Cutibacterium acnes invades submicron osteocyte lacuno-canalicular networks following implant-associated osteomyelitis.

Cutibacterium acnes, part of normal skin flora, is increasingly recognized as an opportunistic pathogen capable of causing chronic prosthetic joint infections (PJI) associated with total hip and knee arthroplasty. However, there is a paucity of literature examining the pathogenesis of C. acnes during PJI. To study this, we developed an implant-associated osteomyelitis murine model in which 8-10-week-old C57BL6 mice were subjected to transtibial implantation of titanium or stainless-steel L-shaped pins contaminated with C. acnes. Postsurgery, mice were killed on Days 14 and 28 for terminal assessments of (1) bacterial load in bone, implant, and internal organs (heart, spleen, kidney, and liver), (2) bone osteolysis (micro-CT), (3) abscess formation (histology), and (4) systematic electron microscopy (EM). In vitro scanning EM (SEM) confirmed that C. acnes can form biofilms on stainless-steel and titanium implants. In mice, C. acnes could persist for 28 days in the tibia. Also, we observed C. acnes dissemination to internal organs. C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation compared to Staphylococcus aureus infections. Importantly, transmission EM (TEM) investigation revealed the presence of C. acnes within canaliculi, demonstrating that C. acnes can invade the osteocyte lacuno-canalicular networks (OLCN) within bone. Our preliminary pilot study, for the first time, revealed that the OLCN in bone can be a reservoir for C. acnes and potentially provides a novel mechanism of why C. acnes chronic implant-associated bone infections are difficult to treat.

Are Quality Scores in the Centers for Medicaid and Medicare Services Merit-based Incentive Payment System Associated With Outcomes After Outpatient Orthopaedic Surgery?

BACKGROUND: The Medicare Merit-based Incentive Payment System (MIPS) ties reimbursement incentives to clinician performance to improve healthcare quality. It is unclear whether the MIPS quality score can accurately distinguish between high-performing and low-performing clinicians. QUESTIONS/PURPOSES: (1) What were the rates of unplanned hospital visits (emergency department visits, observation stays, or unplanned admissions) within 7, 30, and 90 days of outpatient orthopaedic surgery among Medicare beneficiaries? (2) Was there any association of MIPS quality scores with the risk of an unplanned hospital visit (emergency department visits, observation stays, or unplanned admissions)? METHODS: Between January 2018 and December 2019, a total of 605,946 outpatient orthopaedic surgeries were performed in New York State according to the New York Statewide Planning and Research Cooperative System database. Of those, 56,772 patients were identified as Medicare beneficiaries and were therefore potentially eligible. A further 34% (19,037) were excluded because of missing surgeon identifier, age younger than 65 years, residency outside New York State, emergency department visit on the same day as outpatient surgery, observation stay on the same claim as outpatient surgery, and concomitant high-risk or eye procedures, leaving 37,735 patients for analysis. The database does not include a list of all state residents and thus does not allow for censoring of patients who move out of state. We chose this dataset because it includes nearly all hospitals and ambulatory surgery centers in a large geographic area (New York State) and hence is not limited by sampling bias. We included 37,735 outpatient orthopaedic surgical encounters among Medicare beneficiaries in New York State from 2018 to 2019. For the 37,735 outpatient orthopaedic surgical procedures included in our study, the mean ± standard deviation age of patients was 73 ± 7 years, 84% (31,550) were White, and 59% (22,071) were women. Our key independent variable was the MIPS quality score percentile (0 to 19th, 20th to 39th, 40th to 59th, or 60th to 100th) for orthopaedic surgeons. Clinicians in the MIPS program may receive a bonus or penalty based on the overall MIPS score, which ranges from 0 to 100 and is a weighted score based on four subscores: quality, promoting interoperability, improvement activities, and cost. The MIPS quality score, which attempts to reward clinicians providing superior quality of care, accounted for 50% and 45% of the overall MIPS score in 2018 and 2019, respectively. Our main outcome measures were 7-day, 30-day, and 90-day unplanned hospital visits after outpatient orthopaedic surgery. To determine the association between MIPS quality scores and unplanned hospital visits, we estimated multivariable hierarchical logistic regression models controlling for MIPS quality scores; patient-level (age, race and ethnicity, gender, and comorbidities), facility-level (such as bed size and teaching status), surgery and surgeon-level (such as surgical procedure and surgeon volume) covariates; and facility-level random effects. We then used these models to estimate the adjusted rates of unplanned hospital visits across MIPS quality score percentiles after adjusting for covariates in the multivariable models. RESULTS: In total, 2% (606 of 37,735), 2% (783 of 37,735), and 3% (1013 of 37,735) of encounters had an unplanned hospital visit within 7, 30, or 90 days of outpatient orthopaedic surgery, respectively. Most hospital visits within 7 days (95% [576 of 606]), 30 days (94% [733 of 783]), or 90 days (91% [924 of 1013]) were because of emergency department visits. We found very small differences in unplanned hospital visits by MIPS quality scores, with the 20th to 39th percentile of MIPS quality scores having 0.71% points (95% CI -1.19% to -0.22%; p = 0.004), 0.68% points (95% CI -1.26% to -0.11%; p = 0.02), and 0.75% points (95% CI -1.42% to -0.08%; p = 0.03) lower than the 0 to 19th percentile at 7, 30, and 90 days, respectively. There was no difference in adjusted rates of unplanned hospital visits between patients undergoing surgery with a surgeon in the 0 to 19th, 40th to 59th, or 60th to 100th percentiles at 7, 30, or 90 days. CONCLUSION: We found that the rates of unplanned hospital visits after outpatient orthopaedic surgery among Medicare beneficiaries were low and primarily driven by emergency department visits. We additionally found only a small association between MIPS quality scores for individual physicians and the risk of an unplanned hospital visit after outpatient orthopaedic surgery. These findings suggest that policies aimed at reducing postoperative emergency department visits may be the best target to reduce overall postoperative unplanned hospital visits and that the MIPS program should be eliminated or modified to more strongly link reimbursement to risk-adjusted patient outcomes, thereby better aligning incentives among patients, surgeons, and the Centers for Medicare ad Medicaid Services. Future work could seek to evaluate the association between MIPS scores and other surgical outcomes and evaluate whether annual changes in MIPS score weighting are independently associated with clinician performance in the MIPS and regarding clinical outcomes. LEVEL OF EVIDENCE: Level III, therapeutic study.

Short-Term (6 Months or Less) Pain in Cemented versus Cementless Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: Cementless total knee arthroplasty (TKA) has increased in popularity to potentially improve survivorship. Radiostereometric studies demonstrate increased component migration during the first 3 to 6 months in cementless constructs, generating concern for increased postoperative pain during early osseointegration. The purpose of this study was to evaluate short-term (≤ 6 months) pain and function in cemented versus cementless TKA. We hypothesized that cementless TKA patients report increased pain during the short-term (≤ 6 months) postoperative period. METHODS: The MEDLINE, EMBASE, CINAHL, and Cochrane Libraries were searched for studies evaluating short-term (≤ 6 months) outcomes of cemented versus cementless primary TKA. Studies involving hybrid fixation were excluded. A meta-analysis was performed using standardized mean difference for primary outcomes (early postoperative pain) and weighted mean difference (WMD) for secondary outcomes (early postoperative function). RESULTS: There were eleven studies included. There was no significant difference in acute postoperative pain between cemented and cementless TKA within 6 months of index TKA (standardized mean difference 0.08 in favor of cemented TKA; P = .10). Early postoperative forgotten joint scores (WMD 0.81; P = .81) and knee injury and osteoarthritis outcome scores for joint replacement (WMD 0.80 in favor of cemented TKA; P = .14) were also similar between groups. CONCLUSIONS: There is no difference in short-term (≤ 6 months) pain or early function between patients receiving cemented and cementless TKA. This suggests that surgeons may utilize cementless TKA without fear of increased pain due to micromotion within 6 months of index arthroplasty. However, additional studies with uniform assessment methods are needed to further inform differences in short-term pain and early functional outcomes between cemented and cementless TKA.

Association of race and ethnicity with opioid prescribing for Medicare beneficiaries following total joint replacements.

BACKGROUND: Profound racial and ethnic disparities exist in the use and outcomes of total hip/knee replacements (total joint replacements [TJR]). Whether similar disparities extend to post-TJR pain management remains unknown. Our objective is to examine the association of race and ethnicity with opioid fills following elective TJRs for White, Black, and Hispanic Medicare beneficiaries. METHODS: We used the 2019 national Medicare data to identify beneficiaries who underwent total hip/knee replacements. Primary outcomes were at least one opioid fill in the period from discharge to 30 days post-discharge, and 31-90 days following discharge. Secondary outcomes were morphine milligram equivalent per day and number of opioid fills. Key independent variable was patient race-ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic). We estimated multivariable hierarchical logistic regressions and two-part models with state-level clustering. RESULTS: Among 67,550 patients, 93.36% were White, 3.69% were Black, and 2.95% were Hispanic. Compared to White patients, more Black patients and fewer Hispanic patients filled an opioid script (84.10% [Black] and 80.11% [Hispanic] vs. 80.33% [White], p < 0.001) in the 30-day period. On multivariable analysis, Black patients had 18% higher odds of filling an opioid script in the 30-day period (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 1.05-1.33, p = 0.004), and 39% higher odds in the 31-90-day period (OR: 1.39, 95% CI: 1.26-1.54, p < 0.001). There were no significant differences in the endpoints between Hispanic and White patients in the 30-day period. However, Hispanic patients had 20% higher odds of filling an opioid script in the 31- to 90-day period (OR: 1.20, 95% CI: 1.07-1.34, p = 0.002). CONCLUSIONS: Important race- and ethnicity-based differences exist in post-TJR pain management with opioids. The mechanisms leading to the higher use of opioids by racial/ethnic minority patients need to be carefully examined.

Incidence and Risk Factors for Revision Within 1 Year of Primary Carpal Tunnel Release.

BACKGROUND: The annual volume of carpal tunnel release (CTR) in the United States has been estimated to be 577 000 per year. Our objectives were to evaluate the incidence and risk factors for revision CTR within 1 year of primary CTR. METHODS: We identified all adult patients undergoing primary CTR from October 2015 to September 2019 in the New York Statewide Planning and Research Cooperative System database using Current Procedural Terminology (CPT) codes. We used the CPT modifier codes to determine laterality of index and revision procedures. We estimated multivariable hierarchical logistic regression models to evaluate risk factors for revision CTR within 1 year. RESULTS: Of the 80 423 primary CTR procedures, 178 (0.22%) underwent a revision CTR within 1 year of the index surgery. The mean (SD) age of the entire cohort was 58.69 (14.43) years, 61.1% were women, 73.2% were non-Hispanic white, 42.9% were covered through private insurance, and 9.5% had diabetes mellitus. Workers' compensation insurance (odds ratio [OR] = 1.83, 95% confidence interval [CI], 1.13-2.98, P = .02) and simultaneous bilateral CTR (OR = 14.91, 95% CI, 9.62-23.12, P < .001) were associated with revision CTR within 1 year of the index procedure. No models demonstrated an association between endoscopic technique or surgeon volume and revision CTR. CONCLUSIONS: The incidence of revision CTR within 1 year was lower than that previously reported. Patients covered by workers' compensation and those undergoing simultaneous bilateral CTR had higher likelihood of a revision CTR within 1 year, whereas endoscopic technique and surgeon volume were not associated with revision CTR within 1 year.

Disparities in the Epidemiology and Management of Fragility Hip Fractures.

PURPOSE OF REVIEW: The purpose of this review is to synthesize the recently published scientific evidence on disparities in epidemiology and management of fragility hip fractures. RECENT FINDINGS: There have been a number of investigations focusing on the presence of disparities in the epidemiology and management of fragility hip fractures. Race-, sex-, geographic-, socioeconomic-, and comorbidity-based disparities have been the primary focus of these investigations. Comparatively fewer studies have focused on why these disparities may exist and interventions to reduce disparities. There are widespread and profound disparities in the epidemiology and management of fragility hip fractures. More studies are needed to understand why these disparities exist and how they can be addressed.

Association of Total Knee Replacement Removal From the Inpatient-Only List With Outpatient Surgery Utilization and Outcomes in Medicare Patients.

Importance: Little is known about the association of total knee replacement (TKR) removal from the Medicare inpatient-only (IPO) list in 2018 with outcomes in Medicare patients. Objective: To evaluate (1) patient factors associated with outpatient TKR use and (2) whether the IPO policy was associated with changes in postoperative outcomes for patients undergoing TKR. Design, Setting, and Participants: This cohort study included data from administrative claims from the New York Statewide Planning and Research Cooperative System. Included patients were Medicare fee-for-service beneficiaries undergoing TKRs or total hip replacements (THRs) in New York State from 2016 to 2019. Multivariable generalized linear mixed models were used to identify patient factors associated with outpatient TKR use, and with a difference-in-differences strategy to examine association of the IPO policy with post-TKR outcomes relative to post-THR outcomes in Medicare patients. Data analysis was performed from 2021 to 2022. Exposures: IPO policy implementation in 2018. Main Outcomes and Measures: Use of outpatient or inpatient TKR; secondary outcomes included 30-day and 90-day readmissions, 30-day and 90-day postoperative emergency department visits, non-home discharge, and total cost of the surgical encounter. Results: A total of 37 588 TKR procedures were performed on 18 819 patients from 2016 to 2019, with 1684 outpatient TKR procedures from 2018 to 2019 (mean [SD] age, 73.8 [5.9] years; 12 240 female [65.0%]; 823 Hispanic [4.4%], 982 non-Hispanic Black [5.2%], 15 714 non-Hispanic White [83.5%]). Older (eg, age 75 years vs 65 years: adjusted difference, -1.65%; 95% CI, -2.31% to -0.99%), Black (-1.44%; 95% CI, -2.81% to -0.07%), and female patients (-0.91%; 95% CI, -1.52% to -0.29%), as well as patients treated in safety-net hospitals (disproportionate share hospital payments quartile 4: -18.09%; 95% CI, -31.81% to -4.36%), were less likely to undergo outpatient TKR. After IPO policy implementation in the TKR cohort, there were lower adjusted 30-day readmissions (adjusted difference [AD], -2.11%; 95% CI, -2.73% to -1.48%; P < .001), 90-day readmissions ( -3.23%; 95% CI, -4.04% to -2.42%; P < .001), 30-day ED visits ( -2.45%; 95% CI, -3.17% to -1.72%; P < .001), 90-day ED visits (-4.01%; 95% CI, -4.91% to -3.11%; P < .001) and higher cost per encounter ($2988; 95% CI, $415 to $5561; P = .03). However, these changes did not differ from changes in the THR cohort except for increased TKR cost of $770 per encounter ($770; 95% CI, $83 to $1457; P = .03) relative to THR. Conclusions and Relevance: In this cohort study of patients undergoing TKR and THR, we found that older, Black, and female patients and patients treated in safety-net hospitals may have had lesser access to outpatient TKRs highlighting concerns of disparities. IPO policy was not associated with changes in overall health care use or outcomes after TKR, except for an increase of $770 per TKR encounter.

Using MaxDiff Analysis to Elicit Patients' Treatment Preferences for Distal Radius Fractures in Patients Aged 60 Years and Older.

PURPOSE: The objective of our study was to determine how the attributes of surgical and nonsurgical distal radius fracture (DRF) treatments affect patient treatment preferences. METHODS: Two hundred fifty patients aged 60 years and older were contacted from a single-hand surgeon's practice, and 172 chose to participate. We built a series of best-worst scaling experiments for the MaxDiff analysis to determine the relative importance of treatment attributes. Hierarchical Bayes analysis was used to generate individual-level item scores (ISs) for each attribute that together have a total sum of 100. RESULTS: One hundred general hand clinic patients without a history of a DRF and 43 patients with a history of a DRF completed the survey. For the general hand clinic patients, the most important attributes to avoid when choosing a DRF treatment (in descending order) were the longer time to full recovery (IS, 24.9; 95% confidence interval [CI]: 23.4-26.3), longer time spent in a cast (IS, 22.8; 95% CI, 21.5-24.2), and higher complication rates (IS, 18.4; 95% CI, 16.9-19.8). Meanwhile, for patients with a history of a DRF, the most important attributes to avoid (in descending order) were a longer time to full recovery (IS, 25.6; 95% CI, 23.3-27.9), longer time spent in a cast (IS, 22.8; 95% CI, 19.9-25.7), and abnormal alignment of the radius on x-ray (IS, 18.3; 95% CI, 15.4-21.3). For both the groups, the least concerning attributes based on the IS were appearance-scar, appearance-bump, and the need for anesthesia. CONCLUSIONS: Eliciting patient preferences is a vital component of shared decision-making and advancing patient-centered care. As conceptualized in this MaxDiff analysis, when choosing a DRF treatment, patients mostly want to avoid a longer time to full recovery and a longer time in a cast, whereas patients have the least concern about appearance and need for anesthesia. CLINICAL RELEVANCE: Eliciting patient preferences is a vital component of shared decision-making. Our results may provide guidance to surgeons in discussions on the relative benefits of surgical and nonsurgical DRF treatments, by quantifying the most and least important factors to patients.

What Factors Are Associated With Revision Cubital Tunnel Release Within 3 Years?

BACKGROUND: It has been shown that patient demographics such as age, payer factors such as insurance type, clinical characteristics such as preoperative opioid use, and disease grade but not surgical procedure are associated with revision surgery to treat cubital tunnel syndrome. However, prior studies evaluating factors associated with revision surgery after primary cubital tunnel release have been relatively small and have involved patients from a single institution or included only a single payer. QUESTIONS/PURPOSES: (1) What percentage of patients who underwent cubital tunnel release underwent revision within 3 years? (2) What factors are associated with revision cubital tunnel release within 3 years of primary cubital tunnel release? METHODS: We identified all adult patients who underwent primary cubital tunnel release from January 1, 2011, to December 31, 2017, in the New York Statewide Planning and Research Cooperative System database using Current Procedural Terminology codes. We chose this database because it includes all payers and nearly all facilities in a large geographic area where cubital tunnel release may be performed. We used Current Procedural Terminology modifier codes to determine the laterality of primary and revision procedures. The mean age of the cohort overall was 53 ± 14 years, 43% (8490 of 19,683) were women, and 73% (14,308 of 19,683) were non-Hispanic White. The Statewide Planning and Research Cooperative System database organization does not include a listing of all state residents and thus does not allow for censoring of patients who move out of state. All patients were followed for 3 years. We developed a multivariable hierarchical logistic regression model to model factors independently associated with revision cubital tunnel release within 3 years. Key explanatory variables included age, gender, race or ethnicity, insurance, patient residential location, medical comorbidities, concomitant procedures, whether the procedure was unilateral or bilateral, and year. The model also controlled for facility-level random effects to account for the clustering of observations among these entities. RESULTS: The risk of revision cubital tunnel release within 3 years of the primary procedure was 0.7% (141 of 19,683). The median time to revision cubital tunnel release was 448 days (interquartile range 210 to 861 days). After controlling for patient-level covariates and facility random effects, and compared with their respective counterparts, the odds of revision surgery were higher for patients with workers compensation insurance (odds ratio 2.14 [95% confidence interval 1.38 to 3.32]; p < 0.001), a simultaneous bilateral index procedure (OR 12.26 [95% CI 5.93 to 25.32]; p < 0.001), and those who underwent submuscular transposition of the ulnar nerve (OR 2.82 [95% CI 1.35 to 5.89]; p = 0.006). The odds of revision surgery were lower with increasing age (OR 0.79 per 10 years [95% CI 0.69 to 0.91]; p < 0.001) and a concomitant carpal tunnel release (OR 0.66 [95% CI 0.44 to 0.98]; p = 0.04). CONCLUSION: The risk of revision cubital tunnel release was low. Surgeons should be cautious when performing simultaneous bilateral cubital tunnel release and when performing submuscular transposition in the setting of primary cubital tunnel release. Patients with workers compensation insurance should be informed they are at increased odds for undergoing subsequent revision cubital tunnel release within 3 years. Future work may seek to better understand whether these same effects are seen in other populations. Future work might also evaluate how these and other factors such as disease severity could affect functional outcomes and the trajectory of recovery. LEVEL OF EVIDENCE: Level III, therapeutic study.

Risk Factors for Failed Nonsurgical Treatment Resulting in Surgery on Thumb Carpometacarpal Arthritis.

PURPOSE: The thumb carpometacarpal (CMC) joint is the second most common site of osteoarthritis in the hand, yet reported symptoms and ultimate treatment decisions are not simply a function of radiographic appearance. This study aimed to determine the patient- and/or disease-related factors associated with patients undergoing surgical treatment of thumb CMC arthritis. METHODS: This retrospective cohort study analyzed 1,994 patients with thumb CMC arthritis treated at 2 institutions between February 2015 and November 2018. Patient demographic and clinical information was obtained from medical records to characterize treatment modalities before hand surgeon evaluation, mental and physical comorbidities, and Patient-Reported Outcomes Measurement Information System assessments. After bivariate analysis, a multivariable logistic regression model evaluated factors associated with undergoing thumb CMC surgery. RESULTS: This cohort was predominately female (70%) and white (91%), mean age at first appointment, 62 ± 10 years. A total of 170 patients underwent surgery for thumb CMC arthritis (9%) at a median of 114 days (interquartile range, 27-328) after the first visit. Patient-Reported Outcomes Measurement Information System Depression scores correlated with Pain Interference and Physical Function scores. A history of diagnosed depression or anxiety was associated with less perceived Physical Function at presentation. However, only prior contralateral thumb CMC surgery, younger patient age, and treating institution were associated with undergoing surgery in regression modeling. CONCLUSIONS: Pain and functional limitations associated with thumb CMC arthritis are influenced by mental health comorbidities, but these factors do not predict surgical treatment. Instead, patients' prior surgical experience and surgeon attitudes toward thumb CMC arthritis appear to have a strong influence on the odds of patients undergoing surgery for thumb CMC arthritis. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Pelvic rotation after total hip arthroplasty is dynamic and variable.

AIMS: The aims of this study were to determine the change in the sagittal alignment of the pelvis and the associated impact on acetabular component position at one-year follow-up after total hip arthroplasty (THA). METHODS: This study represents the one-year follow-up of a previous short-term study at our institution. Using the patient population from our prior study, the radiological pelvic ratio was assessed in 91 patients undergoing THA, of whom 50 were available for follow-up of at least one year (median 1.5; interquartile range (IQR) 1.1 to 2.0). Anteroposterior radiographs of the pelvis were obtained in the standing position preoperatively and at one year postoperatively. Pelvic ratio was defined as the ratio between the vertical distance from the inferior sacroiliac (SI) joints to the superior pubic symphysis and the horizontal distance between the inferior SI joints. Apparent acetabular component position changes were determined from the change in pelvic ratio. A change of at least 5° was considered clinically meaningful. RESULTS: Pelvic ratio decreased (posterior tilt) in 54.0% (27) of cases, did not change significantly in 34.0% (17) of cases, and increased (anterior tilt) in 12.0% (6) of cases when comparing preoperative to one-year postoperative radiographs. This would correspond with 5° to 10° of abduction error in 22.0% of cases and > 10° of error in 6.0%. Likewise, this would correspond with 5° to 10° of version error in 22.0% of cases and > 10° of error in 44.0%. CONCLUSION: Pelvic sagittal alignment is dynamic and variable after THA, and these changes persist to the one-year postoperative period, altering the orientation of the acetabular component. Surgeons who individualize the acetabular component placement based on preoperative functional radiographs should consider that the rotation of the pelvis (and thus the component version and inclination) changes one year postoperatively. Cite this article: Bone Joint J 2020;102-B(7 Supple B):47-51.

Utility of Serum Biomarkers in the Diagnosis and Stratification of Mild Traumatic Brain Injury.

OBJECTIVE: The objective was to compare test characteristics of a single serum concentration of glial fibrillary acidic protein (GFAP), S-100ß, and ubiquitin carboxyl terminal hydrolase L1 (UCH-L1), obtained within 6 hours of head injury, to diagnose mild traumatic brain injury (mTBI) in head-injured subjects. METHODS: Adults aged 18 to 80 years who presented to one of seven EDs with a blunt closed head injury underwent head CT within 4 hours of injury and had blood drawn for biomarker analysis within 6 hours of injury were eligible. Subjects were considered to have mTBI if they had an initial Glasgow Coma Scale (GCS) > 13 and met one or more of the following criteria: loss of consciousness (LOC), posttraumatic amnesia, or confusion. Subjects with mTBI and an abnormal head computed tomography (CT) scan were categorized as complicated mTBI; those with a normal head CT were categorized as uncomplicated mTBI; and subjects with a GCS = 15, no LOC, no posttraumatic amnesia, and no confusion were considered to not have a mTBI. Biomarker concentration measurements for GFAP and UCH-L1 were performed using an enzyme-linked immunosorbent assay. S-100ß concentration was determined using an electrochemiluminescence immunoassay. Median biomarker concentration for each group was compared using the Kruskal-Wallis test. Logistic regression was used to determine area under the receiver operating curve (AUC) for each of the three biomarkers. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and negative and positive likelihood ratios (LRs) for the three biomarkers to differentiate between complicated mTBI, uncomplicated mTBI, and no mTBI were calculated. RESULTS: A total of 247 subjects were enrolled and had adequate clinical and biomarker information for analysis. A total of 188 met criteria for mTBI, with 34 (18.1%) having an acute abnormality on CT (complicated mTBI). The mean (±SD) age of the study population was 45.8 (±17.3) years, and 59.9% were male. Median serum concentrations for all biomarkers were significantly different between groups, lowest in the no mTBI group, and progressively increasing in the uncomplicated and complicated mTBI groups (p < 0.0001). All three biomarkers were significant classifiers of mTBI versus no mTBI, with the following AUCs: GFAP, 0.70; S-100ß, 0.69; and UCH-L1, 0.65 (p = 0.17). Sensitivity for mTBI was highest for S-100ß (96.5%). NPVs ranged from 31% for UCH-L1 to 35% for GFAP. PPVs ranged from 75.5% for S-100ß to 96.5% for GFAP. Negative LR ranged from 0.59 for GFAP to 0.71 for UCH-L1, with positive LR ranging from 1.0 for both UCH-L1 and S-100ß to 8.7 for GFAP. CONCLUSION: A single serum concentration of GFAP, UCH-L1, or S-100ß within 6 hours of head injury may be useful in identifying and stratifying the severity of brain injury in emergency department patients with head trauma, but cannot reliably exclude a diagnosis of concussion. A positive GFAP was associated with the presence of concussion.

Cell autonomous or systemic EGFR blockade alters the immune-environment in squamous cell carcinomas.

Targeting mutations and amplifications in the EGFR has been successful precision therapy for cancers of the lung, oral cavity and gastrointestinal track. However, a systemic immune reaction manifested by dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To address the possibility that intra-tumoral immune changes contribute to the anti-cancer activity of EGFR inhibition, squamous cancers were produced by syngeneic orthografts of either EGFR null or wildtype mouse primary keratinocytes transduced with an oncogenic H-ras retrovirus. Flow cytometric, RNA and Bioplex immunoassay analyses of the tumor immune milieu were performed. Cancers forming from keratinocytes genetically depleted of EGFR were smaller than wildtype cancers and had fewer infiltrating FoxP3 Treg cells, lower Foxp3 RNA and a lower percentage of CD4 PD1 positive cells indicating a tumor cell autonomous regulation of its microenvironment. Hosts bearing wildtype cancers treated with gefitinib for 1 week showed a trend for smaller tumors. In this short term pharmacological model, there was also a trend to reduced FoxP3 cells and FoxP3 RNA in the tumors of treated mice as well as a substantial increase in the ratio of IL-1A/IL-1RA transcripts. These results suggest that relatively brief systemic inhibition of EGFR signaling alters the immune environment of the targeted cancer. Together these data imply that an EGFR dependent Treg function supports the growth of squamous cancers and is a target for the therapeutic activity of EGFR inhibition.

Accelerated partial breast irradiation through brachytherapy for ductal carcinoma in situ: factors influencing utilization and risks of second breast tumors.

The purpose of this study was to examine influencing factors and outcomes of accelerated partial breast irradiation through brachytherapy (APBIb) versus whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS). From the Surveillance Epidemiology and End Results program of the US National Cancer Institute, we identified 40,749 women who were diagnosed with first primary DCIS between 2002 and 2011 and treated with breast-conserving surgery and radiotherapy. A multi-level logistic regression analysis was performed to estimate odds ratios of APBIb use. Hazard ratios (HRs) of developing ipsilateral breast tumors (IBTs) and contralateral breast tumors (CBTs) were analyzed in 1962 patients with APBIb and 7203 propensity score-matched patients with WBI, using Cox proportional hazards regression. Overall, 2212 (4.5 %) of 40,749 women (the whole cohort) received APBIb. Factors associated with the increased use of APBIb included older age, non-Hispanic white race/ethnicity, smaller tumor size, hormone receptor positivity, comedo subtypes, and urban residence. During the 46-month follow-up, 74 (0.8 %) and 131 (1.4 %) of 9165 propensity score-matched patients developed IBTs and CBTs, respectively. Compared with WBI, APBIb was associated with a significantly increased risk of IBTs (HR 1.74; 95 % CI 1.06-2.85) but not CBTs (OR 0.91; 95 % CI 0.59-1.41). This population-based study suggests that APBIb use for DCIS was influenced by patient and tumor characteristics as well as urbanization of residence. We observed a moderately increased IBT risk associated with APBIb versus WBI, suggesting that APBIb should be used with caution for DCIS before data from randomized controlled trials with long-term follow-ups are available.