Targeted Mutations in the Fusion Peptide Region of La Crosse Virus Attenuate Neuroinvasion and Confer Protection against Encephalitis.

La Crosse virus (LACV) is a major cause of pediatric encephalitis and aseptic meningitis in the Midwestern, Mid-Atlantic, and Southern United States, where it is an emerging pathogen. The LACV Gc glycoprotein plays a critical role in the neuropathogenesis of LACV encephalitis as the putative virus attachment protein. Previously, we identified and experimentally confirmed the location of the LACV fusion peptide within Gc and generated a panel of recombinant LACVs (rLACVs) containing mutations in the fusion peptide as well as the wild-type sequence. These rLACVs retained their ability to cause neuronal death in a primary embryonic rat neuronal culture system, despite decreased replication and fusion phenotypes. To test the role of the fusion peptide in vivo, we tested rLACVs in an age-dependent murine model of LACV encephalitis. When inoculated directly into the CNS of young adult mice (P28), the rLACV fusion peptide mutants were as neurovirulent as the rLACV engineered with a wild-type sequence, confirming the results obtained in tissue culture. In contrast, the fusion peptide mutant rLACVs were less neuroinvasive when suckling (P3) or weanling (P21) mice were inoculated peripherally, demonstrating that the LACV fusion peptide is a determinant of neuroinvasion, but not of neurovirulence. In a challenge experiment, we found that peripheral challenge of weanling (P21) mice with fusion peptide mutant rLACVs protected from a subsequent WT-LACV challenge, suggesting that mutations in the fusion peptide are an attractive target for generating live-attenuated virus vaccines. Importantly, the high degree of conservation of the fusion peptide amongst the Bunyavirales and, structurally, other arboviruses suggests that these findings are broadly applicable to viruses that use a class II fusion mechanism and cause neurologic disease.

A study protocol for a Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin versus Saline in Open Tibia Fractures (pGO-Tibia) in Dar es Salaam, Tanzania.

BACKGROUND: Open tibia fractures are a major source of disability in low- and middle-income countries (LMICs) due to the high incidence of complications, particularly infection and chronic osteomyelitis. One proposed adjunctive measure to reduce infection is prophylactic local antibiotic delivery, which can achieve much higher concentrations at the surgical site than can safely be achieved with systemic administration. Animal studies and retrospective clinical studies support the use of gentamicin for this purpose, but no high-quality clinical trials have been conducted to date in high- or low-income settings. METHODS: We describe a protocol for a pilot study conducted in Dar es Salaam, Tanzania, to assess the feasibility of a single-center masked randomized controlled trial to compare the efficacy of locally applied gentamicin to placebo for the prevention of fracture-related infection in open tibial shaft fractures. DISCUSSION: The results of this study will inform the design and feasibility of a definitive trial to address the use of local gentamicin in open tibial fractures. If proven effective, local gentamicin would be a low-cost strategy to reduce complications and disability from open tibial fractures that could impact care in both high- and low-income countries. TRIAL REGISTRATION: ClinicalTrials.gov, Registration # NCT03559400 ; Registered June 18, 2018.

Analysis and Review of Automated Risk Calculators Used to Predict Postoperative Complications After Orthopedic Surgery.

PURPOSE OF REVIEW: To discuss the automated risk calculators that have been developed and evaluated in orthopedic surgery. RECENT FINDINGS: Identifying predictors of adverse outcomes following orthopedic surgery is vital in the decision-making process for surgeons and patients. Recently, automated risk calculators have been developed to quantify patient-specific preoperative risk associated with certain orthopedic procedures. Automated risk calculators may provide the orthopedic surgeon with a valuable tool for clinical decision-making, informed consent, and the shared decision-making process with the patient. Understanding how an automated risk calculator was developed is arguably as important as the performance of the calculator. Additionally, conveying and interpreting the results of these risk calculators with the patient and its influence on surgical decision-making are paramount. The most abundant research on automated risk calculators has been conducted in the spine, total hip and knee arthroplasty, and trauma literature. Currently, many risk calculators show promise, but much research is still needed to improve them. We recommend they be used only as adjuncts to clinical decision-making. Understanding how a calculator was developed, and accurate communication of results to the patient, is paramount.

Outcomes and Quality of Life Improvement After Multilevel Spinal Fusion in Elderly Patients.

STUDY DESIGN: Retrospective case series. OBJECTIVES: Both the rate and complexity of spine surgeries in elderly patients has increased. This study reports the outcomes of multilevel spine fusion in elderly patients and provides evidence on the appropriateness of complex surgery in elderly patients. METHODS: We identified 101 patients older than70 years who had ≥5 levels of fusion. Demographic, medical, and surgical data, and change between preoperative and >500 days postoperative health survey scores were collected. Health surveys were visual analogue scale (VAS), EuroQoL 5 Dimensions (EQ-5D), Oswestry Disability Index (ODI), Scoliosis Research Society questionnaire (SRS-30), and Short Form health survey (SF-12) (physical composite score [PCS] and mental composite score [MCS]). Minimal clinically important differences (MCIDs) were defined for each survey. RESULTS: Complications included dural tears (19%), intensive care unit admission (48%), revision surgery within 2 to 5 years (24%), and death within 2 to 5 years (16%). The percentage of patients who reported an improvement in health-related quality of life (HRQOL) of at least an MCID was: VAS Back 69%; EQ-5D 41%; ODI 58%; SRS-30 45%; SF-12 PCS 44%; and SF-12 MCS 48%. Improvement after a primary surgery, as compared with a revision, was on average 13 points higher in ODI (P = .007). Patients who developed a surgical complication averaged an improvement 11 points lower on ODI (P = .042). Patients were more likely to find improvement in their health if they had a lower American Society of Anesthesiologists or Charlson Comorbidity Index score or a higher metabolic equivalent score. CONCLUSIONS: In multilevel surgery in patients older than 70 years, complications are common, and on average 77% of patients attain some improvement, with 51% reaching an MCID. Physiological status is a stronger predictor of outcomes than chronological age.

Practice Patterns for Management of Pediatric Femur Fractures in Low- and Middle-Income Countries.

BACKGROUND: Femoral shaft fractures in children are common in low and middle income countries. In high-income countries, patient age, fracture pattern, associated injuries, child/family socioeconomic status, and surgeon preference dictate fracture management. There is limited literature on treatment patterns for pediatric femur fractures in resource-limited settings. This study surveys surgeons from low (LIC), lower-middle (LMIC), and upper-middle income (UMIC) countries regarding treatment patterns for pediatric femur fractures. METHODS: Surgeons completed an electronic survey reporting surgeon demographics and treatment preference for pediatric femur fractures. Treatment preferences and indications for treatment were separated into 4 groups: infant (0 to 6 mo); toddler (7 mo to 4 y); child (5 to 12 y); adolescent (12 to 17 y). The survey was available in English, Spanish, and French. Analysis was completed with t test and χ test for continuous and categorical variables, respectively, and weighted Pearson correlation (P<0.05). RESULTS: Survey respondents consisted of 413 surgeons from 83 countries (20 LIC, 33 LMIC, 30 UMIC). The majority of respondents were fellowship trained (83%) most commonly in pediatrics (26%) and trauma (43%). Most treated >10 pediatric femur fractures per year (68%). Respondents reported treating infant femur fractures nonoperatively using Pavlik harness (19%), spica cast (60%), or traction with delayed spica cast (14%). Decreasing socioeconomic status was associated with higher nonoperative treatment rate in toddlers, children, and adolescents. Respondents commonly utilize bed rest and traction for child femur fractures in LICs (63%) and LMICs (65%) compared with UMICs (35%) (UMIC vs. LMIC P<0.001; UMIC vs. LIC P<0.001). Surgeries in children more commonly involve open reduction with internal fixation (UMIC 19%, LMIC 33%, LIC 40%; P<0.05 between UMIC-LMIC and UMIC-LIC). CONCLUSION: This is one of the largest surveys describing treatment patterns for pediatric femur fractures in low and middle income countries. Differences are evident including lower operative treatment rate in younger children and lower intramedullary fixation rates in older children. Future studies should investigate the value of treatment options in resource-limited settings. LEVEL OF EVIDENCE: Level II-prospective comparative study.

The extent of pediatric orthopaedic research in low- and middle-income countries and the impact of academic collaboration on research quality: a scoping review.

INTRODUCTION: This review aims to (1) assess the breadth of pediatric orthopaedic research in low- and middle-income countries (LMICs) and (2) determine the impact of academic collaboration (an LMIC and a non-LMIC investigator) in published LMIC research. METHODS: Pediatric orthopaedic clinical studies conducted in LMICs from 2004 to 2014 were extracted from Embase, Cochrane, and Pubmed databases. Of 22,714 searched studies, 129 met inclusion criteria. RESULTS: 85% generated low-quality evidence (level IV or lower). 21% were collaborative, and these were more likely than non-collaborative papers to generate level III evidence or higher (25% vs 13%, p = 0.141). DISCUSSION: Pediatric orthopaedic research produced by LMICs rarely achieves level I-III evidence, but collaborative studies are associated with higher levels of evidence. LEVEL OF EVIDENCE: N/A.

Predictors of lower health-related quality of life after operative repair of diaphyseal femur fractures in a low-resource setting.

BACKGROUND: Little data exists on the negative impact of orthopaedic trauma on quality of life (QOL) in low- and middle-income countries (LMICs). The goal of this study is to investigate the factors associated with lower QOL after operative fixation of femoral shaft fractures in adult patients in a low-resource setting. METHODS: This prospective cohort study followed 272 factures in adults undergoing operative fixation for diaphyseal femur fractures at Tanzania. Patient demographics, injury characteristics, treatment modalities, and functional outcomes up to 1-year post-operatively were evaluated for association with 1-year post-operative EQ-5D QOL scores via univariate linear regression analysis. RESULTS: EQ-5D values were significantly lower at 1 year than at baseline (0.941 vs 0.991, p < 0.0005). CONCLUSIONS: Operative fixation of femoral shaft fractures in LMICs results in return to near baseline QOL. Demographic and treatment factors were not significantly associated with EQ-5D. and several markers of recovery were associated with lower 1 year QOL, including pain, knee stiffness, delayed radiographic healing, complications requiring reoperation. Efforts to reduce perioperative complications may help improve post-operative QOL.