Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.

During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108 - CX3CR1 + effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108 + CX3CR1 + state. These Ly108 + CX3CR1 + cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells.

HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells.

The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1α in T cells (HIF1α-/-) and glycolytic inhibition significantly abrogate IFN-γ induction. Conversely, HIF1α stabilization in T cells by hypoxia and VHL deletion (VHL-/-) promotes IFN-γ production. Mechanistically, reduced IFN-γ production in hypoxic HIF1α-/- T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1α-/- T cells are less able to kill tumor cells, and HIF1α-/- tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1α in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-γ production in hypoxic HIF1α-/- T cells and re-sensitizes HIF1α-/- tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1α-anaerobic glycolysis as a principal mediator of IFN-γ induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need.

In Vivo Analysis of Acromioclavicular Kinematics and Distance During Multiplanar Humeral Elevation.

BACKGROUND: Knowledge of acromioclavicular (AC) joint kinematics and distance may provide insight into the biomechanical function and development of new treatment methods. However, accurate data on in vivo AC kinematics and distance between the clavicle and acromion remain unknown. PURPOSE/HYPOTHESIS: The purpose of this study was to investigate 3-dimensional AC kinematics and distance during arm elevation in abduction, scaption, and forward flexion in a healthy population. It was hypothesized that AC kinematics and distance would vary with the elevation angle and plane of the arm. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 19 shoulders of healthy participants were enrolled. AC kinematics and distance were investigated with a combined dual fluoroscopic imaging system and computed tomography. Rotation and translation of the AC joint were calculated. The AC distance was measured as the minimum distance between the medial border of the acromion and the articular surface of the distal clavicle (ASDC). The minimum distance point (MDP) ratio was defined as the length between the MDP and the posterior edge of the ASDC divided by the anterior-posterior length of the ASDC. AC kinematics and distance between different elevation planes and angles were compared. RESULTS: Progressive internal rotation, upward rotation, and posterior tilt of the AC joint were observed in all elevation planes. The scapula rotated more upward relative to the clavicle in abduction than in scaption (P = .002) and flexion (P = .005). The arm elevation angle significantly affected translation of the AC joint. The acromion translated more laterally and more posteriorly in scaption than in abduction (P < .001). The AC distance decreased from the initial position to 75° in all planes and was significantly greater in flexion (P < .001). The MDP ratio significantly increased with the elevation angle (P < .001). CONCLUSION: Progressive rotation and significant translation of the AC joint were observed in different elevation planes. The AC distance decreased with the elevation angle from the initial position to 75°. The minimum distance between the ASDC and the medial border of the acromion moved anteriorly as the shoulder elevation angle increased. CLINICAL RELEVANCE: These results could serve as benchmark data for future studies aiming to improve the surgical treatment of AC joint abnormalities to restore optimal function.

Adipose-derived mesenchymal stem cells (MSCs) are a superior cell source for bone tissue engineering.

Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors, osteoinductive biofactors and biocompatible scaffold materials. Mesenchymal stem cells (MSCs) represent the most promising seed cells for bone tissue engineering. As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat, MSCs can be isolated from numerous tissues and exhibit varied differentiation potential. To identify an optimal progenitor cell source for bone tissue engineering, we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources, including immortalized mouse embryonic fibroblasts (iMEF), immortalized mouse bone marrow stromal stem cells (imBMSC), immortalized mouse calvarial mesenchymal progenitors (iCAL), and immortalized mouse adipose-derived mesenchymal stem cells (iMAD). We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro, whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair. Transcriptomic analysis revealed that, while each MSC line regulated a distinct set of target genes upon BMP9 stimulation, all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt, TGF-ß, PI3K/AKT, MAPK, Hippo and JAK-STAT pathways. Collectively, our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.

The relationship between preoperative opioid use and adverse events following total shoulder arthroplasty.

Introduction: Few studies have analyzed the effect of preoperative opioid use on postoperative outcomes after total shoulder arthroplasty (TSA). Methods: Patients undergoing TSA were identified in the Pearldiver Humana Claims Dataset and stratified by level of preoperative opioid use. Primary outcomes were 90-day complications, readmissions, and revision surgery. Chi-square test and ANOVA were used to evaluate categorical and continuous variables respectively. A multivariable logistic regression analysis and a sub analysis excluding fracture as a primary diagnosis were completed. Results: 18,791 patients underwent aTSA and rTSA including 9933 opioid naïve patients, 3016 sporadic opioid users and 5842 persistent opioid users. Significant differences were found in complications (6.0% vs 6.1% vs 9.1%, p < .001), readmission (7.6% vs 8.2% vs 12.6%, p < .001), and revision procedures (1.1% vs 1.1% vs 2.3%, p < .001) which remained significant after excluding fractures. After adjusting for comorbidity burden, persistent opioid use was associated with increased likelihood of complications (OR 1.4, 1.2-1.6), readmission (OR 1.6, 1.5-1.8) and revision procedures (OR 1.9, 1.5-2.4). This association remained after excluding fractures. Conclusion: Persistent preoperative opioid use is associated with increased risk of early postoperative complications, readmission, and revision surgery for patients undergoing shoulder arthroplasty.

Optimal Treatment of Proximal Humeral Fractures in the Elderly: Risks and Management Challenges.

Proximal humeral fractures (PHFs) are a common type of fracture, particularly in older adults, accounting for approximately 5-6% of all fractures. This article provides a comprehensive review of PHFs, focusing on epidemiology, injury mechanism, clinical and radiographic assessment, classification systems, and treatment options. The incidence of PHFs varies across regions, with rates ranging from 45.7 to 60.1 per 100,000 person-years. Females are more susceptible to PHFs than males, and the incidence is highest in women over the age of 85. The injury mechanism of PHFs is typically bimodal, with high-energy injuries predominant in younger individuals and low-energy injuries in the elderly. Clinical assessment of PHFs involves obtaining a thorough history, physical examination, and evaluation of associated injuries, particularly neurovascular injuries. Radiographic imaging helps assess fracture displacement and plan for treatment. The Neer classification system is the most commonly used classification for PHFs, although other systems, such as AO/OTA, Codman-Hertel, and Resch classifications, also exist. The choice of treatment depends on factors such as patient age, activity level, fracture pattern, and surgeon expertise. Nonoperative management is typically preferred for elderly patients with minimal displacement, while operative fixation is considered for more complex fractures. Nonoperative treatment involves sling immobilization followed by physiotherapy, with good outcomes reported for certain fracture patterns. Operative management options include closed reduction and percutaneous pinning (CRPP), open reduction and internal fixation (ORIF), or arthroplasty. CRPP is suitable for specific fracture patterns, but the quality of reduction is crucial for favorable outcomes. ORIF is used when CRPP is not feasible, and various surgical approaches are available, each with its advantages and potential complications. PHFs are a significant clinical challenge due to their prevalence and complexity. Treatment decisions should be patient centered based on patient factors and fracture severity.

Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases.

Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Corrigendum to "Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)" [Genes & Diseases 4 (2017) 229-239].

[This corrects the article DOI: 10.1016/j.gendis.2017.10.004.].

National Benchmarks for the Efficacy of Trigger Finger and the Risk Factors Associated With Failure.

BACKGROUND: The purpose of this study was to compare the efficacy of single and multiple corticosteroid injections used for symptomatic trigger finger. The rates of subsequent injections and the rate of tendon sheath release are reported along with the identification of risk factors correlated with failure of injection. METHODS: A retrospective review of a national healthcare database was conducted identifying patients with a diagnosis of trigger finger or thumb. Inclusion required a tendon sheath injection on the same day or within six weeks of diagnosis. Patient cohorts were further stratified based on treatment success and those requiring additional injections within 6 months or surgery within 1 year of initial diagnosis. RESULTS: Thirty-one thousand seven hundred fifty-one patients met inclusion criteria and underwent an initial injection within the study period. The efficacy of initial, second, and third injection was 66.3%, 79.4%, and 79.6%, respectively. Of the patients who failed an injection, 9.4% had tendon sheath release after a primary injection, 23.1% had surgery after a second injection, and 30.4% had surgery after a third injection. Only obesity (OR 1.2; P < 0.0001) and concomitant diagnosis of carpal tunnel syndrome (OR 1.4; P < 0.0001) were found to be significant for injection failure on multivariate logistic regression analysis. DISCUSSION: Overall corticosteroid injections were effective in greater than 65% of patients. This information may help guide treatment practice because there seems to be continued additional benefit to repeat corticosteroid injections after injection failure.

HiJAKing Immunotherapy-Resistant Melanoma for a Cure.

Immune checkpoint blockers (ICBs) have brought great promise to patients with advanced melanoma, a tumor type that was claimed largely incurable not long ago. However, therapeutic resistance to ICBs has limited their utility in the clinic. Here, we provide a commentary on recent research endeavors concerning ICB resistance in melanoma patients.

Proximal Humerus Fractures: Leave It Alone, Fix It, Replace It?

Proximal humerus fractures are common injuries that account for 10% of all fractures in the elderly. Several options are available for the management of proximal humerus fractures. Optimal treatment is based on the fracture pattern and the patient characteristics. Most of these fractures are minimally displaced and managed nonsurgically. Approximately 15% of proximal humerus fractures are comminuted, head-split, fracture-dislocation, or severely displaced, which make the best treatment option more challenging. Hemiarthroplasty is still a viable option in selected patients of these groups; however, advancements in locking plate designs and introduction of reverse total shoulder arthroplasty have led to better clinical outcome in meticulously selected patients. Nonetheless, the debate continues regarding the best management. It is important to discuss the best treatment options based on current literature.

Total hip arthroplasty after acetabular fractures in the older population: timing of intervention may improve patient outcomes.

PURPOSE: This study evaluates complication rates following treatment modalities of THA for acetabular fractures in the older population. METHODS: A national insurance database was used to identify acetabular fracture patients of age > 50 who underwent THA treatment within two years of fracture. Four subgroups were identified: primary THA < 2 months after injury (acute THA), primary THA > 2 months after injury (delayed THA), simultaneous ORIF and THA, and conversion THA after ORIF (THA after ORIF). A 3:1 match was performed between these subgroups and patients undergoing THA for non-fracture causes. Patients were matched based on age, gender and the diagnosis of diabetes, hypertension, obesity or tobacco use. Complication rates were compared, including hospital readmission, revision, infection and deep vein thrombosis (DVT). RESULTS: In total, 3807 patients met inclusion criteria and were matched with 11,421 controls. Compared to controls, acute THA and delayed THA patients had significantly increased rates of all complications (OR ranges 1.45 - 2.82, p < 0.001). Simultaneous ORIF and THA and THA after ORIF patients had significantly increased rates of revision, infection and DVT (OR ranges 1.76 - 3.96, p ranges < 0.001 - p = 0.031). Compared to delayed THA, acute THA patients had significantly higher rates of readmission (OR = 1.16, p = 0.021) and DVT (OR = 1.89, p < 0.001). CONCLUSION: Consistent with prior literature, THA after acetabular fracture is associated with higher complication rates than THA for non-fracture causes. Acute THA following acetabular fracture is also associated with higher rates of readmission and DVT than delayed THA.

Surgical Outcomes, Trends, and Risk Factors of Distal Triceps Repairs.

BACKGROUND: Distal triceps ruptures are rare, and complete ruptures are commonly treated with surgery. Studies of patients in small cohorts with distal triceps tear have reported outcomes and risk factors; however, large-scale data are scant. This study seeks to determine current trends, outcomes, and risk factors of distal triceps tears. METHODS: Within a large insurance claims database, distal triceps repair patients were identified through Current Procedural Terminology coding with concomitant distal triceps International Classification of Diseases, 9th Revision/10th Revision diagnosis codes and 1-year active status before and after surgery. Demographics, total costs, 90-day complications, and revision rates within 1 year of index surgery were analyzed. Logistic regression was performed for revision and complication rates using sex, age, and comorbidities (anabolic steroid use, diabetes, ischemic heart disease, tobacco use, rheumatoid arthritis, and chronic kidney disease). RESULTS: A total of 8143 patients were included in the cohort. Male patients and patients aged 40 to 59 years comprised most of the study population. The postoperative complication rate was 5.8%, and the 1-year revision rate was 2.6%. Male sex, age >60 years, ischemic heart disease, rheumatoid arthritis, and chronic kidney disease were statistically significant risk factors for higher 90-day complication rates. Anabolic steroid use significantly increased the risk of surgical revision. CONCLUSIONS: Distal triceps repairs in this large cohort study occur most frequently in men aged 40 to 59 years. Complications are generally low, with age >60 years, male sex, ischemic heart disease, rheumatoid arthritis, and chronic kidney disease as risk factors for 90-day complications and prior anabolic steroid use as a risk factor for 1-year revision surgery. This information can help to improve education and expectations of this procedure.

Glenoid Prosthesis Design Considerations in Anatomic Total Shoulder Arthroplasty.

Total shoulder arthroplasty is an increasingly popular option for the treatment of glenohumeral arthritis. Historically, the effectiveness of the procedure has largely been determined by the long-term stability of the glenoid component. Glenoid component loosening can lead to clinically concerning complications including pain with movement, loss of function, and accumulation of debris which may require surgery to revise. In response, there has been a push to optimize the design of the glenoid prosthesis. Traditional contemporary glenoid components use pegs for fixation and are made entirely of polyethylene. Variations on the standard implant include keeled, metal-backed, hybrid, augmented, and inlay designs. There is a wealth of biomechanical and clinical studies that report on the effectiveness of these different designs. The purpose of this review is to summarize existing literature regarding glenoid component design and identify key areas for future research. Knowledge of the rationale underlying glenoid design will help surgeons select the best component for their patients and optimize outcomes following TSA.

B cell-T cell interplay in immune regulation: A focus on follicular regulatory T and regulatory B cell functions.

B cells are the core components of humoral immunity. A mature B cell can serve in multiple capacities, including antibody production, antigen presentation, and regulatory functions. Forkhead box P3 (FoxP3)-expressing regulatory T cells (Tregs) are key players in sustaining immune tolerance and keeping inflammation in check. Mounting evidence suggests complex communications between B cells and Tregs. In this review, we summarize the yin-yang regulatory relationships between B cells and Tregs mainly from the perspectives of T follicular regulatory (Tfr) cells and regulatory B cells (Bregs). We discuss the regulatory effects of Tfr cells on B cell proliferation and the germinal center response. Additionally, we review the indispensable role of B cells in ensuring homeostatic Treg survival and describe the function of Bregs in promoting Treg responses. Finally, we introduce a new subset of Tregs, termed Treg-of-B cells, which are induced by B cells, lake the expression of FoxP3 but still own immunomodulatory effects. In this article, we also enumerate a sequence of research from clinical patients and experimental models to clarify the role of Tfr cells in germinal centers and the role of convention B cells and Bregs to Tregs in the context of different diseases. This review offers an updated overview of immunoregulatory networks and unveils potential targets for therapeutic interventions against cancer, autoimmune diseases and allograft rejection.

Management of Proximal Humerus Fractures in Adults-A Scoping Review.

Proximal humerus fractures are the third most common fracture type in adults, with their incidence increasing over time. There are varied approaches to both the classification and treatment of proximal humerus fractures. Optimal treatments for this fracture type are still widely open to debate. This review summarizes the current and historical treatment modalities for proximal humerus fractures. In this paper, we provide updates on the advances and trends in the epidemiology, classification, and operative and nonoperative treatments of proximal humerus fractures.

Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling.

Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue, of which tumor loss of IFN-γ signaling genes is a major underlying mechanism. However, strategies of overcoming this resistance mechanism have been largely elusive. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1KO) impacts TILs. Here, we report that IFNγR1KO melanomas have reduced infiltration and function of TILs. IFNγR1KO melanomas harbor a network of constitutively active protein tyrosine kinases centered on activated JAK1/2. Mechanistically, JAK1/2 activation is mediated by augmented mTOR. Importantly, JAK1/2 inhibition with Ruxolitinib selectively suppresses the growth of IFNγR1KO but not scrambled control melanomas, depending on T cells and host TNF. Together, our results reveal an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a targeted therapy to bypass ICB resistance of melanomas defective of IFN-γ signaling.

Qualitative and Quantitative Anatomy of the Deep Radioulnar Ligaments' Insertion on Ulna: Cadaveric, Histologic, and MRI Study.

PURPOSE: To qualitatively and quantitatively analyze the anatomic features of the insertion of deep radioulnar ligaments (RULs) and provide an anatomic basis for further studies. METHODS: The anatomic features of deep RUL insertion were observed macroscopically in 26 cadaveric wrists, after which the size of the deep RUL footprint and distance from the center of the footprint to the ulnar-sided margin of articular cartilage of the ulnar head were each measured. Five specimens were analyzed histologically to examine the attachment of the RUL on the ulna. In addition, we evaluated 21 asymptomatic wrists from healthy volunteers using 3.0 T magnetic resonance imaging. RESULTS: The insertion of the deep RUL was located mainly on the radial aspect of the ulnar fovea from the foveal center to the articular cartilage. The footprint of the deep RUL appeared in 3 different shapes. The maximal width, length, and area of the footprint of the deep RUL were 3.7 (95% confidence interval [CI], 3.3-4.0) mm, 8.4 (95% CI, 7.9-8.9) mm, and 26.3 (95% CI, 23.4-29.1) mm2, respectively. Histologic analyses showed the attachment of the deep RUL on the radial wall of the fovea exhibited a direct insertion with typical 4-layer structures. The deep RUL fibers formed an acute angle with the distal component of the triangular fibrocartilage complex. CONCLUSIONS: The deep RUL was inserted on the radial side of the ulnar fovea and not the foveal center; it had direct insertion on the radial wall continuous with articular cartilage, and the fibers in the direct insertion formed an acute angle with the distal component of the triangular fibrocartilage complex. CLINICAL RELEVANCE: Understanding the quantitative anatomy of the deep RUL insertion may help guide surgeons to perform an anatomic foveal repair of the triangular fibrocartilage complex in its native footprint.

Effect of Physical Therapy and Rehabilitation Timing on Rotator Cuff Repair Revisions and Capsulitis.

INTRODUCTION: One variable that could potentially affect failure of a rotator cuff repair (RCR) is the timing of beginning physical therapy (PT) after the procedure. Although many studies have demonstrated decreased stiffness with beginning PT early, studies have also demonstrated that early PT increases repair failure. The goal of this study was to identify revision surgery and capsulitis rates after RCRs from an available database and determine whether an association was present with the timing of PT post-RCR. METHODS: Medicare patients within the PearlDiver database who underwent RCR were stratified based on the timing of their first PT session postoperatively, and revision surgery and capsulitis rates were determined among the groups for both open and arthroscopic RCR. Demographics and comorbidities of the cohort were also used to formulate a multivariate analysis for revision surgery rate. RESULTS: The cohort consisted of 64,842 patients who underwent RCR and started PT within 13 weeks of surgery. Starting PT within 1 week postoperatively resulted in a significantly higher revision surgery rate compared with starting PT in weeks 2 to 5, 6 to 9, or 10 to 13 (6.9% vs. 3.6% among all other groups, P = <0.001). The multivariate analysis for revision surgery further demonstrated that starting PT within 1 week postoperatively was associated with a significantly higher rate of revision surgery compared with beginning PT after 1 week (OR = 2.086, P < 0.001). No association was found between timing of beginning PT and capsulitis rates. CONCLUSION: In the Medicare patient cohort, beginning PT within 1 week postoperatively was associated with a significantly higher revision surgery rate; however, no associated benefit was noted in capsulitis rates for beginning PT early. This calls into question the use of an early passive range of motion protocol for older patient cohort; however, further studies should be completed to conclusively determine the most efficacious time to begin rehabilitation post-RCR. LEVEL OF EVIDENCE: Level III.

Effect of Body Mass Index on Femur Fracture Location: A Retrospective Database Study.

OBJECTIVES: Use a large database design and multivariable analyses to assess the associations between body mass index (BMI) and femur fracture patterns after controlling for other risk factors. DESIGN: Retrospective cohort study. SETTING: National insurance claims database of patient records from 2010 to 2018. PATIENTS/PARTICIPANTS: Patients with femur fracture diagnoses were identified. Patients with multiple fractures within 1 week (polytrauma patients), patients without a BMI diagnosis code within 6 months of fracture, and patients with multiple BMI diagnosis codes (implying a substantial change in weight) were excluded. INTERVENTION: N/A. MAIN OUTCOME MEASUREMENTS: Patients were divided into groups based on fracture location: proximal (OTA/AO 31), shaft (OTA/AO 32), or distal (OTA/AO 33). The distribution of femur fractures was compared across BMI categories. RESULTS: A total of 57,042 patients with femur fracture were identified: 45,586 proximal fractures, 4216 shaft fractures, and 7240 distal fractures. Patients with BMI <29.9 have increased odds ( P < 0.0001) of proximal fracture and decreased odds ( P < 0.0001) of shaft or distal fractures. Patients with BMI >30.0 have decreased odds ( P < 0.0001) of proximal fracture and increased odds ( P < 0.0001) of distal fractures. CONCLUSIONS: Increasing BMI is associated with a decreased proportion of proximal femur fractures and a corresponding increase in the proportion of shaft and distal fractures. Regression analyses determined that age, sex, osteoporosis, diabetes, and tobacco use are not the cause of this trend. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.