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Systemic NF-κB-mediated inflammation promotes an aging phenotype in skeletal stem/progenitor cells

Josephson, Anne Marie; Leclerc, Kevin; Remark, Lindsey H; Lopeź, Emma Muiños; Leucht, Philipp
Aging tissues undergo a progressive decline in regenerative potential. This decline in regenerative responsiveness has been attributed to changes in tissue-specific stem cells and their niches. In bone, aged skeletal stem/progenitor cell dysfunction is characterized by decreased frequency and impaired osteogenic differentiation potential. This aging phenotype ultimately results in compromised regenerative responsiveness to injury. The age-associated increase of inflammatory mediators, known as inflamm-aging, has been identified as the main culprit driving skeletal stem cell dysfunction. Here, we utilized a mouse model of parabiosis to decouple aging from inflammation. Using the Nfkb1-/- mouse as a model of inflamm-aging, we demonstrate that a shared systemic circulation between a wild-type and Nfkb1-/- mouse results in an aging phenotype of the wild-type skeletal stem and progenitor cells, shown by CFU-fs and osteogenic and adipogenic differentiation assays. Our findings demonstrate that exposure to an inflammatory secretome results in a phenotype similar to the one observed in aging.
PMID: 34035186
ISSN: 1945-4589
CID: 4887802

The Influence of Selective Serotonin Reuptake Inhibitors on Lumbar Arthrodesis

Pirkle, Sean; Bhattacharjee, Sarah; El Dafrawy, Mostafa; Leucht, Philipp; Shi, Lewis L; Lee, Michael J
STUDY DESIGN/METHODS:Retrospective analysis using the PearlDiver national insurance claims database. OBJECTIVE:To investigate the relationship between chronic preoperative selective serotonin reuptake inhibitor (SSRI) prescriptions and nonunion following spine fusion surgery. SUMMARY OF BACKGROUND DATA/BACKGROUND:Contemporary literature has linked SSRIs to decreased bone mineral density and increased rates of future bone fracture. Furthermore, a recent murine model has suggested a potential role in the quality of fracture healing itself. METHODS:All single-level lumbar fusion patients were identified. The rate of nonunion diagnosis between 6 and 24 months following surgery was assessed. A stratified analysis of chronic SSRI use and a number of comorbidities was conducted, followed by a multiple logistic regression analysis of nonunion accounting for qualifying risk factors. Finally, subanalyses of individual procedure codes were carried out. RESULTS:In total, 7905 single-level lumbar fusion patients were included. In the multivariate analysis, chronic SSRI [odds ratio (OR): 1.558, P=0.004] and tobacco use (OR: 1.500, P=0.011) were identified as independent risk factors for nonunion, whereas patient age over 60 years (OR: 0.468, P<0.001) was observed to be negatively associated with nonunion. In the individual procedure subanalyses, SSRIs were significantly associated with nonunion in 2 of 3 univariate analyses and observed to be an independent risk factor for nonunion in 2 of the 3 procedure populations. CONCLUSIONS:These data suggest that patients treated concomitantly for mental health disorders with SSRIs before arthrodesis may be at an increased risk of postoperative nonunion. Closer follow-up may be indicated in this patient population.
PMID: 32991364
ISSN: 2380-0194
CID: 4616722

Clinical outcomes of a combined osteoligamentous reconstruction technique of Neer Type IIB distal clavicle fractures

Perskin, Cody R; Tejwani, Nirmal C; Jazrawi, Laith M; Leucht, Philipp; Egol, Kenneth A
Purpose/UNASSIGNED:To evaluate outcomes for a combined osteoligamentous reconstruction technique for Neer Type IIB clavicle fractures. Methods/UNASSIGNED:Patients with Neer Type IIB clavicle fractures treated with combined clavicular locking plate and coracoclavicular ligament suture reconstruction were identified. Demographics, clinical outcomes, and radiographic outcomes were collected. Results/UNASSIGNED:Twenty-four patients with mean 13 months of follow-up were included. Bony union and normal radiographic coracoclavicular relationship were achieved in 23 (96%) patients. The mean UCLA Shoulder score was 33.3. Three (13%) complications occurred. Discussion/UNASSIGNED:The combined osteoligamentous reconstruction approach as described is a successful option for treating Neer Type IIB clavicle fractures.
PMCID:8131854
PMID: 34025057
ISSN: 0972-978x
CID: 4887462

How are peri-implant fractures below short versus long cephalomedullary nails different?

Goodnough, L Henry; Salazar, Brett P; Furness, Jamie; Feng, James E; DeBaun, Malcolm R; Campbell, Sean T; Lucas, Justin F; Cross, William W; Leucht, Philipp; Grant, Kevin D; Gardner, Michael J; Bishop, Julius A
BACKGROUND:Cephalomedullary nails are a commonly used implant for the treatment of many pertrochanteric femur fractures and are available in short and long configurations. There is no consensus on ideal nail length. Relative advantages can be ascribed to short and long intramedullary nails, yet both implant styles share the potentially devastating complication of peri-implant fracture. Determining the clinical sequelae after fractures below nails of different lengths would provide valuable information for surgeons choosing between short or long nails. Thus, the purpose of the study was to compare injury patterns and treatment outcomes following peri-implant fractures below short or long cephalomedullary nails. METHODS:This was a multicenter retrospective cohort study that identified 33 patients referred for treatment of peri-implant fractures below short and long cephalomedullary nails (n = 19 short, n = 14 long). We compared fracture pattern, treatment strategy, complications, and outcomes between these two groups. RESULTS:Short nails were associated with more diaphyseal fractures (odds ratio [OR] 13.75, CI 2.2-57.9, p 0.002), which were treated more commonly with revision intramedullary nailing (OR, infinity; p 0.01), while long nails were associated with distal metaphyseal fractures (OR 13.75, CI 2.2-57.9, p 0.002), which were treated with plate and screw fixation (p 0.002). After peri-implant fracture, there were no differences in blood loss, operative time, weight bearing status, or complication rates based on the length of the initial nail. In patients treated with revision nailing, there was greater estimated blood loss (EBL, median 300 cc, interquartile range [IQR] 250-1200 vs median 200 cc, IQR 100-300, p 0.03), blood product utilization and complication rates (OR 11.1, CI 1.1-135.7, p 0.03), but a trend toward unrestricted post-operative weight-bearing compared to patients treated with plate and screw constructs. CONCLUSION/CONCLUSIONS:Understanding fracture patterns and patient outcomes after fractures below nails of different lengths will help surgeons make more informed implant choices when treating intertrochanteric hip fractures. Revision to a long nail for the treatment of fractures at the tip of a short nail may be associated with increased patient morbidity.
PMID: 32909108
ISSN: 1633-8065
CID: 4589362

The Impact of Subspecialty Fellows on Orthopaedic Resident Surgical Experience: A Multicenter Study of 51,111 Cases

Jiang, Sam Y; Carlock, Kurtis D; Campbell, Sean T; Vorhies, John S; Gardner, Michael J; Leucht, Philipp; Bishop, Julius A
INTRODUCTION/BACKGROUND:Meaningful participation in surgery is important for orthopaedic resident education. This study aimed to quantify the effect of fellows on resident surgical experience. We hypothesized that as fellowship programs expanded, resident caseload would decrease, whereas "double-scrubbed" cases would increase. METHODS:This multicenter retrospective study included 9 years of surgical caselog data from two orthopaedic residency programs. Six subspecialty services on which fellow number varied over time were included (trauma, spine, foot and ankle, adult reconstruction, and hand). Case volume and personnel composition per case were extracted. Statistical analysis was performed with two-sample equal variance Student t-tests. RESULTS:A total of 51,111 cases were assessed. Surgical volume increased across all sites/services over time. Fellow numbers did not affect average resident caseload. However, in years with more fellows, an 11% decrease in one-on-one resident-attending cases (P = 0.002) and a 17% increase in resident-fellow-attending "double-scrubbed" cases was observed (P < 0.001). DISCUSSION/CONCLUSIONS:Increasing orthopaedic fellows did not affect resident case volume but resulted in fewer one-on-one cases with the attending and more "double-scrubbed" cases with a fellow. The implications of these findings to resident education require further study, but orthopaedic educators should be aware of these findings to try to maximize educational opportunities. LEVEL OF EVIDENCE/METHODS:Level III.
PMID: 32649442
ISSN: 1940-5480
CID: 4518382

What's New in Musculoskeletal Basic Science

Leucht, Philipp; Einhorn, Thomas A
PMID: 33079894
ISSN: 1535-1386
CID: 4693452

Radiographic Humerus Union Measurement (RHUM) Demonstrates High Inter- and Intraobserver Reliability in Assessing Humeral Shaft Fracture Healing

Christiano, Anthony V; Goch, Abraham M; Burke, Christopher J; Leucht, Philipp; Konda, Sanjit R; Egol, Kenneth A
Background/UNASSIGNED:Orthopedic surgeons use radiographs to determine degrees of fracture healing, guide progression of clinical care, and assist in determining weight bearing and removal of immobilization. However, no gold standard exists to determine the progression of healing of humeral shaft fractures treated non-operatively. Purpose/UNASSIGNED:The purpose of this study was to determine whether a scale comparable to the modified Radiographic Union Score for Tibial (RUST) fractures applied to non-operatively treated humeral shaft fractures can increase interobserver reliability in determining fracture healing. Methods/UNASSIGNED:A retrospective review was undertaken by three orthopedic traumatologists and one musculoskeletal radiologist, who evaluated 50 sets of anteroposterior and lateral radiographs, presented at random, of non-operatively treated humeral shaft fractures at various stages of healing from 17 patients. The radiographs were scored using a modified RUST scale called the Radiographic Humerus Union Measurement (RHUM). Observers were blinded to the time from injury. After a 4-week washout period, observers again scored the same radiographs. Observers classified each fracture as either healed or not healed based on the combination of radiographs. Inter- and intraobserver reliability of the RHUM were determined using an intraclass correlation coefficient (ICC). Interobserver reliability of determining a healed fracture was calculated using Cohen's kappa (κ) statistics. A receiver operator characteristic curve was conducted to determine the RHUM score predictive of a fracture being considered healed. Results/UNASSIGNED:ICC demonstrated almost perfect interobserver reliability (ICC, 0.838; ICC 95% CI, 0.765 to 0.896) and intraobserver reliability (ICC range, 0.822 to 0.948) of the RHUM. κ demonstrated substantial agreement between observers in considering a fracture healed (κ = 0.647). Receiver operating characteristic (ROC) curve demonstrated that a RHUM of 10 or higher is an excellent predictor of the observer considering the fracture healed (area under the ROC curve = 0.946, specificity = 0.957, 95% CI specificity, 0.916 to 0.979). Conclusions/UNASSIGNED:This cortical scoring system has excellent interobserver reliability in humeral shaft fractures treated non-operatively. Consistent with previous cortical scoring systems, a RHUM score of 10 or above can be considered radiographically healed.
PMCID:7749905
PMID: 33380949
ISSN: 1556-3316
CID: 4731882

PPARγ agonists delay age-associated metabolic disease and extend longevity

Xu, Lingyan; Ma, Xinran; Verma, Narendra; Perie, Luce; Pendse, Jay; Shamloo, Sama; Marie Josephson, Anne; Wang, Dongmei; Qiu, Jin; Guo, Mingwei; Ping, Xiaodan; Allen, Michele; Noguchi, Audrey; Springer, Danielle; Shen, Fei; Liu, Caizhi; Zhang, Shiwei; Li, Lingyu; Li, Jin; Xiao, Junjie; Lu, Jian; Du, Zhenyu; Luo, Jian; Aleman, Jose O; Leucht, Philipp; Mueller, Elisabetta
Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.
PMCID:7681041
PMID: 33219735
ISSN: 1474-9726
CID: 4679992

Modification of a Validated Risk Stratification Tool to Characterize Geriatric Hip Fracture Outcomes and Optimize Care in a Post-COVID-19 World

Konda, Sanjit R; Ranson, Rachel A; Solasz, Sara J; Dedhia, Nicket; Lott, Ariana; Bird, Mackenzie L; Landes, Emma K; Aggarwal, Vinay K; Bosco, Joseph A; Furgiuele, David L; Gould, Jason; Lyon, Thomas R; McLaurin, Toni M; Tejwani, Nirmal C; Zuckerman, Joseph D; Leucht, Philipp; Ganta, Abhishek; Egol, Kenneth A
OBJECTIVES:(1) To demonstrate how a risk assessment tool modified to account for the COVID-19 virus during the current global pandemic is able to provide risk assessment for low-energy geriatric hip fracture patients. (2) To provide a treatment algorithm for care of COVID-19 positive/suspected hip fractures patients that accounts for their increased risk of morbidity and mortality. SETTING:One academic medical center including 4 Level 1 trauma centers, 1 university-based tertiary care referral hospital, and 1 orthopaedic specialty hospital. PATIENTS/PARTICIPANTS:One thousand two hundred seventy-eight patients treated for hip fractures between October 2014 and April 2020, including 136 patients treated during the COVID-19 pandemic between February 1, 2020 and April 15, 2020. INTERVENTION:The Score for Trauma Triage in the Geriatric and Middle-Aged ORIGINAL (STTGMAORIGINAL) score was modified by adding COVID-19 virus as a risk factor for mortality to create the STTGMACOVID score. Patients were stratified into quartiles to demonstrate differences in risk distribution between the scores. MAIN OUTCOME MEASUREMENTS:Inpatient and 30-day mortality, major, and minor complications. RESULTS:Both STTGMA score and COVID-19 positive/suspected status are independent predictors of inpatient mortality, confirming their use in risk assessment models for geriatric hip fracture patients. Compared with STTGMAORIGINAL, where COVID-19 patients are haphazardly distributed among the risk groups and COVID-19 inpatient and 30 days mortalities comprise 50% deaths in the minimal-risk and low-risk cohorts, the STTGMACOVID tool is able to triage 100% of COVID-19 patients and 100% of COVID-19 inpatient and 30 days mortalities into the highest risk quartile, where it was demonstrated that these patients have a 55% rate of pneumonia, a 35% rate of acute respiratory distress syndrome, a 22% rate of inpatient mortality, and a 35% rate of 30 days mortality. COVID-19 patients who are symptomatic on presentation to the emergency department and undergo surgical fixation have a 30% inpatient mortality rate compared with 12.5% for patients who are initially asymptomatic but later develop symptoms. CONCLUSION:The STTGMA tool can be modified for specific disease processes, in this case to account for the COVID-19 virus and provide a robust risk stratification tool that accounts for a heretofore unknown risk factor. COVID-19 positive/suspected status portends a poor outcome in this susceptible trauma population and should be included in risk assessment models. These patients should be considered a high risk for perioperative morbidity and mortality. Patients with COVID-19 symptoms on presentation should have surgery deferred until symptoms improve or resolve and should be reassessed for surgical treatment versus definitive nonoperative treatment with palliative care and/or hospice care. LEVEL OF EVIDENCE:Prognostic Level III. See Instructions for Authors for a complete description of Levels of Evidence.
PMID: 32815845
ISSN: 1531-2291
CID: 4574902

Increased Mortality and Major Complications in Hip Fracture Care During the COVID-19 Pandemic: A New York City Perspective

Egol, Kenneth A; Konda, Sanjit R; Bird, Mackenzie L; Dedhia, Nicket; Landes, Emma K; Ranson, Rachel A; Solasz, Sara J; Aggarwal, Vinay K; Bosco, Joseph A; Furgiuele, David L; Ganta, Abhishek; Gould, Jason; Lyon, Thomas R; McLaurin, Toni M; Tejwani, Nirmal C; Zuckerman, Joseph D; Leucht, Philipp
OBJECTIVES/OBJECTIVE:To examine one health system's response to the essential care of its hip fracture population during the COVID-19 pandemic and report on its effect on patient outcomes. DESIGN/METHODS:Prospective cohort study SETTING:: Seven musculoskeletal care centers with New York City and Long Island. PATIENTS/PARTICIPANTS/METHODS:138 recent and 115 historical hip fracture patients. INTERVENTION/METHODS:Patients with hip fractures occurring between February 1, 2020 and April 15, 2020 or between February 1, 2019 and April 15, 2019 were prospectively enrolled in an orthopedic trauma registry and chart reviewed for demographic and hospital quality measures. Patients with recent hip fractures were identified as COVID positive (C+), COVID suspected (Cs) or COVID negative (C-). MAIN OUTCOME MEASUREMENTS/METHODS:Hospital quality measures, inpatient complications and mortality rates. RESULTS:Seventeen (12.2%) patients were confirmed C+ by testing and another 14 (10.1%) were suspected (Cs) of having had the virus but were never tested. The C+ cohort, when compared to Cs and C- cohorts, had: an increased mortality rate (35.3% vs 7.1% vs 0.9%), increased length of hospital stay, a greater major complication rate and a greater incidence of ventilator need postoperatively. CONCLUSIONS:COVID-19 had a devastating effect on the care of hip fracture patients during the pandemic. Although practice patterns generally remained unchanged, treating physicians need to understand the increased morbidity and mortality in hip fracture patients complicated by COVID-19. LEVEL OF EVIDENCE/METHODS:Prognostic Level III. See Instructions for Authors for a complete description of Levels of Evidence.
PMID: 32482976
ISSN: 1531-2291
CID: 4468782