Efficacy and safety of different oral prednisone tapering courses in adult anti-NMDAR encephalitis: A multicenter prospective cohort study.

OBJECTIVE: In adult anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, corticosteroids are commonly used as first-line treatment. However, the optimal oral prednisone tapering (OPT) following intravenous methylprednisolone pulse therapy remains unclear. We aim to compare the efficacy and safety of different OPT courses in anti-NMDAR encephalitis. METHODS: The CHASE study, a multicenter prospective observational cohort study, enrolled patients with autoimmune encephalitis from October 2011 to March 2023. Patients were grouped based on oral prednisone tapering course: ≤3 months (Group ≤3 month), 3-6 months (Group 3-6 months, including 3 months), and >6 months (Group > 6 months). Kaplan-Meier plots were used to analyze time to relapse and time to total recovery within 2 years. RESULTS: Among 666 screened patients, 171 (median [IQR] age 27 [21.0-36.5] years, 55.0% female) met selection criteria. Responders at 3 months were prevalent in Group ≤3 months (OR 7.251 [95% CI 2.252 to 23.344] and Group 3-6 months (OR, 3.857 [95% CI 1.107 to 13.440] than in Group >6 months. Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at 12 months were higher in Group >6 months than in Group ≤3 months and Group 3-6 months (ß, -2.329 [95% CI -3.784 to -.875]; ß, -2.871 [95% CI -4.490, -1.253]). CASE seizures subscore was higher in Group >6 months than in Group 3-6 months (ß, -.452 [95% CI -.788 to -.116]). No significant difference in seizure freedom rates among the groups. Adverse events were higher in Group 3-6 months and Group >6 months than in Group ≤3 months (OR 6.045 [95% CI 2.352 to 15.538]; OR 6.782 [95% CI 1.911 to 24.073]). SIGNIFICANCE: Longer oral prednisone courses for adult patients with anti-NMDAR encephalitis did not show superior effects compared to shorter courses in improving modified Rankin Scale (mRS) scores and CASE scores, reducing the risk of relapse within 2 years, or achieving seizure freedom. Instead, extended prednisone courses may lead to more side effects- particularly weight gain. This outcome recommends evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment.

Estimating the axial strain of circular short columns confined with CFRP under centric compressive static load using ANN and GRA techniques.

This investigation introduces advanced predictive models for estimating axial strains in Carbon Fiber-Reinforced Polymer (CFRP) confined concrete cylinders, addressing critical aspects of structural integrity in seismic environments. By synthesizing insights from a substantial dataset comprising 708 experimental observations, we harness the power of Artificial Neural Networks (ANNs) and General Regression Analysis (GRA) to refine predictive accuracy and reliability. The enhanced models developed through this research demonstrate superior performance, evidenced by an impressive R-squared value of 0.85 and a Root Mean Square Error (RMSE) of 1.42, and significantly advance our understanding of the behavior of CFRP-confined structures under load. Detailed comparisons with existing predictive models reveal our approaches' superior capacity to mimic and forecast axial strain behaviors accurately, offering essential benefits for designing and reinforcing concrete structures in earthquake-prone areas. This investigation sets a new benchmark in the field through meticulous analysis and innovative modeling, providing a robust framework for future engineering applications and research.

Influence of retainer design and number of inlay boxes on the biomechanical behavior of zirconia cantilever resin bonded fixed dental prosthesis.

OBJECTIVES: The development of dental adhesives with enhanced bond strength has assisted minimally invasive dentistry. The aim of this study was to evaluate the fracture load and stress distribution pattern of two retainer designs for posterior cantilever resin bonded fixed dental protheses (RBFDPs). MATERIALS AND METHODS: Forty human mandibular molars were divided into two groups according to the retainer design; lingual coverage (LC) and occlusal coverage (OC) retainers. Each main group was then divided according to the number of inlay boxes (n = 10); one inlay and two inlay boxes. High translucency (3Y) zirconia was used to manufacture all restorations, and a dual-polymerizing adhesive resin cement was used for bonding. All specimens underwent 10,000 cycles of thermocycling (5-55°C), 240,000 cycles of dynamic loading (50 N, descending speed v = 30 mm/second, frequency = 1.6 Hz), and failure load test. Both one-way and two-way ANOVA tests were used to analyze the data. The four models included in the in-vitro study are part of the finite element analysis (FEA). When the restorations failed, maximal principal stress values on restorations, enamel, dentin, and luting resin were investigated. RESULTS: A statistically significant (p = 0.018) higher failure load was recorded for OC1 (627.00 ± 153.4 N) than the other groups; (548.0 ± 75.6 N, 521.20 ± 11.3 N, and 509.20 ± 14.9 N for LC1, LC2, and OC2, respectively). With regard to failure mode, one inlay box designs showed more favorable failure pattern than those of two inlay boxes. FEA showed higher stress magnitude transmitted to the tooth structure in models LC2 and OC2. CONCLUSIONS: Lingual coverage and occlusal coverage retainers are promising designs capable to withstand the normal occlusal force for cantilever RBFDP in premolar area. The use of two inlay boxes decreased the fracture load of the two retainer designs and increased the stress transmitted to the tooth and resulted in high incidence of catastrophic failure. CLINICAL SIGNIFICANCE: Monolithic high translucent zirconia RBFDP could be considered as a viable treatment option to substitute missing posterior tooth, with improved esthetics and biocompatibility.

Evaluation of different designs for posterior cantilever zirconia inlay-retained fixed dental prostheses in missing tooth replacement: Stage one results with 18-month follow-up assessment.

OBJECTIVES: This clinical study aimed to investigate the outcomes and survival rates of different variations of inlay-retained fixed dental prostheses (IR-FDPs) composed of monolithic zirconia ceramic. The IR-FDPs with a single-retainer design were used for replacing missing mandibular second premolars. The research evaluated the effectiveness and longevity of these prostheses in clinical settings. METHODS: A total of 30 IR-FDPs (n = 30) were placed for 27 female patients who presented with missing mandibular second premolar teeth. For this study, the mandibular first molar was chosen as a retainer for the cantilever IR-FDPs and the study involved a random assignment of participants into three distinct groups, each comprising 10 individuals (n = 10). The criterion for the grouping was the retainer design: inlay ring (IR), lingual coverage (LC), and occlusal coverage (OC). The three groups included mesial inlay box with the same dimensions (3 mm height, 3 mm width and 2 mm depth). All IR-FDPs were manufactured using monolithic high translucent 3Y zirconia and the connector area to the cantilever pontic was adjusted to dimensions of 3 × 3 mm for all designs. The restorations were bonded using adhesive resin cement. The clinical and radiographic evaluations of the restorations were conducted for a duration of 18 months, following the modified FDI (World Dental Federation) criteria. RESULTS: The restorations were observed in stage one for a period of 18 months. Only one restoration in group LC was debonded after 10 months and re-bonded. The clinical quality of all crowns and the patient's satisfaction were high. No adverse soft tissue reactions around the crowns were observed and only one abutment in group IR was endodontically treated after 12 months. CONCLUSIONS: Zirconia cantilever IR-FDPs offer a viable short-term treatment option for replacing missing posterior teeth, providing esthetic and functional benefits while minimizing invasiveness. Over an 18-month observation period, these prostheses have demonstrated a remarkable survival rate of 100% and a success rate of 96.6%. These findings suggest the effectiveness and reliability of zirconia cantilever IR-FDPs as a short-term solution for replacing missing posterior teeth. CLINICAL SIGNIFICANCE: Zirconia cantilever IR-FDPs could present a practical solution for addressing posterior tooth loss, especially in cases where implant placement is not recommended and conventional fixed dental prostheses entail excessive invasiveness.

Dentists' Utilization of Caries Risk Assessment and Individualized Caries Prevention Methods in Pediatric Patients in Saudi Arabia.

Introduction: The first step in any complete oral health care plan for a child is a thorough caries risk assessment (CRA). This study aimed to investigate whether the practice dentists in Saudi Arabia's Western province do CRA methods and offer Individualized Caries Prevention (ICP) to their pediatric patients. Material and Methods: Dentists in active clinical practice in the Western province of Saudi Arabia were the participants of this cross-sectional survey. The participants in this study were chosen using a simple random sampling technique. A self-administered, structured questionnaire was used to gather participants' responses. Results: A majority (88.2%) of the dentists agreed that it is very important to practice CRA on a regular basis among their pediatric patients. About 67% of dentists employed Individualized Caries Prevention methods. No statistically significant correlation was observed between ICP and CRA factors, indicating that interventions primarily focused on patients' financial affordability. Conclusion: Dentists should encourage parents/caregivers to establish a dental home concept at the earliest, which includes CRA, education, and anticipatory guidance on the prevention of oral diseases.

Cantilever resin-bonded fixed dental prosthesis to substitute a single premolar: Impact of retainer design and ceramic material after dynamic loading.

PURPOSE: To evaluate the influence of retainer design and ceramic materials on the durability of minimally invasive cantilever resin-bonded fixed dental prostheses (RBFDPs) after artificial aging. METHODS: One hundred caries-free human mandibular molars were prepared as abutments for all-ceramic cantilevered fixed dental prostheses using the following retainer designs: One wing (OW), Two wings (TW), Inlay ring (IR), Lingual coverage (LC), and Occlusal coverage (OC). Two ceramic materials were used: monolithic high translucent zirconia(z) and zirconia-reinforced lithium disilicate (ZLS2) (n=10). All restorations were adhesively bonded with resin cement. The thermocycling of the specimens were performed between 5°C and 55°C for 10,000 cycles and then exposed to 240.000 cycles of dynamic loading on a chewing simulator. All surviving specimens were loaded onto the pontic until failure using a universal testing machine. RESULTS: The mean failure load ranged from 124.00 to 627.00 N for the zirconia groups and from 133.30 to 230.00 N for the ZLS2 groups. Regarding the materials, a significantly higher failure load was recorded in the zirconia groups than in the ZLS2 groups (P<0.001), except for OW (P=0.748). Regarding the retainer designs, a significant different failure load was recorded between the different designs except for IR and LC in the zirconia groups, IR and OC, OW and TW, and TW and LC in the ZLS2 groups (P<0.001). CONCLUSIONS: Zirconia IR, LC, and OC can be used as cantilever RBFDP in the premolar region. The fracture resistance of the ZLS2 design was below the normal bite force and should not be recommended as the first option.

Effect of different designs of minimally invasive cantilever resin-bonded fixed dental prostheses replacing mandibular premolar: Long-term fracture load and 3D finite element analysis.

PURPOSE: To evaluate the fracture load and stress magnitude of different retainer designs of minimally invasive cantilever resin-bonded fixed dental prostheses (RBFDPs) after artificial aging. MATERIALS AND METHODS: Fifty caries-free human mandibular molars were prepared as abutments for cantilever fixed dental prostheses using different retainer designs: one wing (OW), two wings (TW), inlay ring (IR), lingual coverage (LC), and occlusal coverage (OC). Computer-aided design and computer-aided manufacturing were used for milling the RBFDPs using fiber-reinforced composite (FRC), and the restorations were adhesively bonded. The specimens were then subjected to thermomechanical aging and loaded until failure. The 3D finite element analysis (FEA) was performed with five models of retainer designs similar to the in vitro test. Modified von Mises stress values on enamel, dentine, luting resin, and restorations were examined. Data were analyzed with Kruskal-Wallis and Mann-Whitney U tests (p < 0.001). RESULTS: A statistically significant difference (p < 0.001) was found between all groups except between IR and LC and between OW and TW designs, with the highest mean failure load detected for OC (534.70 N) and the lowest detected for OW (129.80 N). With regard to failure mode, OW, TW, and LC showed more incidences of favorable failure patterns than IR and OC designs. FEA showed that FRC transmitted low stresses in tooth structure and high stresses to the luting resin. CONCLUSIONS: LC and OC designs can be used to design cantilever RBFDPs in premolar area. IR design transmitted more stresses to the tooth structure and resulted in 30% catastrophic failure. OW and TW were below the normal occlusal force and should be carefully used.

Biomechanical behavior of posterior metal-free cantilever fixed dental prostheses: effect of material and retainer design.

OBJECTIVE: To study the fracture resistance and stress distribution pattern of translucent zirconia and fiber-reinforced composite cantilever resin-bonded fixed dental prostheses (RPFDPs) with two retainer designs. MATERIALS AND METHODS: Forty human mandibular molars were divided into two groups according to the retainer design. The restorations included a premolar pontic and 2 retainer designs: (D1) inlay ring retainer and (D2) lingual coverage retainer. Each main group was then divided according to the material used (n = 10): zirconia (Z) or fiber-reinforced composite (FRC) (F). Restorations were cemented using dual polymerizing adhesive luting resin. All specimens were thermo-cycled (5-55 °C for 10,000 cycles), then subjected to dynamic loading (50 N, 240,000, and 1.6 Hz) and fracture resistance test. The finite element analysis includes the two models of retainer designs used in the in vitro test. Modified von Mises stress values on enamel, dentin, luting resin, and restorations were examined when the restorations failed. RESULTS: A significantly higher failure load was recorded for zirconia groups (505.00 ± 61.50 and 548.00 ± 75.63 N for D1Z and D2Z, respectively) than for FRC groups (345.00 ± 42.33 and 375.10 ± 53.62 N for D1F and D2F, respectively) (P = 0.001). With regard to failure mode, D2 showed a more favorable failure pattern than D1. Model D2 resulted in lower stresses in tooth structure than model D1, and zirconia transmitted more stresses to the tooth structure than FRC. CONCLUSIONS: The lingual coverage retainer (D2) enhanced the biomechanical performance of the restoration/tooth complex. Considering the failure mode and tooth stress, FRC is a promising treatment option when constructing a cantilever RPFDP. CLINICAL RELEVANCE: Dentists should be aware of the biomechanical behavior during the selection of the material and for the replacement of a single missing mandibular premolar tooth with minimally invasive RBFDP.

Three-year clinical evaluation of zirconia and zirconia-reinforced lithium silicate crowns with minimally invasive vertical preparation technique.

OBJECTIVES: Large part of the tooth is required to be removed during crown preparation. A minimally invasive method for preparing single crowns is required to increase the durability of teeth. The aim of this study was to evaluate the clinical performance of two ceramic systems fabricated with minimally invasive vertical preparation. MATERIALS AND METHODS: Forty endodontically treated maxillary premolars were prepared with vertical preparation and received temporary crowns for a period of 21 days. Twenty zirconia-reinforced lithium silicate (Celtra Duo HT, Dentsply Sirona, Germany) and 20 monolithic high translucency zirconia (Katana HT, Kuarary Noritake, Japan) crowns were fabricated by CAD/CAM and cemented with dual-polymerizing luting resin. The crowns were evaluated clinically and radiographically for 36 months following modified FDI criteria. Statistical analysis was conducted with t Student test (Cochran Q). RESULTS: Over the follow-up period, there was no need to replace any of the study's crowns. The overall survival rate of the 40 crowns was 100% according to the Kaplan-Meier survival method. The clinical quality of all crowns and the patient's satisfaction were high. No caries was detected and no adverse soft tissue reactions around the crowns were observed. Periodontal probing depth was reported to be increased at mesial and distal sites more than the facial one in the 36-month follow-up with no statistically significant difference between both materials (P = 0.186). CONCLUSIONS: Zirconia and zirconia-reinforced lithium silicate could be used as a material for restoration of teeth prepared with vertical preparation technique. Both ceramic materials achieved good esthetic results, promotes healthy and stable soft tissues with no mechanical complications after 3 years of clinical evaluation. CLINICAL RELEVANCE: Monolithic high translucency zirconia and zirconia-reinforced lithium silicate ceramics can be used for the restorations of minimal invasive vertical preparation in premolar area with 0.5 mm margin thickness.

The Use of Polyetheretherketone (PEEK) as an Alternative Post and Core Material: Five-Year Follow-Up Report.

This clinical report demonstrated the use of polyetheretherketone (PEEK) for manufacturing of custom-made post and core in weakened endodontically treated central incisors. The PEEK structure was manufactured using computer-aided design/computer-aided manufacturing (CAD/CAM). The optimal fit of this custom-made endodontic post allowed a thinner cement layer; and removed the need to manufacture a core build-up. While supplementary clinical trials and in vitro studies are needed to totally elucidate the advantages and limitations of PEEK as an option for post and core manufacturing, this case report showed that it can be promising for a predictable and simplified treatment with five years of success.

pH dependent synthesis and characterization of bismuth molybdate nanostructure for photocatalysis degradation of organic pollutants.

Bismuth molybdate (Bi2MoO6) nanostructures has attracted many researches as an advanced photocalysts for the organic contaminants. In this paper, bismuth molybdate Bi2MoO6 nanoparticles were synthesized using a simple hydrothermal method at varied pH (2, 4, 6, 8, and 10) for 15 h at 180 °C. The results reveal the variation pH precursor solutions have a significant impact on the morphology, phase formations, and photocatalytic activity of samples. The synthesized samples at low pH level were characterized by FESEM analysis revealing Bi2MoO6 nanoplates have formed while gradually convert to Bi2MoO6 spherical nanoparticle at high PH level as shown in energy dispersive X-ray spectroscopy (DES) peaks. The X-ray diffraction patterns reveal characteristic peaks corresponding to mixed phases of Bi2MoO6 and cubic Bi4MoO9 at high pH value. The optical absorption study exhibit Bi2MoO6 nanoplates absorbed visible light with blue shift when compared to the cubic Bi4MoO9 structures. Moreover, the photocatalytic activity results revealed that nanoplates in pH = 4 sample has excellent photocatalytic activity for degradation of rhodamine (RhB), methylene orange (MO), and phenol under visible-light irradiation (λ > 400 nm) as well as exhibit the photodegradation 90% of phenol within 300 min.

Angiotensin 1-7 prevents the excessive force loss resulting from 14- and 28-day denervation in mouse EDL and soleus muscle.

Denervation leads to muscle atrophy, which is described as muscle mass and force loss, the latter exceeding expectation from mass loss. The objective of this study was to determine the efficiency of angiotensin (Ang) 1-7 at reducing muscle atrophy in mouse extensor digitorum longus (EDL) and soleus following 14- and 28-d denervation periods. Some denervated mice were treated with Ang 1-7 or diminazene aceturate (DIZE), an ACE2 activator, to increase Ang 1-7 levels. Ang 1-7/DIZE treatment had little effect on muscle mass loss and fiber cross-sectional area reduction. Ang 1-7 and DIZE fully prevented the loss of tetanic force normalized to cross-sectional area and accentuated the increase in twitch force in denervated muscle. However, they did not prevent the shift of the force-frequency relationship toward lower stimulation frequencies. The Ang 1-7/DIZE effects on twitch and tetanic force were completely blocked by A779, a MasR antagonist, and were not observed in MasR-/- muscles. Ang 1-7 reduced the extent of membrane depolarization, fully prevented the loss of membrane excitability, and maintained the action potential overshoot in denervated muscles. Ang 1-7 had no effect on the changes in α-actin, myosin, or MuRF-1, atrogin-1 protein content or the content of total or phosphorylated Akt, S6, and 4EPB. This is the first study that provides evidence that Ang 1-7 maintains normal muscle function in terms of maximum force and membrane excitability during 14- and 28-d periods after denervation.

Evaluation of zirconia and zirconia-reinforced glass ceramic systems fabricated for minimal invasive preparations using a novel standardization method.

OBJECTIVE: Currently, minimal invasive approaches combining less invasive finish line preparations and reduced ceramic thickness are required. The aim of this study was to evaluate the fracture resistance of two ceramic systems fabricated with two preparation designs using CAD/CAM standardization technology. MATERIALS AND METHODS: Forty intact human maxillary premolars were divided into two main groups according to the preparation technique. Group H (Horizontal): teeth with shoulder finish line and group V (Vertical): teeth with feather edge. Each main group was subdivided randomly into two subgroups according to the material used. Group CD (Celtra Duo) zirconia-reinforced glass ceramics and group K (KATANA) monolithic zirconia. CAD/CAM was used for standardization of natural teeth preparation. After cementation using self-adhesive resin cement, all specimens were subjected to 5000 thermal cycles and then were loaded until fracture. Failure types were evaluated using Stereomicroscopy and Scanning Electron Microscopy (SEM). RESULTS: Nonsignificant; the higher mean value was recorded with VCD group (482.5 ± 103.8 N) and VK group (1347.6 ± 177.4 N) vs HCD group (471 ± 107.6 N) and HK group (1255.6 ± 121.3 N). SEM findings showed that fractures occurred mainly at the occlusal side of the crowns. CONCLUSIONS: Vertical preparation showed a promising alternative to horizontal preparation. Moreover, both Celtra Duo and KATANA crowns can be used in premolar area with 0.5 mm margin thickness. CLINICAL SIGNIFICANCE: Zirconia-reinforced glass ceramic and monolithic zirconia crowns may not necessitate the preparation of invasive finish lines as the type of finish line did not impair the strength after aging conditions.

TuLIP (Tunnelled Line Intraluminal Plasty): An Alternative Technique for Salvaging Haemodialysis Catheter Patency in Fibrin Sheath Formation.

BACKGROUND: Renal patients with a tunnelled haemodialysis line are at risk of fibrin 'sheath' formation which can lead to occlusion. Dysfunctional lines are best treated by catheter exchange with a new subcutaneous tunnel; however, there is a risk of scarring, venous stenosis, potential loss of valuable access as well as the risk of infection. METHOD: We report a retrospective review of our experience using tunnelled line intraluminal plasty (TuLIP) in 11 patients over 16 months with fibrin sheath formation on pre-existing tunnelled haemodialysis catheters. RESULT: All patients responded well to treatment with median line patency post TuLIP reaching 112 days. CONCLUSION: TuLIP may have a role in extending catheter lifespan and delaying more invasive intervention.

Trauma induced heterotopic ossification patient serum alters mitogen activated protein kinase signaling in adipose stem cells.

Post-traumatic heterotopic ossification (HO) is the formation of ectopic bone in non-osseous structures following injury. The precise mechanism for bone development following trauma is unknown; however, early onset of HO may involve the production of pro-osteogenic serum factors. Here we evaluated serum from a cohort of civilian and military patients post trauma to determine early induction gene signatures in orthopaedic trauma induced HO. To test this, human adipose derived stromal/stem cells (hASCs) were stimulated with human serum from patients who developed HO following trauma and evaluated for a gene panel with qPCR. Pathway gene analysis ontology revealed that hASCs stimulated with serum from patients who developed HO had altered gene expression in the activator protein 1 (AP1) and AP1 transcriptional targets pathways. Notably, there was a significant repression in FOS gene expression in hASCs treated with serum from individuals with HO. Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway was activated in hASCs following serum exposure from individuals with HO. Serum from both military and civilian patients with trauma induced HO had elevated downstream genes associated with the MAPK pathways. Stimulation of hASCs with known regulators of osteogenesis (BMP2, IL6, Forskolin, and WNT3A) failed to recapitulate the gene signature observed in hASCs following serum stimulation, suggesting non-canonical mechanisms for gene regulation in trauma induced HO. These findings provide new insight for the development of HO and support ongoing work linking the systemic response to injury with wound specific outcomes.

Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat-related heterotopic ossification.

Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high-energy penetrating injuries and blast-related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast-related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo- and chondrogenic genes by POD-7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD-1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter-related mechanisms including anti-inflammatory, anti-proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135-1144, 2018.

Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification.

A pressing clinical need exists for 63% to 65% of combat-wounded service members and 11% to 20% of civilians who develop heterotopic ossification (HO) after blast-related extremity injury and traumatic injuries, respectively. The mammalian target of rapamycin pathway is a central cellular sensor of injury. We evaluated the prophylactic effects of rapamycin, a selective inhibitor of mammalian target of rapamycin signaling, on HO formation in a rat model of blast-related, polytraumatic extremity injury. Rapamycin was administered intraperitoneally daily for 14 days at 0.5 mg/kg or 2.5 mg/kg. Ectopic bone formation was monitored by micro-computed tomography and confirmed by histologic examination. Connective tissue progenitor cells, platelet-derived growth factor receptor-α-positive cells, and α-smooth muscle actin-positive blood vessels were assayed at postoperative day 7 by colony formation and immunofluorescence. Early gene expression changes were determined by low-density microarray. There was significant attenuation of 1) total new bone and soft tissue ectopic bone with 0.5 mg/kg (38.5% and 14.7%) and 2.5 mg/kg rapamycin (90.3% and 82.9%), respectively, 2) connective tissue progenitor cells, 3) platelet-derived growth factor receptor-α-positive cells, 4) α-smooth muscle actin-positive blood vessels, and 5) of key extracellular matrix remodeling (CD44, Col1a1, integrins), osteogenesis (Sp7, Runx2, Bmp2), inflammation (Cxcl5, 10, IL6, Ccl2), and angiogenesis (Angpt2) genes. No wound healing complications were noted. Our data demonstrate the efficacy of rapamycin in inhibiting blast trauma-induced HO by a multipronged mechanism.

Early local delivery of vancomycin suppresses ectopic bone formation in a rat model of trauma-induced heterotopic ossification.

Heterotopic ossification (HO) is a debilitating sequela of high-energy injuries. It frequently requires surgical excision once symptomatic and there is no practical prophylaxis for combat-injured patients. In this study, we examined the effect of local vancomycin powder on HO formation in a small animal model of blast-related, post-traumatic HO. Male Sprague-Dawley rats were subjected to a polytraumatic extremity injury and amputation with or without methicillin-resistant Staphylococcus aureus infection. Animals were randomized to receive a single local application of vancomycin (20 mg/kg) at the time of injury (POD-0, n = 34) or on postoperative day-3 (POD-3, n = 11). Quantitative volumetric measurement of ectopic bone was calculated at 12-weeks post-injury by micro-CT. Bone marrow and muscle tissues were also collected to determine the bacterial burden. Blood for serum cytokine analysis was collected at baseline and post-injury. Vancomycin treatment on POD-0 suppressed HO formation by 86% and prevented bone marrow and soft tissue infections. We concurrently observed a marked reduction histologically in nonviable tissue, chronic inflammatory cell infiltrates, bone infection, fibrous tissue, and areas of bone necrosis within this same cohort. Delayed treatment was significantly less efficacious. Neither treatment had a marked effect on the production of pro-inflammatory cytokines. Our study demonstrates that local vancomycin treatment at the time of injury significantly reduces HO formation in both the presence and absence of infection, with decreased efficacy if not given early. These findings further support the concept that the therapeutic window for prophylaxis is narrow, highlighting the need to develop early treatment strategies for clinical management. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2397-2406, 2017.