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Author Correction: Hox gene expression determines cell fate of adult periosteal stem/progenitor cells
Bradaschia-Correa, Vivian; Leclerc, Kevin; Josephson, Anne M; Lee, Sooyeon; Palma, Laura; Litwa, Hannah P; Neibart, Shane S; Huo, Jason C; Leucht, Philipp
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
PMID: 32066822
ISSN: 2045-2322
CID: 4312062
Readmissions are Not What They Seem: Incidence and Classification of 30-Day Readmissions Following Orthopedic Trauma Surgery
Kelly, Erin A; Gonzalez, Leah J; Hutzler, Lorraine; Konda, Sanjit R; Leucht, Philipp; Egol, Kenneth A
OBJECTIVES/OBJECTIVE:To evaluate the causes of 30-day readmissions following orthopedic trauma surgery and classify them based on their relation to the index admission. DESIGN/METHODS:Retrospective chart review. SETTING/METHODS:One large, academic medical center. PARTICIPANTS/METHODS:Patients admitted to a large, academic medical center for a traumatic fracture injury over a nine-year period. INTERVENTION/METHODS:Assignment of readmission classification. MAIN OUTCOME MEASUREMENTS/METHODS:Readmissions within 30 days of discharge were identified and classified into: orthopedic complications; medical complications; and non-complications. A chi-square test was performed to assess any difference in the proportion of readmissions between the hospital-reported readmission rate and the orthopedic complication readmission rate. RESULTS:1,955 patients who were admitted between 2011-2018 for an acute orthopedic trauma fracture injury were identified. Eighty-nine patients were readmitted within 30 days of discharge with an overall readmission rate of 4.55%. Within the 30-day readmission cohort, 30 (33.7%) were the direct result of orthopedic treatment complications, 36 (40.4%) were unrelated medical conditions, and 23 (25.8%) were non-complications. Thus, the readmission rate directly due to orthopedic treatment complications was 1.53%. A chi-square test of homogeneity revealed a statistically significant difference between the hospital-reported readmission rate and the orthopedic-treatment complication readmission rate, p < .0005. CONCLUSION/CONCLUSIONS:The use of 30-day readmissions as a measure of hospital quality of care overreports the number of preventable readmissions and penalizes surgeons and hospitals for caring for patients with less optimal health. LEVEL OF EVIDENCE/METHODS:Diagnostic Level III.
PMID: 31652186
ISSN: 1531-2291
CID: 4161882
The 2019 American-British-Canadian (ABC) Traveling Fellowship
Chen, Antonia F; Dulai, Sukhdeep K; Grewal, Ruby; Kelly, Derek; Lee, Michael; Leucht, Philipp; Mir, Hassan
PMID: 31596817
ISSN: 1535-1386
CID: 4129792
What's New in Musculoskeletal Basic Science
Leucht, Philipp; Einhorn, Thomas A
PMID: 31800419
ISSN: 1535-1386
CID: 4218662
KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone
Tassone, Evelyne; Bradaschia-Correa, Vivian; Xiong, Xiaozhong; Sastre-Perona, Ana; Josephson, Anne Marie; Khodadadi-Jamayran, Alireza; Melamed, Jonathan; Bu, Lei; Kahler, David J; Ossowski, Liliana; Leucht, Philipp; Schober, Markus; Wilson, Elaine L
We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.
PMID: 31239516
ISSN: 1476-5594
CID: 3953842
Radiographic union score for tibia fractures predicts success with operative treatment of tibial nonunion
Christiano, Anthony V; Goch, Abraham M; Leucht, Philipp; Konda, Sanjit R; Egol, Kenneth A
Background/UNASSIGNED:The purpose of this study is to evaluate the ability of preoperative and postoperative radiographic union scores for tibia fractures (RUST) to predict treatment success of tibia fracture nonunion. Materials and methods/UNASSIGNED:Patients presenting for operative treatment of tibia fracture nonunion were enrolled in a prospective data registry. Enrolled patients were followed at regular intervals for 12 months. Preoperative and 12 week postoperative radiographs were reviewed and scored using the RUST criteria. Postoperative time to union was determined by clinical and radiographic measures. Multivariate regressions were conducted to predict time to union using preoperative and postoperative RUST while controlling for treatment method. Receiver operating characteristic (ROC) curve was conducted to determine the accuracy of preoperative RUST in predicting failure of treatment. Results/UNASSIGNED:Sixty-eight patients with aseptic tibia fracture nonunion treated operatively were identified. Sixty-one patients achieved union. Mean preoperative RUST was 7.5 (SD 1.4). Mean postoperative RUST was 9.2 (SD 1.4). Multivariate linear regressions demonstrated that preoperative (p = 0.043) and postoperative (p = 0.007) RUST are significant predictors of time to union after tibia fracture nonunion surgery. ROC curve demonstrated preoperative RUST below 7 was a good predictor of developing persistent tibia fracture nonunion (AUC = 0.83, Sensitivity = 1.000, Specificity = 0.745). Conclusions/UNASSIGNED:RUST preoperatively and postoperatively predicts outcome after nonunion surgery. RUST can be used as part of the complete clinical picture to shape patient expectations and guide treatment.
PMCID:6611993
PMID: 31316233
ISSN: 0976-5662
CID: 3986102
Age-related inflammation triggers skeletal stem/progenitor cell dysfunction
Josephson, Anne Marie; Bradaschia-Correa, Vivian; Lee, Sooyeon; Leclerc, Kevin; Patel, Karan S; Muinos Lopez, Emma; Litwa, Hannah P; Neibart, Shane S; Kadiyala, Manasa; Wong, Madeleine Z; Mizrahi, Matthew M; Yim, Nury L; Ramme, Austin J; Egol, Kenneth A; Leucht, Philipp
Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.
PMID: 30894483
ISSN: 1091-6490
CID: 3735202
Final outcomes of radial nerve palsy associated with humeral shaft fracture and nonunion
Belayneh, Rebekah; Lott, Ariana; Haglin, Jack; Konda, Sanjit; Leucht, Philipp; Egol, Kenneth
BACKGROUND:Little evidence regarding the extent of recovery of radial nerve lesions with associated humerus trauma exists. The aim of this study is to examine the incidence and resolution of types of radial nerve palsy (RNP) in operative and nonoperative humeral shaft fracture populations. MATERIALS AND METHODS/METHODS:Radial nerve lesions were identified as complete (RNPc), which included motor and sensory loss, and incomplete (RNPi), which included sensory-only lesions. Charts were reviewed for treatment type, radial nerve status, RNP resolution time, and follow-up time. Descriptive statistics were used to document incidence of RNP and time to resolution. Independent-samples t-test was used to determine significant differences between RNP resolution time in operative and nonoperative cohorts. RESULTS:A total of 175 patients (77 operative, 98 nonoperative) with diaphyseal humeral shaft injury between 2007 and 2016 were identified and treated. Seventeen out of 77 (22.1%) patients treated operatively were diagnosed preoperatively with a radial nerve lesion. Two (2.6%) patients developed secondary RNPc postoperatively. Eight out of 98 (8.2%) patients presented with RNP postinjury for nonoperatively treated humeral shaft fracture. All patients who presented with either RNPc, RNPi, or iatrogenic RNP had complete resolution of their RNP. No statistically significant difference was found in recovery time when comparing the operative versus nonoperative RNPc, operative versus nonoperative RNPi, or RNPc versus RNPi patient groups. CONCLUSIONS:All 27 (100%) patients presenting with or developing radial nerve palsy in our study recovered. No patient required further surgery for radial nerve palsy. Radial nerve exploration in conjunction with open reduction and internal fixation (ORIF) appears to facilitate speedier resolution of RNP when directly compared with observation in nonoperative cases, although not statistically significantly so. These findings provide surgeons valuable information they can share with patients who sustain radial nerve injury with associated humerus shaft fracture or nonunion. LEVEL OF EVIDENCE/METHODS:Level III treatment study.
PMID: 30923949
ISSN: 1590-9999
CID: 3777502
Surgical Delay Is Not Warranted for Patients With Hip Fractures Receiving Non-Warfarin Anticoagulants
Lott, Ariana; Haglin, Jack; Belayneh, Rebekah; Konda, Sanjit R; Leucht, Philipp; Egol, Kenneth A
The purpose of this study was to evaluate whether patients with hip fractures receiving antiplatelet and direct oral anticoagulants treated within 48 hours of admission had worse surgical and clinical outcomes than those whose surgery was delayed more than 48 hours. Consecutive patients 55 years and older with an operatively treated hip fracture were analyzed. Patients receiving the following anticoagulants were included: antiplatelet drugs, factor Xa inhibitors, and direct thrombin inhibitors. Outcomes included surgical blood loss, procedure time, transfusion requirement, length of stay, complication rate, and need for intensive care unit or step-down unit level care. Patients who underwent surgery within 48 hours of presentation were compared with patients whose surgery was delayed more than 48 hours. Of 551 consecutive operative hip fracture patients, 78 (14.2%) were receiving the anticoagulant medications included in this study. Of these 78 patients, 58 had surgery within 48 hours and 20 had surgery after 48 hours. When comparing the early and delayed fixation cohorts, there was no difference in transfusion requirement, length of surgery, or blood loss. Type of anticoagulant made no difference in transfusion requirement, blood loss, or length of surgery. There was also no difference in the mean number of complications or in the need for intensive care unit or step-down unit level care. In this study, patients receiving antiplatelet therapy, factor Xa inhibitors, or direct thrombin inhibitors who underwent surgical fixation of their hip fracture within 48 hours of admission were at no higher risk for transfusion, increased surgical blood loss, longer operative time, or inpatient mortality. [Orthopedics. 201x; xx(x):xx-xx.].
PMID: 30913296
ISSN: 1938-2367
CID: 3776962
Hox gene expression determines cell fate of adult periosteal stem/progenitor cells
Bradaschia-Correa, Vivian; Leclerc, Kevin; Josephson, Anne M; Lee, Sooyeon; Palma, Laura; Litwa, Hannah P; Neibart, Shane S; Huo, Jason C; Leucht, Philipp
Hox genes are evolutionarily conserved transcription factors that during embryonic development function as master regulators of positional identity. In postnatal life, the function of Hox proteins is less clear: Hox genes are expressed during tissue repair, but in this context their function(s) are largely unknown. Here we show that Hox genes are expressed in periosteal stem/progenitor cells in a distribution similar to that during embryonic development. Using unbiased sequencing, we established that periosteal stem/progenitor cells from distinct anatomic sites within the skeleton significantly differ in their transcriptome, and that Hox expression status best defines these differences. Lastly, we provide evidence that Hox gene expression is one potential mechanism that maintains periosteal stem/progenitor cells in a more primitive, tripotent state, while suppression of Hox genes leads to fate changes with loss of tripotency. Together, our data describe an adult role of Hox genes other than positional identity, and the modulatory role of Hox genes in fate decisions may offer potential druggable targets for the treatment of fractures, non-unions and bone defects.
PMID: 30911091
ISSN: 2045-2322
CID: 3776882