 years for KOOS activities of daily living, 66.0 points at 1 year and 66.0 points at 3 years for KOOS quality of life, 83.0 points at 1 year and 90.5 points at 3 years for EQ-VAS, 0.80 point at 1 year and 0.80 point at 3 years for EQ-5D, and 1.8 points at 1 year and 1.8 points at 3 years for NRS pain., Conclusions: The current study is the first, to our knowledge, to propose PASS thresholds for the KOOS subscales at 1 and 3 years after total knee arthroplasty and contributes to PASS literature on other common PROMs. These findings will provide a useful reference for future total knee arthroplasty outcome studies and will help to determine what patients consider to be satisfactory operations., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: Despite innovations in THA, there remains a subgroup of patients who experience only modest pain relief and/or functional improvement after the procedure. Although several studies have previously sought to identify factors before surgery that were associated with achieving or not achieving a meaningful improvement after THA, there is no consensus on which factors are most associated; many studies have relied on single-center or single-country multicenter studies for their cohorts., Questions/purposes: We sought to identify (1) the proportion of patients who do not achieve a minimum clinically important difference (MCID) in pain and function 1 year after THA, and (2) the preoperative factors that were associated with not achieving MCIDs in pain and function 1 year after THA., Methods: This retrospective study analyzed data gathered from a prospective international, multicenter study examining the long-term clinical outcomes of two different polyethylene liners and two different acetabular shells. A total of 814 patients from 12 centers across four countries were enrolled in the study, with the final cohort consisting of 594 patients (73%) who all had complete preoperative and 1-year PROMs as well as a valid preoperative radiograph used to measure minimum joint space width. The outcomes in this study were achieving evidence-derived MCIDs in (1) pain, defined as a reduction of two points on an 11-point (0 = very little, 10 = worst imaginable) numerical rating scale (NRS) for hip-related pain or reporting a 1 year NRS-pain score of 0, and (2) function, defined as an increase equal to or greater than 8.3 on the SF-36 Physical Function subscore (range: 0 to 100; 0 = maximum disability, 100 = no disability) or reporting a 1-year SF-36 Physical Function subscore within the 95th percentile of scores in our cohort. All demographic variables, such as age, sex, country; surgical factors, including body mass index (BMI), surgical approach, acetabular liner type, and preoperative PROMs, were included as covariates in a binary logistic regression model. We used a backwards stepwise elimination algorithm to reach the simplest, best-fit model., Results: In the final analysis cohort of 594 patients, 54 patients (9%) did not achieve the MCID in pain and 146 (25%) patients did not achieve the MCID in physical function after THA. After controlling for potential confounding variables such as age, BMI, and preoperative PROMs, we found that higher joint space width (odds ratio (OR) = 2.19; 95% confidence interval (CI) = 1.49-3.22; p < 0.001), lower preoperative SF-36 Mental Component Summary (MCS) (OR = 0.95; 95% CI = 0.93-0.98; p = 0.001), and female sex (OR = 2.04; 95% CI = 1.08-3.82; p = 0.027) were associated with failing to achieve a MCID in pain. It is important to note that the effect size of having a higher preoperative SF-36 MCS is small, with a 1- or 10-point increase in SF-36 MCS decreasing the odds of a patient not achieving the pain MCID by 5% or 63%, respectively.In a separate multivariable model, after controlling for potential confounding variables such as age, BMI, and preoperative PROMs, we found that higher joint space width (OR = 1.54; 95% CI = 1.18-2.02; p = 0.002), higher preoperative Harris hip score (HHS) (OR = 1.01; 95% CI = 1.00-1.03; p = 0.019) and undergoing surgery in Scandinavia (OR = 1.73; 95% CI = 1.17-2.55; p = 0.006) were associated with failing to achieve a MCID in physical function. It is important to note that the effect size of having a higher preoperative HHS is very small, with a 1- or t10-point increase in HHS increasing the odds of not achieving the physical function MCID by only 1% or 15%, respectively., Conclusions: These findings suggest that surgeons should counsel patients with high joint space width, female patients, and patients undergoing surgery in Scandinavia that they may be much less likely to experience meaningful pain relief or functional improvement after THA, and in light of that, determine whether indeed surgery should be postponed or avoided in those patients. Lower SF-36 MCS score and higher HHS before surgery were also found to be associated with not achieving MCIDs in pain and physical function, respectively, after surgery, but both had relatively small effect sizes. Future prospective studies may consider exploring the relationship between less pain relief or functional improvement and the risk factors identified in this study, such as high joint space width, to validate our findings and determine if the variables we identified are truly predictive of worse postoperative outcomes. Future retrospective studies of regional or national registry data should use the analysis methods presented within this study to both identify the portion of the THA patients who do not achieve a MCID in pain or physical function after surgery and confirm if the preoperative risk factors for poor improvement identified within our international, multicenter cohort are also found in a larger patient population with more diverse implants and comorbidities., Level of Evidence: Level III, therapeutic study.

Background: Adverse local tissue reaction (ALTR) is not only a prominent cause of metal-on-metal (MoM) implant revision, but may also compromise the result of revision surgery. Patients treated with MoM arthroplasty and subsequently revised as a result of ALTR have been shown to experience worse patient-reported outcomes, inferior survivorship, and more complications when compared with patients receiving MoM implants who were revised for reasons other than ALTR. There is conflicting evidence as to whether the presence of symptoms is associated with ALTR in patients with MoM implants. Blood metal ions are associated with ALTR, but a consensus on appropriate thresholds associated with ALTR risk is lacking., Questions/purposes: (1) Was the presence of symptoms as measured by patient-reported outcome measures associated with ALTR presence and severity as noted on metal artifact reduction sequence (MARS)-MRI in patients treated with one design of MoM THA or hip resurfacing arthroplasty (HRA)? (2) Could reliable thresholds for blood metal ion levels be determined that were associated with ALTR presence on MARS-MRI?, Methods: This retrospective study presents a secondary analysis of data drawn from a prospective, international, multicenter study of the recalled Articular Surface Replacement (ASR) hip system. This larger study aims to identify risk factors for revision and provide followup guidelines for the many unrevised ASR patients. A total of 1721 patients were enrolled from 16 centers in six countries after the device was recalled and are followed annually for 5 years. In the present analysis, data from the enrollment visit (mean time from index surgery, 7.5 years; SD 3.5 years) were considered. Only patients from two centers conducting MARS-MRI on all patients regardless of clinical presentation as a standard of care were included to avoid selection bias. A total of 327 unilateral patients fulfilled our inclusion criteria (90% of those eligible). The level of symptoms was systematically determined using the Harris hip score and a visual analog scale for pain, and whole blood metal ion levels were collected from all patients. MARS-MRIs were analyzed by a single reader for ALTR presence (Anderson classification), diameter, and synovial thickness. A validation series of 35 MARS-MRIs indicated excellent intrareader reproducibility of the evaluations (intraclass correlation = 0.82) and substantial agreement (κ coefficient = 0.64) was achieved between the MARS-MRI reader and a musculoskeletal radiologist with > 10 years of experience with MARS-MRI. Binary logistic regression was used to determine variables independently associated with ALTR. Receiver operator characteristic curves were used to determine sensitive and specific cut points for cobalt and chromium., Results: After controlling for confounding variables, presence of symptoms was determined to be a risk factor for ALTR (odds ratio, 2.9; p = 0.007) in patients treated with ASR MoM THA. Moreover, among patients undergoing ASR MoM THA with ALTR, synovial thickness correlated with symptomaticity (p = 0.030). For patients undergoing ASR MoM HRA, we found no association between symptoms and ALTR prevalence or severity. A cobalt cutoff of 3.2 parts per billion (ppb) was associated with increased risk of ALTR (p < 0.001; sensitivity, 68%; specificity, 71%) in ASR MoM THA. In patients with ASR MoM HRA, a cobalt threshold of 2.9 ppb was indicative of ALTR (p < 0.001; sensitivity, 79%; specificity, 69%)., Conclusions: The risk factors identified in the current study may be used to stratify patients receiving MoM implants in terms of ALTR risk. We found that symptoms are associated with an increased likelihood of ALTR presence in ASR MoM THA and that cobalt ion level is associated with ALTR in ASR MoM THA as well as ASR MoM HRA. Importantly, MoM HRA followup protocols that exempt asymptomatic patients from annual followup are not justified because asymptomatic patients are no less likely to have ALTR than symptomatic patients. Blood metal ion levels may reliably be used to screen patients undergoing MoM HRA. For patients undergoing MoM THA, a combination of symptom state and blood metal ion levels may be used to determine ALTR risk., Level of Evidence: Level III, diagnostic study.

Since the first arthroplasty registries were established in the 1970s, they have become powerful tools in improving the efficiency of health care delivery and patient outcomes. As demonstrated over the past decades, registries can offer benefits not only to patients and surgeons but also to a variety of other stakeholders, such as hospitals, payers, and implant manufacturers. Registry data may be leveraged to address a variety of pressing concerns in the field of arthroplasty. These examples include the role of registries in (1) informing the financial aspects of an increasingly value-based payment system, (2) identifying best clinical practices, (3) improving the outcomes of individual health care providers, and (4) selecting new technologies through outlier detection and benchmarking. As registries continue to mature by improving data coverage and quality, they will play a central role in shaping the future of arthroplasty as well as orthopaedics in general.

: The intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs. SIGNIFICANCE: The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines., (©2018 American Association for Cancer Research.)

Aims: The primary aim of this study was to compare the wear properties of vitamin E-diffused, highly crosslinked polyethylene (VEPE) and one formulation of moderately crosslinked and mechanically annealed ultra-high molecular weight polyethylene (ModXLPE) in patients five years after primary total hip arthroplasty (THA). The secondary aim was to assess the clinical results of patients treated with VEPE by evaluating patient-reported outcome measures (PROMs), radiological evidence of fixation, and the incidence of mechanical failure., Patients and Methods: A total of 208 patients (221 THAs) from four international centres were recruited into a prospective study involving radiostereometric analysis (RSA) and the assessment of clinical outcomes. A total of 193 hips (87%) were reviewed at the five-year follow-up. Of these, 136 (70%) received VEPE (vs ModXLPE) liners and 68 (35%) received ceramic (vs metal) femoral heads. PROMs and radiographs were collected preoperatively and at one, two, and five years postoperatively. In addition, RSA images were collected to measure PE wear postoperatively and at one, two, and five years after surgery., Results: We observed similar bedding in one year postoperatively and wear two years postoperatively between the two types of liner. However, there was significantly more penetration of the femoral head in the ModXLPE cohort compared with the VEPE cohort five years postoperatively (p < 0.001). The only variables independently predictive of increased wear were ModXLPE (vs VEPE) liner type (β = 0.22, p = 0.010) and metal (vs ceramic) femoral head (β = 0.21, p = 0.013). There was no association between increased wear and the development of radiolucency (p = 0.866) or PROMs. No patient had evidence of osteolysis., Conclusion: Five years postoperatively, patients with VEPE (vs ModXLPE) and ceramic (vs metal) femoral heads had decreased wear. The rates of wear for both liners were very low and have not led to any osteolysis or implant failure due to aseptic loosening.

Background: The purpose of this study was to identify which patient and clinical factors are predictive of adverse local tissue reaction (ALTR) and to use these factors to create a highly sensitive algorithm for indicating metal artifact reduction sequence magnetic resonance imaging (MARS-MRI) in Articular Surface Replacement (ASR) XL total hip arthroplasty patients. Our secondary aim was to compare our algorithm to existing national guidelines on when to take MARS-MRI in metal-on-metal total hip arthroplasty patients., Methods: The study consisted of 137 patients treated with unilateral ASR XL implants from a prospective, multicenter study. Patients underwent MARS-MRI regardless of clinical presentation at a mean of 6.2 (range, 3.3-10.4) years from surgery. Univariate and multivariate analyses were conducted to determine which variables were predictive of ALTR. Predictors were used to create an algorithm to indicate MARS-MRI. Finally, we compared our algorithm's ability to detect ALTR to existing guidelines., Results: We found a visual analog scale pain score ≥2 (odds ratio [OR] = 2.53; P = .023), high blood cobalt (OR = 1.05; P = .023), and male gender (OR = 2.37; P = .034) to be significant predictors of ALTR presence in our cohort. The resultant algorithm achieved 86.4% sensitivity and 60.2% specificity in detecting ALTR within our cohort. Our algorithm had the highest area under the curve and was the only guideline that was significantly predictive of ALTR (P = .014)., Conclusion: Our algorithm including patient-reported pain and sex-specific cutoffs for blood cobalt levels could predict ALTR and indicate MARS-MRI in our cohort of ASR XL metal-on-metal patients with high sensitivity., Level of Evidence: Level II, diagnostic study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Recent registry studies show that aseptic loosening secondary to osteolysis is the second leading cause of hip implant failure in patients implanted with metal-on-metal (MoM) bearings. The primary aim of our study was to report on the progression of acetabular osteolysis during mid-term follow-up in patients treated with MoM hip resurfacing arthroplasty (HRA) and MoM total hip arthroplasty (THA). The secondary aim was to identify independent predictors of osteolytic lesion progression., Materials and Methods: A total of 805 patients (805 hips) were included in this study (541 MoM HRA, 264 MoM THA) from a prospective, international clinical registry of the Articular Surface Replacement Hip System. Patients were enrolled a median of 6.6 years from surgery. Osteolytic lesion progression was defined either as any lesion developing de novo, or as an existing lesion progressing from radiolucency to osteolysis during the study period (range 0.5-4.3 years)., Results: The number of cases with any osteolysis or radiolucency was 21 (3.9%) for ASR HRA and 29 (11.0%) for ASR XL THA at enrollment and increased to 69 (12.8%) for ASR HRA and 41 (15.5%) for ASR XL THA after follow-up. Osteolytic lesion progression was found in 66 (12.2%) ASR HRA patients and 31 (11.7%) ASR XL THA patients. Multivariate models determined that lower acetabular version angle (OR 0.963, p = 0.011) and elevated whole blood chromium (OR 1.110, p = 0.044) were independent predictors of osteolytic lesion progression in ASR HRA., Conclusion: We suggest that physicians of patients implanted with ASR HRA implants closely monitor patients with higher chromium levels and lower version angles, as they are at increased risk for osteolytic lesion progression, and we recommend annual radiographic follow-up on all patients with ASR implants.

Background: Currently, there are no universally accepted guidelines on when to obtain metal artifact reduction sequence magnetic resonance imaging (MARS-MRI) in metal-on-metal (MoM) hip resurfacing arthroplasty (HRA) patients. Our primary aims were to identify which patient and clinical factors are predictive of adverse local tissue reaction (ALTR) and create an algorithm for indicating MARS-MRI in patients with Articular Surface Replacement (ASR) HRA. The secondary aim was to compare our algorithm to existing guidelines on when to perform MARS-MRI in MoM HRA patients., Methods: The study cohort consisted of 182 patients with unilateral ASR HRA from a prospective, multicenter study. Subjects received MARS-MRI at a mean of 7.8 years from surgery, regardless of symptoms. We determined which variables were predictive of ALTR and generated cutoffs for each variable. Finally, we created an algorithm to predict ALTR and indicate MARS-MRI in ASR HRA patients using these cutoffs and compared it to existing guidelines., Results: We found high blood cobalt (Co) (odds ratio = 1.070; P = .011) and high blood chromium (Cr) (odds ratio = 1.162; P = .002) to be significant predictors of ALTR presence. Our algorithm using a blood Co cutoff of 1.15 ppb and a Cr cutoff of 1.09 ppb achieved 96.6% sensitivity and 35.3% specificity in predicting ALTR, which outperformed the existing guidelines., Conclusion: Blood Co and Cr levels are predictive of ALTR in ASR HRA patients. Our algorithm considering blood Co and Cr levels predicts ALTR in ASR HRA patients with higher sensitivity than previously established guidelines., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Data on the association between stem type and metal-on-metal (MoM) total hip arthroplasty (THA) performance are limited. The aim of this study is to investigate the effect of stem type on the prevalence of osteolysis and radiolucency, blood metal ion levels, and functional outcomes in patients with Articular Surface Replacement THA (ASR XL), a type of MoM THA., Methods: We analyzed 539 unilateral MoM THAs coupled with Summit (48%), Corail (35%), or S-ROM (17%) hip stems at a mean follow-up of 6.4 years. Fifty-four percent of the patients were male, and the mean age was 60 years. We studied radiographs, patient-reported outcome measures, and ion levels., Results: Patients with S-ROM hip stems were 3.8 times more likely to have osteolysis (P = .003) and 7.6 times more likely to have radiolucency (P < .001) than those treated with Summit hip stems. In addition, patients treated with S-ROM hip stems scored worse than those with Summit hip stems in 4 of the 5 patient-reported outcome measures: Harris Hip Score, Visual Analog Scale pain, University of California at Los Angeles activity, and EQ-5D index. All these differences were statistically significant and ranged from 5% to 10%, which is clinically significant., Conclusion: Patients with S-ROM hip stems had inferior functional and radiographic results compared to patients with Summit hip stems. Retrieval studies on large diameter head MoM THA and close follow-up of these patients with hip stems are needed to understand the mechanism causing the differences in outcomes between these stem types., (Copyright © 2017. Published by Elsevier Inc.)

Aims: Our first aim was to determine whether there are significant changes in the level of metal ions in the blood at mid-term follow-up, in patients with an Articular Surface Replacement (ASR) arthroplasty. Secondly, we sought to identify risk factors for any increases., Patients and Methods: The study involved 435 patients who underwent unilateral, metal-on-metal (MoM) hip resurfacing (HRA) or total hip arthroplasty (THA). These patients all had one measurement of the level of metal ions in the blood before seven years had passed post-operatively (early evaluation) and one after seven years had passed post-operatively (mid-term evaluation). Changes in ion levels were tested using a Wilcoxon signed-rank test. We identified subgroups at the highest risk of increase using a multivariable linear logistic regression model., Results: There were significant increases in the levels of metal ions for patients who underwent both MoM HRA (Chromium (Cr): 0.5 parts per billion (ppb); Cobalt (Co): 1.1 ppb) and MoM THA (Cr: 0.5 ppb; Co: 0.7 ppb). In a multivariable model considering MoM HRAs, the change in the levels of metal ions was influenced by female gender (Co: Odds Ratio (OR) 1.42; p = 0.002 and Cr: OR 1.08; p = 0.006). The change was found to be irrespective of the initial level for the MoM HRAs, whereas there was a negative relationship between the initial level and the change in the level for those with a MoM THA (Co: OR -0.43; p < 0.001 and Cr: OR -0.14; p = 0.033)., Conclusion: The levels of metal ions in the blood increase significantly over the period until mid-term follow-up in patients with both a MoM HRA and those with a MoM THA. We recommend that the levels of metal ions be measured most frequently for women with a MoM HRA. While those with a MoM THA appear to stabilise at a certain level, the accuracy of this trend is not yet clear. Vigilant follow-up is still recommended. Cite this article: Bone Joint J 2017;99-B(4 Supple B):33-40., (©2017 Galea et al.)

One function of the gut microbiota gaining recent attention, especially in herbivorous mammals and insects, is the metabolism of plant secondary metabolites (PSMs). We investigated whether this function exists within the gut communities of a specialist avian herbivore. We sequenced the cecal metagenome of the Greater Sage-Grouse (Centrocercus urophasianus), which specializes on chemically defended sagebrush (Artemisia spp.). We predicted that the cecal metagenome of the sage-grouse would be enriched in genes associated with the metabolism of PSMs when compared to the metagenome of the domestic chicken. We found that representation of microbial genes associated with 'xenobiotic degradation and metabolism' was 3-fold higher in the sage-grouse cecal metagenomes when compared to that of the domestic chicken. Further, we identified a complete metabolic pathway for the degradation of phenol to pyruvate, which was not detected in the metagenomes of the domestic chicken, bovine rumen or 14 species of mammalian herbivores. Evidence of monoterpene degradation (a major class of PSMs in sagebrush) was less definitive, although we did detect genes for several enzymes associated with this process. Overall, our results suggest that the gut microbiota of specialist avian herbivores plays a similar role to the microbiota of mammalian and insect herbivores in degrading PSMs., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Many plants produce plant secondary metabolites (PSM) that inhibit digestive enzymes of herbivores, thus limiting nutrient availability. In response, some specialist herbivores have evolved digestive enzymes that are resistant to inhibition. Monoterpenes, a class of PSMs, have not been investigated with respect to the interference of specific digestive enzymes, nor have such interactions been studied in avian herbivores. We investigated this interaction in the Greater Sage-Grouse (Phasianidae: Centrocercus urophasianus), which specializes on monoterpene-rich sagebrush species (Artemisia spp.). We first measured the monoterpene concentrations in gut contents of free-ranging sage-grouse. Next, we compared the ability of seven individual monoterpenes present in sagebrush to inhibit a protein-digesting enzyme, aminopeptidase-N. We also measured the inhibitory effects of PSM extracts from two sagebrush species. Inhibition of aminopeptidase-N in sage-grouse was compared to inhibition in chickens (Gallus gallus). We predicted that sage-grouse enzymes would retain higher activity when incubated with isolated monoterpenes or sagebrush extracts than chicken enzymes. We detected unchanged monoterpenes in the gut contents of free-ranging sage-grouse. We found that three isolated oxygenated monoterpenes (borneol, camphor, and 1,8-cineole) inhibited digestive enzymes of both bird species. Camphor and 1,8-cineole inhibited enzymes from chickens more than from sage-grouse. Extracts from both species of sagebrush had similar inhibition of chicken enzymes, but did not inhibit sage-grouse enzymes. These results suggest that specific monoterpenes may limit the protein digestibility of plant material by avian herbivores. Further, this work presents additional evidence that adaptations of digestive enzymes to plant defensive compounds may be a trait of specialist herbivores.

Effective long-term wildlife conservation planning for a species must be guided by information about population vital rates at multiple scales. Greater sage-grouse (Centrocercus urophasianus) populations declined substantially during the twentieth century, largely as a result of habitat loss and fragmentation. In addition to the importance of conserving large tracts of suitable habitat, successful conservation of this species will require detailed information about factors affecting vital rates at both the population and range-wide scales. Research has shown that sage-grouse population growth rates are particularly sensitive to hen and chick survival rates. While considerable information on hen survival exists, there is limited information about chick survival at the population level, and currently there are no published reports of factors affecting chick survival across large spatial and temporal scales. We analyzed greater sage-grouse chick survival rates from 2 geographically distinct populations across 9 years. The effects of 3 groups of related landscape-scale covariates (climate, drought, and phenology of vegetation greenness) were evaluated. Models with phenological change in greenness (NDVI) performed poorly, possibly due to highly variable production of forbs and grasses being masked by sagebrush canopy. The top drought model resulted in substantial improvement in model fit relative to the base model and indicated that chick survival was negatively associated with winter drought. Our overall top model included effects of chick age, hen age, minimum temperature in May, and precipitation in July. Our results provide important insights into the possible effects of climate variability on sage-grouse chick survival.

Population sex ratio is an important metric for wildlife management and conservation, but estimates can be difficult to obtain, particularly for sexually monomorphic species or for species that differ in detection probability between the sexes. Noninvasive genetic sampling (NGS) using polymerase chain reaction (PCR) has become a common method for identifying sex from sources such as hair, feathers or faeces, and is a potential source for estimating sex ratio. If, however, PCR success is sex-biased, naively using NGS could lead to a biased sex ratio estimator. We measured PCR success rates and error rates for amplifying the W and Z chromosomes from greater sage-grouse (Centrocercus urophasianus) faecal samples, examined how success and error rates for sex identification changed in response to faecal sample exposure time, and used simulation models to evaluate precision and bias of three sex assignment criteria for estimating population sex ratio with variable sample sizes and levels of PCR replication. We found PCR success rates were higher for females than males and that choice of sex assignment criteria influenced the bias and precision of corresponding sex ratio estimates. Our simulations demonstrate the importance of considering the interplay between the sex bias of PCR success, number of genotyping replicates, sample size, true population sex ratio and accuracy of assignment rules for designing future studies. Our results suggest that using faecal DNA for estimating the sex ratio of sage-grouse populations has great potential and, with minor adaptations and similar marker evaluations, should be applicable to numerous species., (© 2013 Blackwell Publishing Ltd.)

Animal habitat selection is a process that functions at multiple, hierarchically. structured spatial scales. Thus multi-scale analyses should be the basis for inferences about factors driving the habitat selection process. Vertebrate herbivores forage selectively on the basis of phytochemistry, but few studies have investigated the influence of selective foraging (i.e., fine-scale habitat selection) on habitat selection at larger scales. We tested the hypothesis that phytochemistry is integral to the habitat selection process for vertebrate herbivores. We predicted that habitats selected at three spatial scales would be characterized by higher nutrient concentrations and lower concentrations of plant secondary metabolites (PSMs) than unused habitats. We used the Greater Sage-Grouse (Centrocercus urophasianus), an avian herbivore with a seasonally specialized diet of sagebrush, to test our hypothesis. Sage-Grouse selected a habitat type (black sagebrush, Artemisia nova) with lower PSM concentrations than the alternative (Wyoming big sagebrush, A. tridentata wyomingensis). Within black sagebrush habitat, Sage-Grouse selected patches and individual plants within those patches that were higher in nutrient concentrations and lower in PSM concentrations than those not used. Our results provide the first evidence for multi-scale habitat selection by an avian herbivore on the basis of phytochemistry, and they suggest that phytochemistry may be a fundamental driver of habitat selection for vertebrate herbivores.

CHEK2 encodes a serine/threonine kinase (Chk2) activated by ATM in response to DNA double-strand breaks. On the one hand, CHEK2 has been described as a tumor suppressor with proapoptotic, cell-cycle checkpoint and mitotic functions. On the other hand, Chk2 is also commonly activated (phosphorylated at T68) in cancers and precancerous lesions. Here, we report an extensive characterization of CHEK2 across the panel of 60 established cancer cell lines from the NCI Anticancer Screen (the NCI-60) using genomic and proteomic analyses, including exon-specific mRNA expression, DNA copy-number variation (CNV) by aCGH, exome sequencing, as well as western blot analyses for total and activated (pT68-Chk2) Chk2. We show that the high heterogeneity of Chk2 levels in cancer cells is primarily due to its inactivation (owing to low gene expression, alternative splicing, point mutations, copy-number alterations and premature truncation) or reduction of protein levels. Moreover, we observe that a significant percentage of cancer cells (12% of the NCI-60 and HeLa cells) show high endogenous Chk2 activation, which is always associated with p53 inactivation, and which is accompanied by downregulation of the Fanconi anemia and homologous recombination pathways. We also report the presence of activated Chk2 (pT68-Chk2) along with histone γ-H2AX in centrosomes.

UCN-01 is undergoing Phase I evaluation and is a candidate for combination strategies in the clinic. UCN-01 has been shown to have a variety of effects on cellular targets and the cell cycle. It has also been reported to sensitize cells to several clinical drugs in vitro, possibly in a manner related to p53 status. Thus, combinations of UCN-01 with a series of clinical agents in variety of cell lines have been investigated in vitro. Certain cell lines demonstrated synergistic interactions with combinations of UCN-01 (20-150 nM) and thiotepa, mitomycin C, cisplatin, melphalan, topotecan, gemcitabine, fludarabine or 5-fluorouracil. In contrast, UCN-01 combinations with the antimitotic agents, paclitaxel and vincristine, or topoisomerase II inhibitors, adriamycin and etoposide, did not result in synergy, only in additive toxicity. Cells with non-functional p53 were significantly more susceptible to the supra-additive effects of certain DNA-damaging agents and UCN-01 combinations, than cells expressing functional p53 activity. In contrast, there was no significant relationship between p53 status and susceptibility to synergy between antimetabolites and UCN-01. The mechanism behind the observed synergy appeared unrelated to effects on protein kinase C or abrogation of the cell cycle in G2. Moreover, increased apoptosis did not fully explain the supradditive response. These data indicate that UCN-01 sensitizes a variety of cell lines to certain DNA-damaging agents (frequently covalent DNA-binding drugs) and antimetabolites in vitro, but the mechanism underlying this interaction remains undefined.