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Introduction: Diabetes mellitus (DM) impairs fracture healing and is associated with susceptibility to infection, which further inhibits fracture healing. While intermittent parathyroid hormone (1-34) (iPTH) effectively improves fracture healing, it is unknown whether infection-associated impaired fracture healing can be rescued with PTH (teriparatide). Methods: A chronic diet-induced type 2 diabetic mouse model was used to yield mice with decreased glucose tolerance and increased blood glucose levels compared to lean-fed controls. Methicillin-resistant Staphylococcus aureus (MRSA) was inoculated in a surgical tibia fracture model to simulate infected fracture, after which mice were treated with a combination of antibiotics and adjunctive teriparatide treatment. Fracture healing was assessed by Radiographic Union Scale in Tibial Fractures (RUST), micro-computed tomography (mCT), biomechanical testing, and histology. Results: RUST score was significantly poorer in diabetic mice compared to their lean nondiabetic counterparts. There were concomitant reductions in micro-computed tomography (mCT) parameters of callus architecture including bone volume/total volume, trabecular thickness, and total mineral density in type 2 diabetes mellitus (T2DM) mice. Biomechanicaltesting of fractured femora demonstrated diminished torsional rigidity, stiffness, and toughness to max torque. Adjuvant teriparatide treatment with systemic antibiotic therapy improved numerous parameters of bone microarchitecture bone volume, increased connectivity density, and increased trabecular number in both the lean and T2DM group. Despite the observation that poor fracture healing in T2DM mice was further impaired by MRSA infection, adjuvant iPTH treatment significantly improved fracture healing compared to antibiotic treatment alone in infected T2DM fractures. Discussion: Our results suggest that teriparatide may constitute a viable adjuvant therapeutic agent to improve bony union and bone microarchitecture to prevent the development of septic nonunion under diabetic conditions. [ABSTRACT FROM AUTHOR]

Fracture healing is impaired in the setting of infection, which begets protracted inflammation. The most problematic causative agent of musculoskeletal infection is methicillin‐resistant Staphylococcus aureus (MRSA). We hypothesized that modulation of excessive inflammation combined with cell‐penetrating antibiotic treatments facilitates fracture healing in a murine MRSA‐infected femoral fracture model. Sterile and MRSA‐contaminated open transverse femoral osteotomies were induced in 10‐week‐old male C57BL/6 mice and fixed via intramedullary nailing. In the initial therapeutic cohort, empty, vancomycin (V), rifampin (R), vancomycin‐rifampin (VR), or vancomycin‐rifampin‐trametinib (VRT) hydrogels were applied to the fracture site intraoperatively. Rifampin was included because of its ability to penetrate eukaryotic cells to target intracellular bacteria. Unbiased screening demonstrated ERK activation was upregulated in the setting of MRSA infection. As such, the FDA‐approved mitogen‐activated protein kinase kinase (MEK)1‐pERK1/2 inhibitor trametinib was evaluated as an adjunctive therapeutic agent to selectively mitigate excessive inflammation after infected fracture. Two additional cohorts were created mimicking immediate and delayed postoperative antibiotic administration. Systemic vancomycin or VR was administered for 2 weeks, followed by 2 weeks of VRT hydrogel or oral trametinib therapy. Hematologic, histological, and cytokine analyses were performed using serum and tissue isolates obtained at distinct postoperative intervals. Radiography and micro‐computed tomography (μCT) were employed to assess fracture healing. Pro‐inflammatory cytokine levels remained elevated in MRSA‐infected mice with antibiotic treatment alone, but increasingly normalized with trametinib therapy. Impaired callus formation and malunion were consistently observed in the MRSA‐infected groups and was partially salvaged with systemic antibiotic treatment alone. Mice that received VR alongside adjuvant MEK1‐pERK1/2 inhibition displayed the greatest restoration of bone and osseous union. A combinatorial approach involving adjuvant cell‐penetrating antibiotic treatments alongside mitigation of excessive inflammation enhanced healing of infected fractures. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking. We exposed three murine strains, C57BL/6J, 129X1/SvJ, and BALB/cJ, to cigarette smoke for 3 months before the induction of a midshaft transverse femoral osteotomy. We evaluated fracture healing 4 weeks after the osteotomy using radiography, micro‐computed tomography (μCT), and biomechanical testing. Radiographic analysis demonstrated a significant decrease in the fracture healing capacity of smoking 129X1/SvJ mice. μCT results showed delayed remodeling of fracture calluses in all three strains after cigarette smoke exposure. Biomechanical testing indicated the most significant impairment in the functional properties of 129X1/SvJ in comparison with C57BL/6J and BALB/cJ mice after cigarette smoke exposure. Thus, the 129X1/SvJ strain is most suitable in simulating smoking‐induced impaired fracture healing. Furthermore, in smoking 129X1/SvJ murine models, we investigated the molecular and cellular alterations in fracture healing caused by cigarette smoking using histology, flow cytometry, and multiplex cytokine/chemokine analysis. Histological analysis showed impaired chondrogenesis in cigarette smoking. In addition, the important reparative cell populations, including skeletal stem cells and their downstream progenitors, demonstrated decreased expansion after injury as a result of cigarette smoking. Moreover, significantly increased pro‐inflammatory mediators and the recruitment of immune cells in fracture hematomas were demonstrated in smoking mice. Collectively, our findings demonstrate the significant cellular and molecular alterations during fracture healing impaired by smoking, including disrupted chondrogenesis, aberrant skeletal stem and progenitor cell activity, and a pronounced initial inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

The complete Beighton criteria, commonly used to establish the diagnosis of generalized ligamentous laxity (GLL), include nine discrete examination maneuvers. However, busy examiners may perform only a single maneuver (e.g. passive apposition of the thumb to the forearm) as a rapid method of assessment. We hypothesize that the use of a single-joint hypermobility test does not reliably identify the presence of GLL. Healthy patients 2-18 years old presenting to a general pediatric orthopaedic clinic were screened for participation. Exclusion criteria included the presence of a systemic illness, neuromuscular disease, and inability to complete the examination. Subjects were assessed for GLL according to the Beighton criteria, using a cutoff score of 5. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio were calculated for the thumb-to-forearm apposition test with the composite Beighton score used as the gold standard. Two hundred and four patients were included in the study, 111 females and 93 males, with an average age of 10.7 years. The prevalence of GLL was 13.3%. When thumb-to-forearm apposition was performed unilaterally, the PPV was poor (34%). Conversely, the NPV was excellent (99%). Sensitivity of thumb-to-forearm motion was extremely high (99%), although the specificity of this test was modest (67%). The likelihood ratio was fair (+3.3). Performing the test bilaterally did not significantly change its utility. Thumb-to-forearm apposition testing was equally effective in identifying the presence of GLL in males and females. When performed in isolation, assessment of thumb-to-forearm apposition has a poor PPV, excellent NPV, and modest likelihood ratio. It is an extremely sensitive test, with only fair specificity. Other upper extremity tests of GLL perform similarly. Therefore, while single tests like thumb-to-forearm apposition may be helpful for 'ruling out' GLL, they are less reliable at identifying it correctly. When single tests are used to identify GLL in either clinical or research settings, the results should be interpreted with caution. Level of evidence Level I (diagnostic)., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)