Repair of distal finger soft-tissue defects with free fibular great toe neurovascular flaps.

BACKGROUND: This work aimed to investigate the change in fingerprint depth and the recovery rule of fingerprint biological recognition function after repairing finger abdominal defects and rebuilding fingerprint with a free flap. METHOD: From April 2018 to March 2023, we collected a total of 43 cases of repairing finger pulp defects using the free flap of the fibular side of the great toe with the digital nerve. After surgery, irregular follow-up visits were conducted to observe fingerprint clarity, perform the ninhydrin test or detect visible sweating with the naked eye. We recorded fingerprint clarity, nail shape, two-point discrimination, cold perception, warm perception and fingerprint recognition using smartphones. The reconstruction process of the repaired finger was recorded to understand the changes in various observation indicators and their relationship with the depth of the fingerprint. The correlation between fingerprint depth and neural repair was determined, and the process of fingerprint biological recognition function repair was elucidated. RESULT: All flaps survived, and we observed various manifestations in different stages of nerve recovery. The reconstructed fingerprint had a clear fuzzy process, and the depth changes of the fingerprint were consistent with the changes in the biological recognition function curve. CONCLUSION: The free flap with the digital nerve is used to repair finger pulp defects. The reconstructed fingerprint has a biological recognition function, and the depth of the fingerprint is correlated with the process of nerve repair. The fingerprint morphology has a dynamic recovery process, and it can reach a stable state after 6-8 months.

Tartaric acid ameliorates experimental non-alcoholic fatty liver disease by activating the AMP-activated protein kinase signaling pathway.

Tartaric acid (TA) has been shown beneficial effects on blood pressure and lipid levels. However, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. This study aimed to investigate the role of TA in experimental NAFLD. Mice were fed a Western diet for 8 weeks, followed by administration of TA or a vehicle for an additional 12 weeks while continuing on the Western diet. Blood biochemistry including transaminases and glucose tolerance test and liver tissue RNA sequencing (RNA-seq), lipid content, and histology were investigated. The HepG2 cell line was used to explore the mechanism by which TA regulates lipid metabolism. We found that TA significantly improved weight gain, insulin resistance, hepatic steatosis, inflammation and fibrosis in Western diet-fed mice. By comparing gene expression differences, we found that TA affects pathways related to lipid metabolism, inflammatory response, and fibrosis. Furthermore, TA effectively reduced oleic acid-induced lipid accumulation in HepG2 cells and downregulated the genes associated with fatty acid synthesis, which were enriched in the AMP-activated protein kinase (AMPK) signaling pathway. TA also enhanced the phosphorylation of AMPK which could be reverted by the AMPK inhibitor Compound C in HepG2 cells. Our study suggests that TA improves experimental NAFLD by activating the AMPK signaling pathway. These findings indicate that TA may serve as a potential therapy for the human NAFLD.

RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Cu-Tremella fuciformis polysaccharide-based tumor microenvironment-responsive injectable gels for cuproptosis-based synergistic osteosarcoma therapy.

Cuproptosis affects osteosarcoma locally, and the exploitation of cuproptosis-related biomaterials for osteosarcoma treatment is still in its infancy. We designed and synthesized a novel injectable gel of Cu ion-coordinated Tremella fuciformis polysaccharide (TFP-Cu) for antiosteosarcoma therapy. This material has antitumor effects, the ability to stimulate immunity and promote bone formation, and a controlled Cu2+ release profile in smart response to tumor microenvironment stimulation. TFP-Cu can selectively inhibit the proliferation of K7M2 tumor cells by arresting the cell cycle and promoting cell apoptosis and cuproptosis. TFP-Cu also promoted the M1 polarization of RAW264.7 cells and regulated the immune microenvironment. These effects increased osteogenic gene and protein expression in MC3T3-E1 cells. TFP-Cu could significantly limit tumor growth in tumor-bearing mice by inducing tumor cell apoptosis and improving the activation of anti-CD8 T cell-mediated immune responses. Therefore, TFP-Cu could be a potential candidate for treating osteosarcoma and bioactive drug carrier for further cancer-related applications.

Bone mineral density in lower thoracic vertebra for osteoporosis diagnosis in older adults during CT lung cancer screening.

BACKGROUND: Quantitative computed tomography (QCT)-based lumbar bone mineral density (LBMD) has been used to diagnose osteoporosis. This study explored the value of lower thoracic BMD (TBMD) in diagnosing osteoporosis in older adults during CT lung cancer screening. METHODS: This study included 751 subjects who underwent QCT scans with both LBMD and TBMD. 141 of them was selected for a validation. Osteoporosis was diagnosed based on LBMD using the ACR criteria (gold standard). TBMD thresholds were obtained using receiver operating characteristic curve. TBMD was also translated into LBMD (TTBMD) and osteoporosis was defined based on TTBMD using ACR criteria. The performance of TBMD and TTBMD in identifying osteoporosis was determined by Kappa test. The associations between TBMD- and TTBMD-based osteoporosis and fracture were tested in 227 subjects with followed up status of spine fracture. RESULTS: The performance of TBMD in identifying osteoporosis was low (kappa = 0.66) if using the ACR criteria. Two thresholds of TBMD for identifying osteopenia (128 mg/cm3) and osteoporosis (91 mg/cm3) were obtained with areas under the curve of 0.97 and 0.99, respectively. The performance of the identification of osteoporosis/osteopenia using the two thresholds or TTBMD both had good agreement with the gold standard (kappa = 0.78, 0.86). Similar results were observed in validation population. Osteoporosis identified using the thresholds (adjusted hazard ratio (HR) = 18.72, 95% confidence interval (CI): 5.13-68.36) or TTBMD (adjusted HR = 10.28, 95% CI: 4.22-25.08) were also associated with fractures. CONCLUSION: Calculating the threshold of TBMD or normalizing TBMD to LBMD are both useful in identifying osteoporosis in older adults during CT lung cancer screening.

Opportunistic Muscle Evaluation During Chest CT Is Associated With Vertebral Compression Fractures in Old Adults: A Longitudinal Study.

BACKGROUND: Sarcopenia and bone loss are both common in older individuals. However, the association between sarcopenia and bone fractures has not been evaluated longitudinally. In this study, we evaluated the association between computed tomography (CT)-based erector spinae muscle area and attenuation and vertebral compression fracture (VCF) in elderly individuals in a longitudinal study. METHODS: This study recruited individuals 50 years of age and older, who did not have VCF and underwent CT imaging for lung cancer screening during January 2016 to December 2019. Participants were followed up annually until January 2021. Muscle CT value and muscle area of the erector spinae were determined for muscle assessment. Genant score was used to define new-onset VCF. Cox proportional hazards models were used to assess the association between muscle area/attenuation and VCF. RESULTS: Of the 7 906 included participants, 72 developed new VCF over a median follow-up of 2 years. Large area of the erector spinae (adjusted hazard ratio [HR] = 0.2, 95% confidence interval [CI]: 0.1-0.7) and high bone attenuation (adjusted HR = 0.2, 95% CI: 0.1-0.5) were independently associated with VCF. High muscle attenuation was associated with severe VCF (adjusted HR = 0.46, 95% CI: 0.24-0.86). The addition of muscle area improved the area under the curve of bone attenuation from 0.79 (95% CI: 0.74-0.86) to 0.86 (95% CI: 0.82-0.91; p = .001). CONCLUSIONS: CT-based muscle area/attenuation of the erector spinae was associated with VCF in elderly individuals, independently of bone attenuation. The addition of muscle area improved the performance of bone attenuation in predicting VCF.

Longitudinal intravital imaging of the bone marrow for analysis of the race for the surface in a murine osteomyelitis model.

Critical knowledge gaps of orthopedic infections pertain to bacterial colonization. The established dogma termed the Race for the Surface posits that contaminating bacteria compete with host cells for the implant post-op, which remains unproven without real-time in vivo evidence. Thus, we modified the murine longitudinal intravital imaging of the bone marrow (LIMB) system to allow real-time quantification of green fluorescent protein (GFP+) host cells and enhanced cyan fluorescent protein (ECFP+) or red fluorescent protein (RFP+) methicillin-resistant Staphylococcus aureus (MRSA) proximal to a transfemoral implant. Following inoculation with ~105 CFU, an L-shaped metal implant was press-fit through the lateral cortex at a 90° angle ~0.150 mm below a gradient refractive index (GRIN) lens. We empirically derived a volume of interest (VOI) = 0.0161 ± 0.000675 mm3 during each imaging session by aggregating the Z-stacks between the first (superior) and last (inferior) in-focus LIMB slice. LIMB postimplantation revealed very limited bacteria detection at 1 h, but by 3 h, 56.8% of the implant surface was covered by ECFP+ bacteria, and the rest were covered by GFP+ host cells. 3D volumetric rendering of the GFP+ and ECFP+ or RFP+ voxels demonstrated exponential MRSA growth between 3 and 6 h in the Z-plane, which was validated with cross-sectional ex vivo bacterial burden analyses demonstrating significant growth by ~2 × 104 CFU/h on the implant from 2 to 12 h post-op (p < 0.05; r2 > 0.98). Collectively, these results show the competition at the surface is completed by 3 h in this model and demonstrate the potential of LIMB to elucidate mechanisms of bacterial colonization, the host immune response, and the efficacy of antimicrobials.

The 2023 Orthopaedic Research Society's International Consensus Meeting on musculoskeletal infection: Summary from the host immunity section.

Musculoskeletal infections (MSKI), which are a major problem in orthopedics, occur when the pathogen eludes or overwhelms the host immune system. While effective vaccines and immunotherapies to prevent and treat MSKI should be possible, fundamental knowledge gaps in our understanding of protective, nonprotective, and pathogenic host immunity are prohibitive. We also lack critical knowledge of how host immunity is affected by the microbiome, implants, prior infection, nutrition, antibiotics, and concomitant therapies, autoimmunity, and other comorbidities. To define our current knowledge of these critical topics, a Host Immunity Section of the 2023 Orthopaedic Research Society MSKI International Consensus Meeting (ICM) proposed 78 questions. Systematic reviews were performed on 15 of these questions, upon which recommendations with level of evidence were voted on by the 72 ICM delegates, and another 12 questions were voted on with a recommendation of "Unknown" without systematic reviews. Two questions were transferred to another ICM Section, and the other 45 were tabled for future consideration due to limitations of available human resources. Here we report the results of the voting with internet access to the questions, recommendations, and rationale from the systematic reviews. Eighteen questions received a consensus vote of ≥90%, while nine recommendations failed to achieve this threshold. Commentary on why consensus was not achieved on these questions and potential ways forward are provided to stimulate specific funding mechanisms and research on these critical MSKI host defense questions.

Dopamine and cyclic adenosine monophosphate-regulated phosphoprotein with an apparent Mr of 32000 promotes colorectal cancer growth.

BACKGROUND: Dopamine and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein with an apparent Mr of 32000 (DARPP-32) is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain. However, recent studies have shown that DARPP-32 is also expressed in other tissues, including colorectal cancer (CRC), where its function is not well understood. AIM: To explore the effect of DARPP-32 on CRC progression. METHODS: The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays. The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, while apoptosis was measured by flow cytometry. The migratory and invasive potential of CRC cell lines were determined using wound healing and transwell chamber assays. In vivo studies involved monitoring the growth rate of xenograft tumors. Finally, the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses. RESULTS: DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC. Overexpression of DARPP-32 was shown to promote cancer cell proliferation, migration, and invasion and reduce apoptosis. DARPP-32 knockdown resulted in the opposite functional effects. Mechanistically, DARPP-32 may regulate the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in order to carry out its biological function. CONCLUSION: DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.

Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis.

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

Sarcopenia assessed by computed tomography or magnetic resonance imaging is associated with the loss of response to biologic therapies in adult patients with Crohn's disease.

Sarcopenia occurs in patients with Crohn's disease (CD). However, the association between sarcopenia and loss of response (LOR) to biologic agents remains unclear. This study explored such an association in CD patients. This retrospective study included 94 CD patients who received biologic therapy. The skeletal muscle cross-sectional area at the third lumbar was assessed by computed tomography or magnetic resonance imaging for sarcopenia evaluation. A LOR was defined by fecal calprotectin (FC) < 250 µg/g or >50% reduction from baseline levels or other factors, such as the used agent being replaced by other biologic agents. The association between sarcopenia and LOR was assessed by logistic regression analysis. LOR was observed in 54 patients (57.4%). The prevalence of sarcopenia in the LOR group was higher than that in response group (70.4% vs. 40.0%, p = 0.003). Sarcopenia (odds ratio [OR] = 3.89, 95% confidence interval [CI]: 1.31-11.54), Montreal L1 type (OR = 0.20, 95% CI: 0.06-0.60), perianal lesions (OR = 4.08, 95% CI: 1.31-12.70), and monocytes percentage (OR = 1.27, 95% CI: 1.02-1.57) at baseline were independent associated factors for LOR. Sarcopenia was also associated with LOR in patients who received infliximab (OR = 3.31, 95% CI: 1.11-9.87). Montreal L1 type, perianal lesions, and monocytes percentage (Model 1), and with additional consideration of sarcopenia (Model 2), were developed to predict LOR. Model 2 showed better performance than Model 1 (area under the curve [AUC] 0.82 vs. 0.75). Sarcopenia was associated with the LOR to biological agents or infliximab in adult patients with CD.

Association between vmPFC gray matter volume and smoking initiation in adolescents.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Probiotics for the management of irritable bowel syndrome: a systematic review and three-level meta-analysis.

OBJECTIVE: Previous systematic reviews demonstrated a potentially beneficial effect of probiotics on irritable bowel syndrome (IBS). However, these studies are either affected by the inclusion of insufficient trials or by the problem of dependent data across multiple outcomes, and an overall effect size has not been provided. We aimed to determine the effect of probiotics on IBS through a three-level meta-analysis and clarify potential effect moderators. METHODS: We searched MEDLINE, Embase, and Web of Science, screening for randomized controlled trials (RCTs) that examine the effect of probiotics on IBS. The primary outcome was the improvement in the severity of global IBS symptoms at the end of treatment. The secondary outcomes were the improvement in abdominal pain and the quality of life. The effect sizes of the probiotics were measured by using the standardized mean difference (SMD) and pooled by a three-level meta-analysis model. RESULTS: We included 72 RCTs in the analysis. The meta-analysis showed significantly better overall effect of probiotics than placebo on the global IBS symptoms (SMD -0.55, 95% CI -0.76 to -0.34, P <0.001), abdominal pain (SMD -0.89, 95% CI -1.29 to -0.5, P <0.001) and quality of life (SMD 0.99, 95% CI 0.45 to 1.54, P <0.001), respectively. Moderator analysis found that a treatment duration shorter than 4 weeks was associated with a larger effect size in all the outcomes, and Bacillus probiotics had better improvement on the abdominal pain. CONCLUSIONS: Probiotics had a short-term effect and a medium effect size on the global IBS symptoms. Treatment duration and types of probiotics affected the effect size of probiotics, and shorter durations and Bacillus probiotics were associated with better treatment effects. REGISTRATION: Open Science Framework.

Cellular dynamics in tumour microenvironment along with lung cancer progression underscore spatial and evolutionary heterogeneity of neutrophil.

BACKGROUND: The cellular dynamics in the tumour microenvironment (TME) along with non-small cell lung cancer (NSCLC) progression remain unclear. METHODS: Multiplex immunofluorescence test detecting 10 immune-related markers on 553 primary tumour (PT) samples of NSCLC was conducted and spatial information in TME was assessed by the StarDist depth learning model. The single-cell transcriptomic atlas of PT (n = 4) and paired tumour-draining lymph nodes (TDLNs) (n = 5 for tumour-invaded, n = 3 for tumour-free) microenvironment was profiled. Various bioinformatics analyses based on Gene Expression Omnibus, TCGA and Array-Express databases were also used to validate the discoveries. RESULTS: Spatial distances of CD4+ T cells-CD38+ T cells, CD4+ T cells-neutrophils and CD38+ T cells-neutrophils prolonged and they were replaced by CD163+ macrophages in PT along with tumour progression. Neutrophils showed unique stage and location-dependent prognostic effects. A high abundance of stromal neutrophils improved disease-free survival in the early-stage, whereas high intratumoural neutrophil infiltrates predicted poor prognosis in the mid-to-late-stage. Significant molecular and functional reprogramming in PT and TDLN microenvironments was observed. Diverse interaction networks mediated by neutrophils were found between positive and negative TDLNs. Five phenotypically and functionally heterogeneous subtypes of tumour-associated neutrophil (TAN) were further identified by pseudotime analysis, including TAN-0 with antigen-presenting function, TAN-1 with strong expression of interferon (IFN)-stimulated genes, the pro-tumour TAN-2 subcluster, the classical subset (TAN-3) and the pro-inflammatory subtype (TAN-4). Loss of IFN-stimulated signature and growing angiogenesis activity were discovered along the transitional trajectory. Eventually, a robust six neutrophil differentiation relevant genes-based model was established, showing that low-risk patients had longer overall survival time and may respond better to immunotherapy. CONCLUSIONS: The cellular composition, spatial location, molecular and functional changes in PT and TDLN microenvironments along with NSCLC progression were deciphered, highlighting the immunoregulatory roles and evolutionary heterogeneity of TANs.

Epidemiological updates of post-traumatic related limb osteomyelitis in china: a 10 years multicentre cohort study.

BACKGROUND: Post-traumatic related limb osteomyelitis (PTRLO) is a complex bone infection. Currently, there are no available microbial data on a national scale that can guide appropriate antibiotic selection, and explore the dynamic changes in dominant pathogens over time. This study aimed to conduct a comprehensive epidemiological analysis of PTRLO in China. METHODS: The study was approved by the Institutional Research Board (IRB), and 3526 PTRLO patients were identified from 212 394 traumatic limb fracture patients at 21 hospitals between 1 January 2008 and 31 December 2017. A retrospective analysis was conducted to investigate the epidemiology of PTRLO, including changes in infection rate (IR), pathogens, infection risk factors and antibiotic resistance and sensitivity. RESULTS: The IR of PTRLO increased gradually from 0.93 to 2.16% (Z=14.392, P <0.001). Monomicrobial infection (82.6%) was significantly higher than polymicrobial infection (17.4%) ( P <0.001). The IR of Gram-positive (GP) and Gram-negative (GN) pathogens showed a significant increase from the lowest 0.41% to the highest 1.15% (GP) or 1.62% (GN), respectively. However, the longitudinal trend of GP vs. GN's composition did not show any significance (Z=±1.1918, P >0.05). The most prevalent GP strains were Methicillin-sensitive Staphylococcus aureus (MSSA) (17.03%), Methicillin-resistant Staphylococcus aureus (MRSA) (10.46%), E. faecalis (5.19%) and S. epidermidis (4.87%). In contrast, the dominant strains GN strains were Pseudomonas Aeruginosa (10.92%), E. cloacae (10.34%), E. coli (9.47%), Acinetobacter Baumannii (7.92%) and Klebsiella Pneumoniae (3.33%). In general, the high-risk factors for polymicrobial infection include opened-fracture (odds ratio, 2.223), hypoproteinemia (odds ratio, 2.328), and multiple fractures (odds ratio, 1.465). It is important to note that the antibiotics resistance and sensitivity analysis of the pathogens may be influenced by complications or comorbidities. CONCLUSIONS: This study provides the latest data of PTRLO in China and offers trustworthy guidelines for clinical practice. (China Clinical Trials.gov number, ChiCTR1800017597).

Evidence of Bisphosphonate-Conjugated Sitafloxacin Eradication of Established Methicillin-Resistant S. aureus Infection with Osseointegration in Murine Models of Implant-Associated Osteomyelitis.

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (bisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy, while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

Case report: Primary pleural giant extraskeletal Ewing sarcoma in a child.

Primary extraskeletal Ewing sarcoma (EES) is a rare small round cell malignancy that accounts for less than 1% of all sarcomas. It is found most commonly in the trunk and lower limbs and very rarely in the pleura and can be easily misdiagnosed in clinical practice. This study presents the case of an 11-year-old boy who presented to our hospital with no apparent cause of left shoulder pain for 6 months. On physical examination, tenderness was noted in the left chest wall and shoulder joint, which had a limited range of motion. Computed tomography (CT) and magnetic resonance imaging (MRI) of the chest revealed an irregular soft tissue mass in the upper left thorax, with a wide base attached to the adjacent pleura and bone destruction of the adjacent left first rib. The patient's bone scan showed a dense focus of increased radiotracer accumulation in the left first rib. A subsequent CT-guided aspiration biopsy of the left pleural mass with histomorphology and immunohistochemical phenotyping led to a diagnosis of extraskeletal Ewing sarcoma. To inhibit tumor growth, alternating systemic chemotherapy cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) and isocyclophosphamide and etoposide (IE) were administered at 3-week intervals. After completing three VDC and two IE cycles, the child's condition was well and the pain in the left shoulder joint was relieved. However, a repeat MRI of the chest showed that the mass did not shrink.

Reduced angiogenesis and delayed endochondral ossification in CD163-/- mice highlights a role of M2 macrophages during bone fracture repair.

While recent studies showed that macrophages are critical for bone fracture healing, and lack of M2 macrophages have been implicated in models of delayed union, functional roles for specific M2 receptors have yet to be defined. Moreover, the M2 scavenger receptor CD163 has been identified as a target to inhibit sepsis following implant-associated osteomyelitis, but potential adverse effects on bone healing during blockage therapy have yet to be explored. Thus, we investigated fracture healing in C57BL/6 versus CD163-/- mice using a well-established closed, stabilized, mid-diaphyseal femur fracture model. While gross fracture healing in CD163-/- mice was similar to that of C57BL/6, plain radiographs revealed persistent fracture gaps in the mutant mice on Day 14, which resolved by Day 21. Consistently, 3D vascular micro-CT demonstrated delayed union on Day 21, with reduced bone volume (74%, 61%, and 49%) and vasculature (40%, 40%, and 18%) compared to C57BL/6 on Days 10, 14, and 21 postfracture, respectively (p < 0.01). Histology confirmed large amounts of persistent cartilage in CD163-/- versus C57BL/6 fracture callus on Days 7 and 10 that resolves over time, and immunohistochemistry demonstrated deficiencies in CD206+ M2 macrophages. Torsion testing of the fractures confirmed the delayed early union in CD163-/- femurs, which display decreased yield torque on Day 21, and a decreased rigidity with a commensurate increase in rotation at yield on Day 28 (p < 0.01). Collectively, these results demonstrate that CD163 is required for normal angiogenesis, callus formation, and bone remodeling during fracture healing, and raise potential concerns about CD163 blockade therapy.