David G. Little

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L‐carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L‐carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12‐week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L‐carnitine. Primary outcomes were safety (self‐reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6‐minute‐walk test [6MWT]), and parent‐reported questionnaires (PedsQL™, CBCL/6–18). Six children completed the trial with no self‐reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89–60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99–134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97–16.03; p = 0.01) and 6MWT distance (95% CI 5.88–75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z‐score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L‐carnitine after the study. Twelve weeks of L‐carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Background Nitrous oxide with intranasal fentanyl is safe and effective in performing closed reduction of paediatric forearm fractures; however, the difference in outcome when compared to those performed under general anaesthesia (GA) is unclear. We aim to compare the outcomes of closed reduction of paediatric forearm fractures under nitrous oxide versus GA. Methods This retrospective study based on a prospective change in protocol reviewed the medical records and radiographs of patients with forearm fractures who presented to a tertiary paediatric centre, and who subsequently underwent closed reduction under either nitrous or GA. Data on patient demographics, type and site of fracture and the method of casting were collected. The primary outcomes were loss of reduction, the need for repeat intervention and the rate of complications. Results There were 301 and 362 patients in the nitrous and GA groups respectively. The overall re‐intervention rate was 7.6% in the nitrous group versus 5.0% in the GA group (P = 0.155). There was no significant difference in loss of reduction which involved 9.0% in the nitrous group and 11.3% in the GA group (P = 0.320). There was no significance difference in overall complications. Nausea and vomiting comprised the majority of adverse events. Conclusion Closed reduction of paediatric forearm fractures performed under nitrous oxide with intranasal fentanyl is safe, effective and achieves comparable re‐intervention rates and adverse events to those performed under GA in the operating theatre.

Neurogenic tumors should be in the differential diagnosis for a posterior mediastinal mass.

Metformin often leads to marked increased uptake throughout the bowel on F18 FDG PET-CT. This can mask underlying colonic lesions and also makes interpretation of the abdomen and pelvis more difficult due to 'noise' of background bowel, which can...

Typical distribution of active large vessel vasculitis on FDG PET-CT.

Infection of orthopedic implants is a growing clinical challenge to manage due to the proliferation of drug‐resistant bacterial strains. In this study, we aimed to investigate whether the treatment of implants with ceragenin‐90 (CSA‐90), a synthetic compound based on endogenous antibacterial peptides, could prevent infection in a novel rat model of periprosthetic joint infection (PJI) challenged with either local or systemic Staphylococcus aureus. A novel preclinical model of PJI was created using press‐fit porous titanium implants in the distal femur of male Wistar rats. Sterile implants were pre‐treated with 500 μg CSA‐90 in saline. S. aureus was applied either directly at the time of surgery or administered via tail vein injection immediately afterward. Animals were monitored daily for clinical and radiographic evidence of infection for a total of 6 weeks. Post‐study microbiological, radiographic, and histological analysis were performed to determine the incidence of PJI and assess osseointegration. CSA‐90 treated groups demonstrated a reduced rate of PJI as confirmed by deep tissue swab culture at the time of cull compared with untreated groups with both local (33% vs 100%; P = .009) and systemic (10% vs 90%; P < .0001) S. aureus inoculation. Median survival time also increased from 8 to 17 days and from 8 to 42 days, respectively. In conclusion, this study describes a novel preclinical model of local and hematogenous PJI using a porous metal implant. CSA‐90 reduced the incidence of PJI in this model supporting its further development as an antimicrobial coating for orthopedic implants.

Osteomyelitis and infections associated with orthopedic implants represent a significant burden of disease worldwide. Ceragenins (CSAs) are a relatively new class of small‐molecule antimicrobials that target a broad range of Gram‐positive and Gram‐negative bacteria as well as fungi, viruses, and parasites. This review sets the context of the need for new antimicrobial strategies by cataloging the common pathogens associated with orthopedic infection and highlighting the increasing challenges of managing antibiotic‐resistant bacterial strains. It then comparatively describes the antimicrobial properties of CSAs with a focus on the CSA‐13 family. More recently developed members of this family such as CSA‐90 and CSA‐131 may have a particular advantage in an orthopedic setting as they possess secondary pro‐osteogenic properties. In this context, we consider several new preclinical studies that demonstrate the utility of CSAs in orthopedic models. Emerging evidence suggests that CSAs are effective against antibiotic‐resistantStaphylococcus aureusstrains and can prevent the formation of biofilms. There remains considerable scope for developing CSA‐based treatments, either as coatings for orthopedic implants or as local or systemic antibiotics to prevent bone infection.

Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46–79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38–63%, p < 0.01) and reduced MAR (32–49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.

Purpose Perthes’ disease (PD) results from loss of blood supply to the hip and can progress to femoral head deformity. MRI in the early course of the disease can provide data on the initial extent of infarct. Vascularity of the femoral head is assessed by gadolinium-enhanced MRI (contrast MRI), which may be improved by the digital subtraction technique (subtraction MRI). We hypothesized that gadolinium-enhanced MRI without subtraction was comparable with subtraction MRI in depicting the femoral head perfusion. Methods In all, 34 patients (34 hips) with unilateral PD had gadolinium-enhanced MRI as part of a prospectively randomized study. Nine patients had three MRIs, 15 had two and ten had a single MRI. Measurement of perfusion of the femoral head (MRI perfusion index) was obtained using digital image analysis on all the MRIs, including both before and after subtraction. A paired sample t-test was performed to compare the measurements. Results The mean age of the patients was 8.9 years (sd 1.6). At the time of diagnosis, the subtraction MRI did not elicit a statistically significant difference in MRI perfusion index measurements when compared with the contrast MRI (p = 0.19). The same findings were found when including all patients at various stages of the disease (p = 0.30). Qualitatively, although some subtraction MRI images showed superior delineation of epiphysis, there are no significant differences throughout the whole series. Conclusion Although the current literature supports the increasing role of the subtraction MRI for PD management, our study proposed that the contrast MRI without subtraction technique appears adequate in assessing femoral head perfusion. Level of Evidence Level I - Diagnostic study