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Thomas Ferbert, Christina Münch, Sebastian Findeisen, William Pauly, Matthias Miska, Tobias Grossner, Michael C Tanner, Gerhard Schmidmaier, Lars Helbig Clinic for Trauma and Reconstructive Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg, D-69118, GermanyCorrespondence: Lars Helbig, Clinic for Trauma and Reconstructive Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, Heidelberg, D-69118, Germany, Tel +496221/5635371, Fax +496221/5626300, Email lars.helbig@med.uni-heidelberg.dePurpose: A central aspect of the treatment of non-unions is the filling of bone defects. The quantity of available autologous bone for this purpose is limited. Alternatively, or additionally, bone substitutes may be used. The aim of this retrospective, single-center study including 404 non-unions in 393 patients is to investigate the effect of tricalcium phosphate (TCP) on the healing of non-unions. Furthermore, the influence of gender, age, smoking status, comorbidities, type of surgical procedure, presence of infection, and length of treatment was investigated.Methods: We evaluated three groups of patients. Group 1 received TCP + BG, group 2 received BG alone and group 3 received no augmentation. Bone stability was assessed 1 and 2 years after non-union revision surgery through analysis of radiographs using the Lane Sandhu Score. Scores ≥ 3 were rated as stable Other influencing factors were collected from the electronic medical record.Results: In 224 non-unions, bone defects were filled with autologous bone and TCP (TCP+BG). In 137 non-unions, bone defects were filled with autologous bone (BG), and in 43 non-unions presenting non-relevant defects, neither autologous bone nor TCP were used (NBG). After 2 years, 72.7% of the TCP+BG patients, 90.1% of the BG patients and 84.4% of the NBG patients achieved a consolidation score ≥ 3. Advanced age, presence of comorbidities and longer treatment period had a significantly negative effect on consolidation 1 year after surgery. Longer treatment periods also showed a negative significant effect after 2 years. It is notable that larger defects, mainly treated with the combination of autologous bone and TCP, showed similar healing rates to that of smaller defects after 2 years.Conclusion: The combination of TCP and autologous bone-grafts shows good results in the reconstruction of complicated bone-defects, but patience is required since the healing period exceeds 1 year in most patients.Keywords: non-unions, bone substitute, Lane Sandhu Score, tricalcium phosphate

Michael C Tanner,1 Raban Arved Heller,1– 3 Andreas Grimm,1 Stefan Zimmermann,4 Maximilian Pilz,5 Louisa Jurytko,1 Matthias Miska,1 Lars Helbig,1 Gerhard Schmidmaier,1 Patrick Haubruck1,6 1HTRG – Heidelberg Trauma Research Group, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Trauma and Reconstructive Surgery, Heidelberg University Hospital, Heidelberg, D-69118, Germany; 2Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt Universität Zu Berlin, Berlin Institute of Health, Berlin, D-13353, Germany; 3Department of General Practice and Health Services Research, Heidelberg University Hospital, Heidelberg, D-69120, Germany; 4Division Bacteriology, Department of Infectious Diseases, Heidelberg University Hospital, Heidelberg, D-69120, Germany; 5Institute of Medical Biometry and Informatics, Heidelberg University Hospital, Heidelberg, D-69120, Germany; 6Raymond Purves Bone and Joint Research Laboratory, Institute of Bone and Joint Research, Kolling Institute, Royal North Shore Hospital, University of Sydney, St. Leonards, New South Wales, A-2068, AustraliaCorrespondence: Patrick HaubruckRaymond Purves Bone and Joint Research Laboratory, Institute of Bone and Joint Research, Kolling Institute, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, A-2068, AustraliaTel +61 (0) 437320789Email patrick.haubruck@sydney.edu.auBackground: Occult infections (OI) lack typical inflammatory signs, making them challenging to diagnose. Uncertainty remains regarding OI’s influence on the outcome of autologous bone grafting (ABG), and evidence-based recommendations regarding an appropriate course of action are missing. Thus, we sought to determine the incidence of an OI in patients receiving ABG, evaluate whether it influences the outcome of ABG and whether associated risk factors have a further negative influence.Methods: This study was designed as a large size single-center case-control study investigating patients treated between 01/01/2010 and 31/12/2016 with a minimum follow-up of 12 months. Patients ≥ 18 years presenting with a recalcitrant non-union of the lower limb receiving surgical bone reconstruction, including bone grafting, were included. A total of 625 patients were recruited, and 509 patients included in the current study. All patients received surgical non-union therapy based on the “diamond concept” including bone reconstruction using ABG. Additionally, multiple tissue samples were harvested and microbiologically analyzed. Tissue samples were microbiologically evaluated regarding an OI. Bone healing was analyzed using clinical and radiological parameters, patient characteristics and comorbidities investigated and ultimately results correlated.Results: Forty-six out of 509 cases with OI resulted in an incidence of 9.04%. Overall consolidation time was increased by 15.08 weeks and radiological outcome slightly impaired (79.38% vs 71.42%), differences were at a non-significant extent. Diabetes mellitus had a significant negative influence on consolidation time (p=0.0313), while age (p=0.0339), smoking status (p=0.0337), diabetes mellitus (p=0.0400) and increased BMI (p=0.0315) showed a significant negative influence on the outcome of bone grafting.Conclusion: Surgeons treating recalcitrant non-unions should be aware that an OI is common. If an OI is diagnosed subsequent to ABG the majority of patients does not need immediate revision surgery. However, special attention needs to be paid to high-risk patients.Keywords: infection, bone healing, bone regeneration, non-union, bone infection

Lars Helbig,1 Maren Bechberger,2 Riyadh Aldeeri,1 Adriana Ivanova,1 Patrick Haubruck,1 Matthias Miska,1 Gerhard Schmidmaier,1 Georg W Omlor1 1Department of Orthopaedics, Trauma Surgery and Paraplegiology, 2Pharmacy Department, Heidelberg University Hospital, Heidelberg, Germany Purpose: Infected nonunions of the long bones belong to the most feared complications in the field of orthopedic and trauma surgery. Optimal antibiotic therapy should start early with the first revision surgery. Therefore, the aim of this study was to evaluate our peri- and postoperative antibiotic regime in context with the microbial spectrum and antibiotic resistances of patients with infected nonunions and to assess the possible impact on healing rates. Methods: We included all patients with first revision surgery during 2010–2015 due to nonunion of long bones with a clinical history of infection treated with radical debridement, local application of a gentamicin-impregnated bone cement, and systemic cefuroxime. Mean follow-up was 34.2 months. Data collection was performed retrospectively using a computerized databank with information about microbial species from intraoperatively acquired tissue samples and respective antibiograms. Bone fusion rates were evaluated based on findings of the latest X-rays and computed tomography scans.Results: Two hundred and twelve patients with nonunion and history of infection were selected; 171 patients had positive intraoperative microbial evidence of infection. Bacterial testing was mostly positive in fractures of the tibia (47.4%) and the femur (27.5%). Coagulase-negative Staphylococcus spp. were the most frequently detected (44.4%) followed by mixed infections (18.7%) and Staphylococcus aureus (10.5%). Antibiograms revealed that 62.6% of our cases were cefuroxime sensitive; 87.7% were gentamicin sensitive. Only 10.5% showed resistance to both cefuroxime and gentamicin. There was no statistically significant difference of fusion rates between patients with different microbial species or different antibiograms. Conclusion: Our data suggest that besides the high variety of different detected species, initial antibiotic treatment with a combination of systemic cefuroxime and local gentamicin-loaded bone cement is effective and in almost 90% the later determined microbial infection was sensitive to this treatment. Therefore, we recommend initial treatment according to this algorithm until specific antibiograms are available from intraoperatively acquired tissue samples. Keywords: infected nonunions, antibiotic treatment, microbial spectrum, antibiogram

Discusses the abstract of the study 'Protein requirements of bison bulls fed for meat ,' presented at the American Society of Animal Science's Midwestern Branch conference on March 17-19, 2003, in Des Moines, Iowa.

Background: Managing bone defects in non-union surgery remains challenging, especially in cases of large defects exceeding 5 cm in size. Historically, amputation and compound osteosynthesis with a remaining PMMA spacer have been viable and commonly used options. The risk of non-union after fractures varies between 2% and 30% and is dependent on various factors. Autologous bone grafts from the iliac crest are still considered the gold standard but are limited in availability, prompting consideration of artificial grafts., Objectives: The aims and objectives of the study are as follows: 1. To evaluate the radiological outcome of e.g., the consolidation and thus the stability of the bone (three out of four consolidated cortices/Lane-Sandhu-score of at least 3) by using S53P4-type bioactive glass (BaG) as a substitute material for large-sized bone defects in combination with autologous bone using the RIA technique. 2. To determine noticeable data-points as a base for future studies., Methods: In our clinic, 13 patients received bioactive glass (BaG) as a substitute in non-union therapy to promote osteoconductive aspects. BaG is a synthetic material composed of sodium, silicate, calcium, and phosphate. The primary endpoint of our study was to evaluate the radiological consolidation of bone after one and two years. To assess bone stabilization, we used a modified Lane-Sandhu score, considering only radiological criteria. A bone was considered stabilized if it achieved a minimum score of 3. For full consolidation (all four cortices consolidated), a minimum score of 4 was required. Each bone defect exceeded 5 cm in length, with an average size of 6.69 ± 1.92 cm., Results: The mean follow-up period for patients without final bone consolidation was 34.25 months, with a standard deviation of 14.57 months, a median of 32.00 months and a range of 33 months. In contrast, patients with a fully consolidated non-union had an average follow-up of 20.11 ± 15.69 months and a range of 45 months. Overall, the mean time from non-union surgery to consolidation for patients who achieved final union was 14.91 ± 6.70 months. After one year, six patients (46.2%) achieved complete bone consolidation according to the Lane-Sandhu score. Three patients (23.1%) displayed evident callus formation with expected stability, while three patients (23.1%) did not develop any callus, and one patient only formed a minimal callus with no expected stability. After two years, 9 out of 13 patients (69.2%) had a score of 4. The remaining four patients (30.8%) without expected stability either did not heal within two years or required a revision during that time., Conclusions: Bioactive glass (BaG) in combination with autologous bone (RIA) appears to be a suitable filler material for treating extensive non-unions of the femur and tibia. This approach seems to show non-inferiority to treatment with Tricalcium Phosphate (TCP). To ensure the success of this treatment, it is crucial to validate the procedure through a randomized controlled trial (RCT) with a control group using TCP, which would provide higher statistical power and more reliable results.

Background: The treatment of large-sized bone defects remains a major challenge in trauma and orthopaedic surgery. Although there are many treatment options, there is still no clear guidance on surgical management, and the influence of defect size on radiological and clinical outcome remains unclear due to the small number of affected patients. The aim of the present study was to determine the influence of defect size on the outcome of atrophic and infected nonunions of the tibia or the femur based on the diamond concept in order to provide recommendations for treatment guidance., Patients and Methods: All medical records, surgical reports, laboratory data and radiological images of patients treated surgically for atrophic or infected nonunions of the lower limbs (femur or tibia) between 1 January 2010 and 31 December 2020 were examined. Patients with proximal, diaphyseal or distal nonunions of the femur or tibia who were surgically treated at our institution according to the "diamond concept" and attended our standardised follow-up program were included in a database. Surgical treatment was performed as a one- or two-step procedure, depending on the type of nonunion. Patients with a segmental bone defect ≥5 cm were matched with patients suffering a bone defect <5 cm based on five established criteria. According to our inclusion and exclusion criteria, 70 patients with a bone defect ≥5 cm were suitable for analysis. Two groups were formed by matching: the study group (bone defect ≥5 cm; n = 39) and control group (bone defect <5 cm; n = 39). The study was approved by the local ethics committee (S-262/2017)., Results: The mean defect size was 7.13 cm in the study and 2.09 cm in the control group. The chi-square test showed equal consolidation rates between the groups (SG: 53.8%; CG: 66.7%). However, the Kaplan-Meier curve and log-rank test showed a significant difference regarding the mean duration until consolidation was achieved, with an average of 15.95 months in the study and 9.24 months in the control group (α = 0.05, p = 0.001). Linear regression showed a significant increase in consolidation duration with increasing defect size (R 2 = 0.121, p = 0.021). Logistic regression modelling showed a significant negative correlation between consolidation rate and revision performance, as well as an increasing number of revisions, prior surgeries and total number of surgeries performed on the limb. Clinical outcomes showed equal full weight bearing of the lower extremity after 5.54 months in the study vs. 4.86 months in the control group ( p = 0.267)., Conclusion: Surprisingly, defect size does not seem to have a significant effect on the consolidation rate and should not be seen as a risk factor. However, for the treatment of large-sized nonunions, the follow-up period should be prolonged up to 24 months, due to the extended time until consolidation will be achieved. This period should also pass before a premature revision with new bone augmentation is performed. In addition, it should be kept in mind that as the number of previous surgeries and revisions increases, the prospects for consolidation decrease and a change in therapeutic approach may be required.

Background: Patients with atraumatic abdominal pain are common in the emergency department and have a relatively high hospital mortality, with a very wide spectrum of different causes. Rapid, goal-directed diagnosis is essential in this context., Methods: In a Delphi process with representatives of different disciplines, a diagnostic treatment pathway was designed, which is called the Abdominal Pain Unit (APU)., Results: The treatment pathway was designed as an extended event process chain. Crucial decision points were specified using standard operating procedures., Discussion: The APU treatment pathway establishes a consistent treatment structure for patients with atraumatic abdominal pain. It has the potential to improve the quality of care and reduce intrahospital mortality over the long term., (© 2021. The Author(s).)

The treatment of non-unions is often complicated by segmental bone defects and bacterial colonization. Because of the limited availability of autologous bone grafts, tissue engineering focuses on antibiotic-loaded bone graft substitutes. HACaS+G is a resorbable calcium sulphate-hydroxyapatite loaded with gentamicin. The osteoinductive, osteoconductive, and anti-infective effect of HACaS+G has already been demonstrated in clinical studies on patients with chronic osteomyelitis. However, especially for the treatment of infected non-unions with segmental bone defects by HACaS+G, reliable clinical testing is difficult and sufficient experimental data are lacking. We used an already established sequential animal model in infected and non-infected rat femora to investigate the osteoinductive, osteoconductive, and anti-infective efficacy of HACaS+G for the treatment of infected non-unions. In biomechanical testing, bone consolidation could not be observed under infected and non-infected conditions. Only a prophylactic effect against infections, but no eradication, could be verified in the microbiological analysis. Using µ-CT scans and histology, osteoinduction was detected in both the infected and non-infected bone, whereas osteoconduction occurred only in the non-infected setting. Our data showed that HACaS+G is osteoinductive, but does not have added benefits in infected non-unions in terms of osteoconduction and mechanical bone stability, especially in those with segmental bone defects.

Bone tissue engineering is a fast-growing field in regenerative medicine. Consequently, there is a high demand for new, fast and reliable methods to track and quantify the osteogenic differentiation of cells. Recently, a novel method was published to non-destructively quantify the hydroxyapatite content of monolayer and 3-dimensional mesenchymal stem cell cultures using the ability of 99 m Technetium-methylene diphosphonate (MDP), a well-established tracer in clinical nuclear medicine, to bind to newly synthesized hydroxyapatite. In the present study, two other commonly used 99 m Technetium tracers, 2,3-dicarboxypropane-1,1-diphosphonate (DPD) and hydroxydiphosphonate (HDP), were evaluated to see if they could also be used for the same purpose. Furthermore, we investigated if labelling at various timepoints influenced the effectiveness of the labelling. The results were analysed using one-factor ANOVA followed by Bonferroni post-hoc testing. This revealed a highly significant difference between the three osteogenic groups at each timepoint compared to their corresponding negative controls. However, there was no statistically significant difference between the three different tracers (MDP, DPD, HDP) in the osteogenic groups. Therefore all three tracers are of similar value when quantifying the extracellular hydroxylapatite content in osteogenic stem cells cultures., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

This study aims to improve emergency department (ED) care for patients suffering from atraumatic abdominal pain. An application-supported pathway for the ED will be implemented, which supports quick, evidence-based, and standardized diagnosis and treatment steps for patients with atraumatic abdominal pain at the ED. A mixed-methods multicentre cluster randomized controlled stepped wedge trial design will be applied. A total of 10 hospitals with EDs (expected n = 2.000 atraumatic abdominal pain patients) will consecutively (every 4 months) be randomized to apply the intervention. Inclusion criteria for patients are a minimum age of 18 years, suffering from atraumatic abdominal pain and being insured with a German statutory health insurance. Primary outcomes: acute pain score at time of discharge from ED, duration of treatment at the ED, patient-reported satisfaction. Secondary endpoints include patient safety and quality of care parameters, process evaluation parameters, and costs and cost-effectiveness parameters. Quantitative data will be gathered from patient-surveys, clinical records, and routine data from hospital information systems as well as from a participating German statutory health insurance. Descriptive and analytic statistical analysis will be performed to provide summaries and associations for primary patient-reported outcomes, process measures, quality measures, and costs. Qualitative data collection consists of participatory patient observations and semi-structured expert interviews, which will be inductively analysed. Findings will be disseminated in publications in peer-reviewed journals, on conferences, as well as via a project website. To ensure data protection, appropriate technical and organisational measures will be taken. Trial registration: DRKS00021052., Competing Interests: The authors have declared that no competing interests exist.

The treatment of infected and non-infected non-unions remains a major challenge in trauma surgery. Due to the limited availability of autologous bone grafts and the need for local anti-infective treatment, bone substitutes have been the focus of tissue engineering for years. In this context, bioactive glasses are promising, especially regarding their anti-infective potential, which could reduce the need for local and systemic treatment with conventional antibiotics. The aim of this study was to investigate the osteoinductive and osteoconductive effects, as well as the anti-infectious potential, of S53P4 using a standardized non-union model, which had not been investigated previously. Using an already established sequential animal model in infected and non-infected rat femora, we were able to investigate bioactive glass S53P4 under realistic non-union conditions regarding its osteoinductive, osteoconductive and anti-infective potential with the use of µCT scans, biomechanical testing and histological, as well as microbiological, analysis. Although S53P4 did not lead to a stable union in the non-infected or the infected setting, µCT analysis revealed an osteoinductive effect of S53P4 under non-infected conditions, which was diminished under infected conditions. The osteoconductive effect of S53P4 remained almost negligible in histological analysis, even 8 weeks after treatment. Additionally, the expected anti-infective effect could not be demonstrated. Our data suggested that S53P4 should not be used in infected non-unions, especially in those with large bone defects.

Non-unions continue to present a challenge to trauma surgeons, as current treatment options are limited, duration of treatment is long, and the outcome often unsatisfactory. Additionally, standard treatment with autologous bone grafts is associated with comorbidity at the donor site. Therefore, alternatives to autologous bone grafts and further therapeutic strategies to improve on the outcome and reduce cost for care providers are desirable. In this study in Sprague-Dawley rats we employed a recently established sequential defect model, which provides a platform to test new potential therapeutic strategies on non-unions while gaining mechanistic insight into their actions. The effects of a combinatorial treatment of a bone graft substitute (HACaS+G) implantation and systemic PTH administration was assessed by µ-CT, histological analysis, and bio-mechanical testing and compared to monotreatment and controls. Although neither PTH alone nor the combination of a bone graft substitute and PTH led to the formation of a stable union, our data demonstrate a clear osteoinductive and osteoconductive effect of the bone graft substitute. Additionally, PTH administration was shown to induce vascularization, both as a single adjuvant treatment and in combination with the bone graft substitute. Thus, systemic PTH administration is a potential synergistic co-treatment to bone graft substitutes.

Parental evaluation of behavioral problems in children with developmental language disorder Abstract. Objective: Children with developmental language disorder (DLD) often suffer from problems in everyday communication and react with social withdrawal or oppositional behavior. In light of the lack of studies in preschool children regarding this topic, the present study analyzes the occurrence of behavioral problems in children with DLD aged 4;0 to 5;11 years. Furthermore, we assessed differences in parental perception regarding their child's behavior. Methods: This monolingual, Caucasian study sample consisted of 30 children with DLD and 40 healthy controls. The groups were matched for nonverbal IQ and socioeconomic status. All children were examined for their language proficiency level. The Child Behavior Checklist was used to detect behavioral problems. Results: The study revealed significant differences between children with DLD and the control group on several syndrome scales including the total problem scale. Children with DLD always showed more severe symptoms and also reached T-scores in clinical range ( ≥ 64) significantly more often. The parental perception did not differ. Conclusions: The results indicate the presence of behavioral problems in children with DLD already in preschool age. In particular, we found social problems, attention problems, and internalizing disorders.

Background: The treatment of fracture-related infections (FRI) is still a challenge for orthopedic surgeons. The prevalence of FRI is particularly high in open fractures with extensive soft-tissue damage. This study aimed to develop a new two-step animal model for non-unions with segmental bone defects, which could be used to evaluate new innovative bone substitutes to improve the therapeutic options in humans with FRI and bone defects., Methods: After randomization to infected or non-infected groups, 30 Sprague-Dawley rats underwent a transverse osteotomy of the mid-shaft femur with a 5 mm defect. Additionally, the periosteum at the fracture zone was cauterized at both sides. After intramedullary inoculation with 10 3  CFU Staphylococcus aureus (infected group) or PBS (non-infected group), a fracture stabilization was done by intramedullary K-wires. After 5 weeks, the bone healing process was evaluated, and revision surgery was performed in order to obtain increased bone healing. The initial K-wires were removed, and debridement of the osteotomy-gap was done followed by a more stable re-osteosynthesis with an angle-stable plate. After further 8 weeks all rats were euthanized and the bone consolidation was tested biomechanically and the callus formation quantitatively by micro-CT analysis., Results: We developed and presented a new two-stage non-union animal model through a targeted S. aureus infection. After 5 weeks, all animals showed a non-union irrespective of assignment to the infected and non-infected group. Lane and Sandhu score showed a higher callus formation in the infected group. In all infected animals, the inoculated S. aureus strain was detected in the revision surgery. The second surgery did not improve bone healing, as shown by the Lane Sandhu score and in the μ-CT analysis. Similarly, biomechanical testing showed in both groups a significantly lower maximum torque as compared to the contralateral side (p < 0.0001)., Conclusions: We were able to successfully develop a new two-stage non-union animal model, which reflects a genuine clinical situation of an infection-related non-union model with segmental bone defects. This model could be used to evaluate various therapeutic anti-infectious and osteoinductive strategies in FRIs.

Abnormal blood vessels and hypoxic and necrotic regions are common features of solid tumors and related to the malignant phenotype and therapy resistance. Certain obligate or facultative anaerobic bacteria exhibit inherent ability to colonize and proliferate within solid tumors in vivo. Escherichia coli Nissle 1917 (EcN), a non-pathogenic probiotic in European markets, has been known to proliferate selectively in the interface between the viable and necrotic regions of solid tumors. The objective of this study was to establish a tumor-targeting therapy system using the genetically engineered EcN for targeted delivery of cytotoxic compounds, including colibactin, glidobactin and luminmide. Biosynthetic gene clusters of these cytotoxic compounds were introduced into EcN and the corresponding compounds were detected in the resultant recombinant EcN strains. The recombinant EcN showed significant cytotoxic activity in vitro and in vivo as well, and significantly suppressed the tumor growth. Together, this study confirmed efficient tumor-targeting colonization of EcN and demonstrated its potentiality in the tumor-specific delivery of cytotoxic compounds as a new tumor-targeting therapy system., (Copyright © 2018. Published by Elsevier Masson SAS.)