Staphylococcus aureus persistence in osteocytes: weathering the storm of antibiotics and autophagy/xenophagy

Staphylococcus aureus is a major causative pathogen of osteomyelitis. Intracellular infections of resident bone cells including osteocytes can persist despite gold-standard clinical intervention. The mechanisms by which intracellular S. aureus evades antibiotic therapy are unknown. In this study, we utilised an in vitro S. aureus infection model of human osteocytes to investigate whether antibiotic-mediated dysregulation of autophagy contributes to this phenomenon. Infected or non-infected osteocyte-like cells were exposed to combinations of rifampicin, vancomycin, and modulators of autophagy. Intracellular bacterial growth characteristics were assessed using colony-forming unit (CFU) analysis, viable bacterial DNA abundance, and the rate of escape into antibiotic-free medium, together with measures of autophagic flux. Rifampicin, alone or in combination with vancomycin, caused a rapid decrease in the culturability of intracellular bacteria, concomitant with stable or increased absolute bacterial DNA levels. Both antibiotics significantly inhibited autophagic flux. However, modulation of autophagic flux did not affect viable bacterial DNA levels. In summary, autophagy was shown to be a factor in the host–pathogen relationship in this model, as its modulation affected the growth state of intracellular S. aureus with respect to both their culturability and propensity to escape the intracellular niche. While rifampicin and vancomycin treatments moderately suppressed autophagic flux acutely, this did not explain the paradoxical response of antibiotic treatment in decreasing S. aureus culturability whilst failing to clear bacterial DNA and hence intracellular bacterial load. Thus, off-target effects of rifampicin and vancomycin on autophagic flux in osteocyte-like cells could not explain the persistent S. aureus infection in these cells

Mechanisms of deaths in captive juvenile New Zealand fur seals (Arctocephalus forsteri)

Abstract Juvenile seals are sometimes encountered in waters around South Australia with injuries and/or diseases that require veterinary treatment. Two cases are reported where apparently stable animals died soon after being rescued due to quite disparate conditions. In Case 1 a juvenile male New Zealand fur seal (Arctocephalus forsteri) was found unexpectedly dead in its enclosure. A necropsy examination revealed an emaciated juvenile male with no injuries. The intestine was filled throughout its length with melena stool that was due to heavy infestation of the stomach with roundworms with adjacent gastritis. Death was due to shock from upper gastrointestinal blood loss secondary to parasitosis. In Case 2 a second juvenile male New Zealand fur seal (Arctocephalus forsteri) also died unexpectedly in its enclosure. It had been listless with loud respirations since capture. At necropsy there was no blood around the head, neck or mouth, and no acute external injuries were identified. An area of induration was, however, present over the snout with fragmentation of underlying bones. The maxilla was freely mobile and CT scanning revealed multiple comminuted fractures of the adjacent facial skeleton. Examination of the defleshed skull showed fragmentation of the facial skeleton with roughening of bones in keeping with osteomyelitis. Death was attributed to sepsis from osteomyelitis of a comminuted midfacial fracture. These cases demonstrate two unusual and occult conditions that may be present in recently retrieved juvenile fur seals. Failure to establish the correct diagnosis rapidly may result in death soon after capture. The usefulness of imaging techniques such as CT scanning in delineating underlying injuries prior to necropsy is clearly demonstrated

Biomechanical changes and recovery of gait function after total hip arthroplasty for osteoarthritis: a systematic review and meta-analysis

© 2018 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (February 2018) in accordance with the publisher’s archiving policyObjective To determine the change in walking gait biomechanics after total hip arthroplasty (THA) for osteoarthritis (OA) compared to the pre-operative gait status, and to compare the recovery of gait following THA with healthy individuals. Methods Systematic review with meta-analysis of studies investigating changes in gait biomechanics after THA compared to (1) preoperative levels and (2) healthy individuals. Data were pooled at commonly reported time points and standardised mean differences (SMDs) were calculated in meta-analyses for spatiotemporal, kinematic and kinetic parameters. Results Seventy-four studies with a total of 2,477 patients were included. At 6 weeks postoperative, increases were evident for walking speed (SMD: 0.32, 95% confidence intervals (CI) 0.14, 0.50), stride length (SMD: 0.40, 95% CI 0.19, 0.61), step length (SMD: 0.41, 95% CI 0.23, 0.59), and transverse plane hip range of motion (ROM) (SMD: 0.36, 95% CI 0.05, 0.67) compared to pre-operative gait. Sagittal, coronal and transverse hip ROM was significantly increased at 3 months (SMDs: 0.50 to 1.07). At 12 months postoperative, patients demonstrated deficits compared with healthy individuals for walking speed (SMD: −0.59, 95% CI −1.08 to −0.11), stride length (SMD: −1.27, 95% CI -1.63, −0.91), single limb support time (SMD: −0.82, 95% CI −1.23, −0.41) and sagittal plane hip ROM (SMD: −1.16, 95% CI −1.83, −0.49). Risk of bias scores ranged from seven to 24 out of 26. Conclusions Following THA for OA, early improvements were demonstrated for spatiotemporal and kinematic gait patterns compared to the pre-operative levels. Deficits were still observed in THA patients compared to healthy individuals at 12 months

Head-Neck Taper Corrosion in Hip Arthroplasty

Copyright © 2015 S. Hussenbocus et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Modularity at the head-neck junction of the femoral component in THA became popular as a design feature with advantages of decreasing implant inventory and allowing adjustment of leg length, offset, and soft tissue balancing through different head options. The introduction of a new modular interface to femoral stems that were previously monoblock, or nonmodular, comes with the potential for corrosion at the taper junction through mechanically assisted crevice corrosion. The incidence of revision hip arthroplasty is on the rise and along with improved wear properties of polyethylene and ceramic, use of larger femoral head sizes is becoming increasingly popular. Taper corrosion appears to be related to all of its geometric parameters, material combinations, and femoral head size. This review article discusses the pathogenesis, risk factors, clinical assessment, and management of taper corrosion at the head-neck junction

Relationships between in vivo dynamic knee joint loading, static alignment and tibial subchondral bone microarchitecture in end-stage knee osteoarthritis

© 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (January 2018) in accordance with the publisher’s archiving policySummary Objective To study, in end-stage knee osteoarthritis (OA) patients, relationships between indices of in vivo dynamic knee joint loads obtained pre-operatively using gait analysis, static knee alignment, and the subchondral trabecular bone (STB) microarchitecture of their excised tibial plateau quantified with 3D micro-CT. Design Twenty-five knee OA patients scheduled for total knee arthroplasty underwent pre-operative gait analysis. Mechanical axis deviation (MAD) was determined radiographically. Following surgery, excised tibial plateaus were micro-CT-scanned and STB microarchitecture analysed in four subregions (anteromedial, posteromedial, anterolateral, posterolateral). Regional differences in STB microarchitecture and relationships between joint loading and microarchitecture were examined. Results STB microarchitecture differed among subregions (P < 0.001), anteromedially exhibiting highest bone volume fraction (BV/TV) and lowest structure model index (SMI). Anteromedial BV/TV and SMI correlated strongest with the peak external rotation moment (ERM; r = −0.74, r = 0.67, P < 0.01), despite ERM being the lowest (by factor of 10) of the moments considered, with majority of ERM measures below accuracy thresholds; medial-to-lateral BV/TV ratios correlated with ERM, MAD, knee adduction moment (KAM) and internal rotation moment (|r|-range: 0.54–0.74). When controlling for walking speed, KAM and MAD, the ERM explained additional 11–30% of the variations in anteromedial BV/TV and medial-to-lateral BV/TV ratio (R2 = 0.59, R2 = 0.69, P < 0.01). Conclusions This preliminary study suggests significant associations between tibial plateau STB microarchitecture and knee joint loading indices in end-stage knee OA patients. Particularly, anteromedial BV/TV correlates strongest with ERM, whereas medial-to-lateral BV/TV ratio correlates strongest with indicators of medial-to-lateral joint loading (MAD, KAM) and rotational moments. However, associations with ERM should be interpreted with caution

The accuracy and precision of radiostereometric analysis in monitoring tibial plateau fractures

Background and purpose: The application of radiostereometric analysis (RSA) to monitor stability of tibial plateau fractures during healing is both limited and yet to be validated. We therefore evaluated the accuracy and precision of RSA in a tibial plateau fracture model. Methods: Combinations of 3, 6, and 9 markers in a lateral condyle fracture were evaluated with reference to 6 proximal tibial arrangements. Translation and rotation accuracy was assessed with displacement-controlled stages, while precision was assessed with dynamic double examinations. A comparison of error according to marker number and arrangement was completed with 2-way ANOVA models. Results: The results were improved using more tantalum markers in each segment. In the fracture fragment, marker scatter in all axes was achieved by a circumferential arrangement (medial, anterior, and lateral) of the tantalum markers above the fixation devices. Markers placed on either side of the tibial tuberosity and in the medial aspect of the fracture split represented the proximal tibial reference segment best. Using 6 markers with this distribution in each segment, the translation accuracy (root mean square error) was less than 37 μm in all axes. The precision (95% confidence interval) was less than ± 16 μm in all axes in vitro. Rotation, tested around the x-axis, had an accuracy of less than 0.123° and a precision of ± 0.024°. Interpretation: RSA is highly accurate and precise in the assessment of lateral tibial plateau fracture fragment movement. The validation of our center's RSA system provides evidence to support future clinical RSA fracture studies.Lucian B Solomon, Aaron W Stevenson, Stuart A Callary, Thomas R Sullivan, Donald W Howie, and Mellick J Chehad

Wear of highly crosslinked polyethylene acetabular components: a review of RSA studies

Background and purpose - Wear rates of highly crosslinked polyethylene (XLPE) acetabular components have varied considerably between different published studies. This variation is in part due to the different techniques used to measure wear and to the errors inherent in measuring the relatively low amounts of wear in XLPE bearings. We undertook a scoping review of studies that have examined the in vivo wear of XLPE acetabular components using the most sensitive method available, radiostereometric analysis (RSA). Methods - A systematic search of the PubMed, Scopus, and Cochrane databases was performed to identify published studies in which RSA was used to measure wear of XLPE components in primary total hip arthroplasty (THA). Results - 18 publications examined 12 primary THA cohorts, comprising only 260 THAs at 2-10 years of follow-up. The mean or median proximal wear rate reported ranged from 0.00 to 0.06 mm/year. However, differences in the manner in which wear was determined made it difficult to compare some studies. Furthermore, differences in RSA methodology between studies, such as the use of supine or standing radiographs and the use of beaded or unbeaded reference segments, may limit future meta-analyses examining the effect of patient and implant variables on wear rates. Interpretation - This scoping review confirmed the low wear rates of XLPE in THA, as measured by RSA. We make recommendations to enhance the standardization of reporting of RSA wear results, which will facilitate early identification of poorly performing implants and enable a better understanding of the effects of surgical and patient factors on wear.Stuart A Callary, Lucian B Solomon, Oksana T Holubowycz, David G Campbell, Zachary Munn, and Donald W Howi

Periprosthetic osteolysis after total hip replacement: molecular pathology and clinical management

Periprosthetic osteolysis is a serious complication of total hip replacement (THR) in the medium to long term. Although often asymptomatic, osteolysis can lead to prosthesis loosening and periprosthetic fracture. These complications cause significant morbidity and require complex revision surgery. Here, we review advances in our understanding of the cell and tissue response to particles produced by wear of the articular and non-articular surfaces of prostheses. We discuss the molecular and cellular regulators of osteoclast formation and bone resorptive activity, a better understanding of which may lead to pharmacological treatments for periprosthetic osteolysis. We describe the development of imaging techniques for the detection and measurement of osteolysis around THR prostheses, which enable improved clinical management of patients, provide a means of evaluating outcomes of non-surgical treatments for periprosthetic osteolysis, and assist in pre-operative planning for revision surgery. Finally, there have been advances in the materials used for bearing surfaces to minimise wear, and we review the literature regarding the performance of these new materials to date.Donald W. Howie, Susan D. Neale, David R. Haynes, Oksana T. Holubowycz, Margaret A. McGee, Lucian B. Solomon, Stuart A. Callary, Gerald J. Atkins, David M. Findla

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Emerging Ideas: Soft Tissue Applications of Radiostereometric Analysis

BackgroundCurrently, the movement that occurs at the site of soft tissue repair cannot be measured accurately in vivo. Radiostereometric analysis (RSA) is the gold standard for measuring movement between two skeletal segments in vivo but its application to studying soft tissue migration has been limited by the unknown stability of tantalum beads in tendons and ligaments and their ability to define rigid bodies in these structures.HypothesisRSA can be used to accurately measure movement between two tendon segments or between a bony and a tendon segment in vivo.Methods of studyThe stability of tantalum beads and the ability to use such beads to define rigid bodies in some soft tissues will be investigated in animal models of tendon repair. Several tantalum bead insertion techniques will be tested using in vivo RSA measurements of bead movement followed by morphologic studies of the repaired tendon and soft tissue reaction to the tantalum beads.SignificanceRSA performed on tantalum beads encapsulated in muscles and tendons could be a powerful new tool to study the in vivo motion at the site of soft tissue repairs, for instance, the tendon gap formation. If RSA could be used to evaluate the efficiency of different tendon repair techniques in vivo, enhanced rehabilitation protocols could be developed and complications associated with prolonged protection or failure of repair could be reduced.Lucian B. Solomon, Stuart A. Callar