Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published (GA questions). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty-eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable. ICM, International Consensus Meeting; MSKI, musculoskeletal infections; RW, research workgroup. * 2018 ICM RW consensus on the current and projected incidences of infection, and costs per patient, for all orthopedic subspecialties. These estimates, which were compiled from information were obtained from: (i) recent peer-reviewed publications, (ii) analysis of 2015 national administrative data using HCUPNet (https://hcupnet.ahrq.gov/#setup), and (iii) RW expertise. 998 SCHWARZ ET AL.

IL-6 is a pleiotropic cytokine involved in cell signaling in the musculoskeletal system, but its role in bone healing remains uncertain. The purpose of this study was to examine the role of IL-6 in fracture healing. Eight-week-old male C57BL/6 and IL-6 -/- mice were subjected to transverse, mid-diaphyseal osteotomies on the right femora. Sacrifice time points were 1, 2, 4, or 6 weeks post-fracture (N=14 per group). Callus tissue properties was analyzed by microcomputed tomography (micro-CT) and Fourier transform infrared imaging spectroscopy (FT-IRIS). Cartilage and collagen content, and osteoclast density were measured histologically. In intact unfractured bone, IL-6 -/- mice had reduced crystallinity, mineral/matrix ratio, tissue mineral density (TMD), and bone volume fraction (BVF) compared to wildtype mice. This suggests that there was an underlying deficit in baseline bone quality in IL-6 -/- mice. At 2 weeks post-fracture, the callus of IL-6 -/- mice had reduced crystallinity and mineral/matrix ratio. These changes were less evident at 4 weeks. At 2 weeks, the callus of the IL-6 -/- mice had an increased tissue mineral density (TMD), an increased cartilage and collagen content, and reduced osteoclast density compared to these parameters in wildtype mice. By 4 and 6 weeks, these parameters were no longer different between the two strains of mice. In conclusion, IL-6 -/- mice had delayed callus maturity, mineralization, and remodeling compared with the callus of the wildtype mice. These effects were transient indicating that the role of IL-6 appears to be most important in the early stages of fracture healing.

Osteomyelitis is an infection of bone that can result from contiguous spread from surrounding tissue, direct bone trauma due to surgery or injury, or haematogenous spread from systemic bacteraemia. It remains a significant health-care burden with a prevalence of ~22 cases per 100,000 person-years in the United States, and its incidence has been rising over time, especially in the elderly and individuals with diabetes 1 . Although it is a heterogeneous disease, subset classifications include implant-associated osteomyelitis (including peri-prosthetic joint infection (PJI) and instrumented spinal infections), fracture-related infection, acute haematogenous osteomyelitis, diabetic foot infection, septic arthritis and native spinal osteomyelitis.Crucial to expanding our understanding of osteomyelitis and advancing treatment algorithms has been the application of animal models, which illustrate the interaction between the pathogen and cells of both the immune and skeletal systems in a manner that in vitro models cannot yet replicate. Animal models are available to study virtually all aspects of skeletal infection, and typically involve inoculation of bacteria at the time of implant placement (Fig. 1). They can vary in complexity from simple models where metal implants are placed under the skin (for example, tissue cage 2 ) or into cortical bone (for example, metal wire 3 ) versus more complex models that mimic functional orthopaedic devices 4 . Additionally, approaches have been developed to induce non-implant infections by haematogenous inoculation into the tail vein 5 , direct inoculation into vertebral bodies or intervertebral discs 6 to induce vertebral osteomyelitis, or inoculation into the foot pad of diabetic obese rodents to induce diabetic foot infection 7 .As disease pathogenesis differs across different infection classes, so does microbial aetiology. Many different microorganisms have been implicated in skeletal infection, and the most common, along with their incidence and tropism, are shown in Table 1. In general, Staphylococcus aureus and coagulase-negative staphylococci (CoNS), such as Staphylococcus epidermidis and Staphylococcus lugdunensis, are responsible for up to two-thirds of all skeletal infections, with S. aureus being the most prevalent single pathogen. Additionally, antimicrobial resistance remains a challenge in osteomyelitis treatment with up to 50% of cases of S. aureus osteomyelitis caused by methicillin-resistant S. aureus (MRSA) strains 8 . Other less commonly identified pathogens include Enterococcus spp., Pseudomonas aeruginosa, Escherichia coli and Cutibacterium acnes (Table 1). Most cases of osteomyelitis are monomicrobial; however,

S. aureus biofilm creates a favorable environment that increases antibiotic resistance, impairs host immunity, and increases tolerance to nutritional deprivation. Secreted proteins from bacterial cells within the biofilm and the quorum-sensing agr system contribute to immune evasion. Additional immunoevasive properties of S. aureus include the formation of staphylococcal abscess communities (SACs) and canalicular invasion. Novel approaches to target biofilm and increase resistance to implant colonization include novel antibiotic therapy, immunotherapy, and local implant treatments. Challenges remain given the diverse mechanisms developed by S. aureus to alter the host immune responses. Further understanding of these processes should provide novel therapeutic mechanisms to enhance eradication after PJI.

➤ Artificial intelligence (AI) provides machines with the ability to perform tasks using algorithms governed by pattern recognition and self-correction on large amounts of data to narrow options in order to avoid errors.➤ The 4 things necessary for AI in medicine include big data sets, powerful computers, cloud computing, and open source algorithmic development.➤ The use of AI in health care continues to expand, and its impact on orthopaedic surgery can already be found in diverse areas such as image recognition, risk prediction, patient-specific payment models, and clinical decision-making.➤ Just as the business of medicine was once considered outside the domain of the orthopaedic surgeon, emerging technologies such as AI warrant ownership, leverage, and application by the orthopaedic surgeon to improve the care that we provide to the patients we serve.➤ AI could provide solutions to factors contributing to physician burnout and medical mistakes. However, challenges regarding the ethical deployment, regulation, and the clinical superiority of AI over traditional statistics and decision-making remain to be resolved.