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Showing papers by "Nuffield Orthopaedic Centre published in 2018"


Journal ArticleDOI
TL;DR: Tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation and strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.
Abstract: Background Recent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture. Methods We studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers. Results Tendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells. Conclusions Tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.

126 citations


Journal ArticleDOI
TL;DR: The aim of this review is to provide the current evidence and technical parameters to support the rheumatologist in the CDS evaluation of patients with suspected GCA.
Abstract: Colour duplex sonography (CDS) of temporal arteries and large vessels is an emerging diagnostic tool for GCA. CDS can detect wall oedema, known as a halo, throughout the length of the vessel and shows higher sensitivity compared with biopsy. Specificity reaches 100% in case of bilateral halos. A positive compression sign has been demonstrated to be a robust marker with excellent inter-observer agreement. The assessment of other large vessels, particularly the axillary arteries, is recognized to further increase the sensitivity and to reliably represent extra-cranial involvement in other areas. Nevertheless, CDS use is still not widespread in routine clinical practice and requires skilled sonographers. Moreover, its role in the follow-up of patients still needs to be defined. The aim of this review is to provide the current evidence and technical parameters to support the rheumatologist in the CDS evaluation of patients with suspected GCA.

110 citations


Journal ArticleDOI
TL;DR: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.
Abstract: Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Methods Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2 , LZTR1 and SMARCB1 on blood and tumour DNA samples when available. Results Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1 -associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). Conclusions Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

99 citations


Journal ArticleDOI
TL;DR: A novel, scalable pipeline for real-time analysis of MinION sequence data is demonstrated and use of this pipeline is used to show initial proof of concept that metagenomic MinION sequencing can provide rapid, accurate diagnosis for prosthetic joint infections.
Abstract: Prosthetic joint infections are clinically difficult to diagnose and treat. Previously, we demonstrated metagenomic sequencing on an Illumina MiSeq replicates the findings of current gold standard microbiological diagnostic techniques. Nanopore sequencing offers advantages in speed of detection over MiSeq. Here, we report a real-time analytical pathway for Nanopore sequence data, designed for detecting bacterial composition of prosthetic joint infections but potentially useful for any microbial sequencing, and compare detection by direct-from-clinical-sample metagenomic nanopore sequencing with Illumina sequencing and standard microbiological diagnostic techniques. DNA was extracted from the sonication fluids of seven explanted orthopaedic devices, and additionally from two culture negative controls, and was sequenced on the Oxford Nanopore Technologies MinION platform. A specific analysis pipeline was assembled to overcome the challenges of identifying the true infecting pathogen, given high levels of host contamination and unavoidable background lab and kit contamination. The majority of DNA classified (> 90%) was host contamination and discarded. Using negative control filtering thresholds, the species identified corresponded with both routine microbiological diagnosis and MiSeq results. By analysing sequences in real time, causes of infection were robustly detected within minutes from initiation of sequencing. We demonstrate a novel, scalable pipeline for real-time analysis of MinION sequence data and use of this pipeline to show initial proof of concept that metagenomic MinION sequencing can provide rapid, accurate diagnosis for prosthetic joint infections. The high proportion of human DNA in prosthetic joint infection extracts prevents full genome analysis from complete coverage, and methods to reduce this could increase genome depth and allow antimicrobial resistance profiling. The nine samples sequenced in this pilot study have shown a proof of concept for sequencing and analysis that will enable us to investigate further sequencing to improve specificity and sensitivity.

98 citations


Journal ArticleDOI
TL;DR: MCGRs improve coronal deformity and maintain spinal growth, but carry a 44.5% complication and 33% unplanned revision rate, and single rods should be avoided.
Abstract: To analyse the complication profile of magnetically controlled growing rods (MCGRs) in early onset scoliosis (EOS). This is a systematic review using PUBMED, Medline, Embase, Google Scholar and the Cochrane Library (keywords: MAGEC, Magnetically controlled growing rods and EOS) of all studies written in English with a minimum of five patients and a 1-year follow-up. We evaluated coronal correction, growth progression (T1–S1, T1–T12) and complications. Fifteen studies (336 patients) were included (42.5% male, mean age 7.9 years, average follow-up 29.7 months). Coronal improvement was achieved in all studies (pre-operative 64.8°, latest follow-up 34.9° p = 0.000), as was growth progression (p = 0.001). Mean complication rate was 44.5%, excluding the 50.8% medical complication rate. The unplanned revision rate was 33%. The most common complications were anchor pull-out (11.8%), implant failure (11.7%) and rod breakage (10.6%). There was no significant difference between primary (39.8%) and conversion (33.3%) procedures (p = 0.462). There was a non-statistically significant increased complication rate with single rods (40 vs. 27% p = 0.588). MCGRs improve coronal deformity and maintain spinal growth, but carry a 44.5% complication and 33% unplanned revision rate. Conversion procedures do not increase this risk. Single rods should be avoided. These slides can be retrieved under Electronic Supplementary material.

95 citations


Journal ArticleDOI
TL;DR: In this article, systemic antibiotic prophylaxis is considered the benchmark in the management of open fractures and is considered to be the best in the world for open fracture management, including debridement and irrigation, soft-tissue coverage, and osseous stabilization.
Abstract: Objectives As well as debridement and irrigation, soft-tissue coverage, and osseous stabilization, systemic antibiotic prophylaxis is considered the benchmark in the management of open fractures an...

93 citations


Journal ArticleDOI
TL;DR: Data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development.
Abstract: Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2 , WNT5A , and more recently, DVL1 and DVL3 . However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered –1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3 , both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

93 citations


Journal ArticleDOI
05 Nov 2018-Trials
TL;DR: The DELTA2 (Difference ELicitation in TriAls) project as discussed by the authors provides guidance for researchers and funders on specifying the target difference, and undertaking and reporting a RCT sample size calculation.
Abstract: A key step in the design of a RCT is the estimation of the number of participants needed in the study. The most common approach is to specify a target difference between the treatments for the primary outcome and then calculate the required sample size. The sample size is chosen to ensure that the trial will have a high probability (adequate statistical power) of detecting a target difference between the treatments should one exist. The sample size has many implications for the conduct and interpretation of the study. Despite the critical role that the target difference has in the design of a RCT, the way in which it is determined has received little attention. In this article, we summarise the key considerations and messages from new guidance for researchers and funders on specifying the target difference, and undertaking and reporting a RCT sample size calculation. This article on choosing the target difference for a randomised controlled trial (RCT) and undertaking and reporting the sample size calculation has been dual published in the BMJ and BMC Trials journals The DELTA2 (Difference ELicitation in TriAls) project comprised five major components: systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2); a Delphi study (stage 3); a two-day consensus meeting bringing together researchers, funders and patient representatives (stage 4); and the preparation and dissemination of a guidance document (stage 5). The key messages from the DELTA2 guidance on determining the target difference and sample size calculation for a randomised caontrolled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided.

80 citations


Journal ArticleDOI
TL;DR: Reflections on adhering to ethical principles throughout the research process are shared to illustrate the complexities and nuances involved and offer critical insights into dilemmas arising in view of the ethical principles driving good conduct.
Abstract: For medical education researchers, a key concern may be the practicalities of gaining ethical approval where this is a national or local requirement. However, in qualitative studies, where the dynamics of human interaction pervade, ethical considerations are an ongoing process which continues long after approval has been granted. Responding to ethical dilemmas arising ‘in the moment’ requires a reflexive approach whereby the researcher questions his/her own motivations, assumptions and interests. Drawing on empirical studies and their experiences in academic and clinical research practice, the authors share their reflections on adhering to ethical principles throughout the research process to illustrate the complexities and nuances involved. These reflections offer critical insights into dilemmas arising in view of the ethical principles driving good conduct, and through domains which distinguish between procedural ethics, situational ethics, ethical relationships and ethical issues in exiting the study. The accounts consider integrity and altruism in research, gatekeeping and negotiating access, consent and confidentiality, power dynamics and role conflict, and challenges in dissemination of findings. The experiences are based on a range of examples of research in a UK context from managing difficult conversations in the classroom to video-ethnography in the operating theatre. These critical reflections make visible the challenges encountered and decisions that must be taken in the moment and on reflection after the event. Through sharing our experiences and debating the decisions we made, we offer insights into reflexivity in qualitative research which will be of value to others.

74 citations


Journal ArticleDOI
TL;DR: Tissue culture is more sensitive and may be more specific than sonication for diagnosis of orthopedic DRI in the authors' setting, and culture yield was highest for both methods combined.
Abstract: Current guidelines recommend collection of multiple tissue samples for diagnosis of prosthetic joint infections (PJI). Sonication of explanted devices has been proposed as a potentially simpler alternative; however, reported microbiological yield varies. We evaluated sonication for diagnosis of PJI and other orthopedic device-related infections (DRI) at the Oxford Bone Infection Unit between October 2012 and August 2016. We compared the performance of paired tissue and sonication cultures against a "gold standard" of published clinical and composite clinical and microbiological definitions of infection. We analyzed explanted devices and a median of five tissue specimens from 505 procedures. Among clinically infected cases the sensitivity of tissue and sonication culture was 69% (95% confidence interval, 63 to 75) and 57% (50 to 63), respectively (P < 0.0001). Tissue culture was more sensitive than sonication for both PJI and other DRI, irrespective of the infection definition used. Tissue culture yield was higher for all subgroups except less virulent infections, among which tissue and sonication culture yield were similar. The combined sensitivity of tissue and sonication culture was 76% (70 to 81) and increased with the number of tissue specimens obtained. Tissue culture specificity was 97% (94 to 99), compared with 94% (90 to 97) for sonication (P = 0.052) and 93% (89 to 96) for the two methods combined. Tissue culture is more sensitive and may be more specific than sonication for diagnosis of orthopedic DRI in our setting. Variable methodology and case mix may explain reported differences between centers in the relative yield of tissue and sonication culture. Culture yield was highest for both methods combined.

73 citations


Journal ArticleDOI
TL;DR: Investigation of clinical features, microbiology culture results, and histological analysis in 156 surgically treated nonunions found histology can be used in a bimodal fashion as a diagnostic test for FRI.
Abstract: Aims This study aimed to investigate the role of quantitative histological analysis in the diagnosis of fracture-related infection (FRI). Patients and Methods The clinical features, microbiology cu...

Journal ArticleDOI
TL;DR: Adding utility of PET–CT in addition to MRI and CT in high-grade sarcoma of bone and soft tissues can add significant benefit to routine CT/MRI staging, and an estimated 21% overall potential benefit was observed.
Abstract: The use of 18F-FDG PET–CT (PET–CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET–CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with 18FDG SUVmax, secondly, the practical uses of PET–CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET–CT over concurrent conventional CT and MRI. A total of 957 consecutive PET–CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET–CT SUVmax values in relation to histology and FNCCC grading. We compared PET–CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and treatment responses. High-grade (II/III) bone and soft tissue sarcoma correlated with high SUVmax, especially undifferentiated pleomorphic sarcoma, leiomyosarcoma, translocation induced sarcomas (Ewing, synovial, alveolar rhabdomyosarcoma), de-differentiated liposarcoma and osteosarcoma. Lower SUVmax values were observed in sarcomas of low histological grade (grade I), and in rare subtypes of intermediate grade soft tissue sarcoma (e.g. alveolar soft part sarcoma and solitary fibrous tumour). SUVmax variation was noted in malignant peripheral nerve sheath tumours, compared to the histologically benign plexiform neurofibroma, whereas PET–CT could clearly differentiate low from high-grade chondrosarcoma. We identified added utility of PET–CT in addition to MRI and CT in high-grade sarcoma of bone and soft tissues. An estimated 21% overall potential benefit was observed for PET–CT over CT/MRI, and in particular, in ‘upstaging’ of high-grade disease (from M0 to M1) where an additional 12% of cases were deemed M1 following PET–CT. PET–CT in high-grade bone and soft tissue sarcoma can add significant benefit to routine CT/MRI staging. Further prospective and multi-centre evaluation of PET–CT is warranted to determine the actual predictive value and cost-effectiveness of PET–CT in directing clinical management of clinically complex and heterogeneous high-grade sarcomas.

Journal ArticleDOI
05 Nov 2018-BMJ
TL;DR: In this paper, the DELTA2 guidance on determining the target difference and sample size calculation for a randomised controlled trial is presented, along with recommendations for subsequent reporting of the sample size calculations.
Abstract: Randomised controlled trials are considered to be the best method to assess comparative clinical efficacy and effectiveness, and can be a key source of data for estimating cost effectiveness. Central to the design of a randomised controlled trial is an a priori sample size calculation, which ensures that the study has a high probability of achieving its prespecified main objective. Beyond pure statistical or scientific concerns, it is ethically imperative that an appropriate number of study participants be recruited, to avoid imposing the burdens of a clinical trial on more patients than necessary. The scientific concern is satisfied and the ethical imperative is further addressed by the specification of a target difference between treatments that is considered realistic or important by one or more key stakeholder groups. The sample size calculation ensures that the trial will have the required statistical power to identify whether a difference of a particular magnitude exists. In this article, the key messages from the DELTA2 guidance on determining the target difference and sample size calculation for a randomised controlled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided.

Journal ArticleDOI
TL;DR: The panel make a strong recommendation against arthroscopy for degenerative knee disease, based on a linked systematic review triggered by a randomised trial published in The BMJ in June 2016.
Abstract: ### What you need to know What is the role of arthroscopic surgery in degenerative knee disease? An expert panel produced these recommendations based on a linked systematic review triggered by a randomised trial published in The BMJ in June 2016, which found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy. The panel make a strong recommendation against arthroscopy for degenerative knee disease. Box 1 shows all of the articles and evidence linked in this Rapid Recommendation package. The infographic provides an overview of the absolute benefits and harms of arthroscopy in standard GRADE format. Table 1 below shows any evidence that has emerged since the publication of this article.Box 1 ### Linked articles in this BMJ Rapid Recommendations cluster

Journal ArticleDOI
TL;DR: Evidence-based guidelines aimed at facilitating transitions through the fostering of progressive independence are proposed, and the two strongest messages arising from current literature are first, transitions should not be viewed as one moment in time: career trajectories are a continuum with valuable opportunities for personal and professional development throughout.
Abstract: Transitions are traditionally viewed as challenging for clinicians. Throughout medical career pathways, clinicians need to successfully navigate successive transitions as they become progressively more independent practitioners. In these guidelines, we aim to synthesize the evidence from the literature to provide guidance for supporting clinicians in their development of independence, and highlight areas for further research. Drawing upon D3 method guidance, four key themes universal to medical career transitions and progressive independence were identified by all authors through discussion and consensus from our own experience and expertise: workplace learning, independence and responsibility, mentoring and coaching, and patient perspectives. A scoping review of the literature was conducted using Medline database searches in addition to the authors’ personal archives and reference snowballing searches. 387 articles were identified and screened. 210 were excluded as not relevant to medical transitions (50 at title screen; 160 at abstract screen). 177 full-text articles were assessed for eligibility; a further 107 were rejected (97 did not include career transitions in their study design; 10 were review articles; the primary references of these were screened for inclusion). 70 articles were included of which 60 provided extractable data for the final qualitative synthesis. Across the four key themes, seven do’s, two don’ts and seven don’t knows were identified, and the strength of evidence was graded for each of these recommendations. The two strongest messages arising from current literature are first, transitions should not be viewed as one moment in time: career trajectories are a continuum with valuable opportunities for personal and professional development throughout. Second, learning needs to be embedded in practice and learners provided with authentic and meaningful learning opportunities. In this paper, we propose evidence-based guidelines aimed at facilitating such transitions through the fostering of progressive independence.

Journal ArticleDOI
TL;DR: Receiving UKA rather than TKA was found to be associated with better scores for Oxford Knee Score, including both its pain and function components, and EQ-5D, with the differences expected to grow over time.
Abstract: For patients with medial compartment arthritis who have failed non-operative treatment, either a total knee arthroplasty (TKA) or a unicompartmental knee arthroplasty (UKA) can be undertaken. This analysis considers how the choice between UKA and TKA affects long-term patient-reported outcome measures (PROMs). The Knee Arthroplasty Trial (KAT) and a cohort of patients who received a minimally invasive UKA provided data. Propensity score matching was used to identify comparable patients. Oxford Knee Score (OKS), its pain and function components, and the EuroQol 5 Domain (EQ-5D) index, estimated on the basis of OKS responses, were then compared over 10 years following surgery. Mixed-effects regressions for repeated measures were used to estimate the effect of patient characteristics and type of surgery on PROMs. Five-hundred and ninety UKAs were matched to the same number of TKAs. Receiving UKA rather than TKA was found to be associated with better scores for OKS, including both its pain and function components, and EQ-5D, with the differences expected to grow over time. UKA was also associated with an increased likelihood of patients achieving a successful outcome, with an increased chance of attaining minimally clinically important improvements in both OKS and EQ-5D, and an ‘excellent’ OKS. In addition, for both procedures, patients aged between 60 and 70 and better pre-operative scores were associated with better post-operative outcomes. Minimally invasive UKAs performed on patients with the appropriate indications led to better patient-reported pain and function scores than TKAs performed on comparable patients. UKA can lead to better long-term quality of life than TKA and this should be considered alongside risk of revision when choosing between the procedures. II.

Journal ArticleDOI
TL;DR: An overview of the radiologic appearances of SAPHO/CRMO and relevant pathogenetic, clinical, and pathologic features to facilitate the diagnosis that often requires an interdisciplinary approach including radiologists is provided.
Abstract: The syndromes synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) constitute a group of chronic relapsing inflammatory osteoarticular disorders with frequently associated skin eruptions such as palmoplantar pustulosis and acne conglobata and rather characteristic imaging features in the form of osteitis and/or hyperostosis. CRMO predominantly occurs in children/adolescents and SAPHO in adults. Any skeletal site can be involved, and the imaging appearances vary, depending on the patient's age and the stage/age of the lesion. The diagnosis may be difficult if there is no skin disease, but attention to characteristic imaging appearances may help avoid misdiagnosis (e.g., infection and tumor) and thereby unnecessary invasive procedures as well as facilitating early diagnosis and appropriate treatment. This article provides an overview of the radiologic appearances of SAPHO/CRMO and relevant pathogenetic, clinical, and pathologic features to facilitate the diagnosis that often requires an interdisciplinary approach including radiologists.

Journal ArticleDOI
TL;DR: The progression of EOS can be controlled using MCGRs allowing growth and improved function, and improvements in Cobb angle, TK and T1‐S1 heights were not related to gender, the aetiology of the EOS, or whether the procedure was primary or conversion from a conventional growing rod system.
Abstract: Aims Magnetically controlled growing rod (MCGR) systems use non-invasive spinal lengthening for the surgical treatment of early-onset scoliosis (EOS). The primary aim of this study was to evaluate ...


Journal ArticleDOI
TL;DR: The serum inflammatory markers CRP, LC, and ESR are insufficiently accurate to diagnose late FRI, but they may be used as a suggestive sign in its diagnosis.
Abstract: Aims To assess the diagnostic value of C-reactive protein (CRP), leucocyte count (LC), and erythrocyte sedimentation rate (ESR) in late fracture-related infection (FRI). Materials and Methods PubMe...

Journal ArticleDOI
TL;DR: In this paper, the authors reported the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA 14 mutations in the C1 domain of PKCγ, H36R and H101Q.
Abstract: Spinocerebellar ataxia type 14 (SCA14) is a subtype of the autosomal dominant cerebellar ataxias that is characterized by slowly progressive cerebellar dysfunction and neurodegeneration SCA14 is caused by mutations in the PRKCG gene, encoding protein kinase C gamma (PKCγ) Despite the identification of 40 distinct disease-causing mutations in PRKCG, the pathological mechanisms underlying SCA14 remain poorly understood Here we report the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA14 mutations in the C1 domain of PKCγ, H36R and H101Q We show that endogenous expression of these mutations results in the cytoplasmic mislocalization and aggregation of PKCγ in both patient iPSCs and cerebellum PKCγ aggregates were not efficiently targeted for degradation Moreover, mutant PKCγ was found to be hyper-activated, resulting in increased substrate phosphorylation Together, our findings demonstrate that a combination of both, loss-of-function and gain-of-function mechanisms are likely to underlie the pathogenesis of SCA14, caused by mutations in the C1 domain of PKCγ Importantly, SCA14 patient iPSCs were found to accurately recapitulate pathological features observed in post-mortem SCA14 cerebellum, underscoring their potential as relevant disease models and their promise as future drug discovery tools

21 Feb 2018
TL;DR: There is a North Atlantic divide, with cementless femoral stemsbeing used more frequently in the USA and cemented stems being used morerequently in many countries in Europe.
Abstract: Cement is the commonest method used to fix femoral components in the UK. This is not surprising as in the UK cemented fixation has provided better results than cementless fixation. The results of c...

21 Feb 2018
TL;DR: In this paper, the outcomes following non-metal-on-metal hip arthroplasty (nonMoMHA) patients requiring revision surgery for adverse reactions to metal debris (ARMD) were determined.
Abstract: Recent studies have reported on non-metal-on-metal hip arthroplasty (non-MoMHA) patients requiring revision surgery for adverse reactions to metal debris (ARMD). Although the outcomes following revision surgery for ARMD in MoMHA patients are known to generally be poor, little evidence exists regarding outcomes following non-MoMHA revision surgery performed for ARMD. We determined the outcomes following non-MoMHA revision surgery performed for ARMD, and identified predictors of re-revision.We performed a retrospective observational study using data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man. All primary non-MoMHA patients who subsequently underwent revision surgery for ARMD between 2008–2014 were included (n=185). Outcome measures following ARMD revision were intraoperative complications, mortality, and re-revision surgery. Predictors of re-revision surgery were identified using Cox regression analysis.Intra-operative complications occurred in 6.0% (n=11) of A...

Journal ArticleDOI
TL;DR: Component positioning for the two groups was similar for the femur but less accurate on the tibial side using PSI, often with some unnecessarily deep resections of the t Tibial plateau.
Abstract: Patient-specific instrumentation (PSI) has been proposed as a means of improving surgical accuracy and ease of implantation during technically challenging procedures such as unicompartmental knee arthroplasty (UKA). The purpose of this prospective randomised controlled trial was to compare the accuracy of implantation and functional outcome of mobile-bearing medial UKAs implanted with and without PSI by experienced UKA surgeons. Mobile-bearing medial UKAs were implanted in 43 patients using either PSI guides or conventional instrumentation. Intra-operative measurements, meniscal bearing size implanted, and post-operative radiographic analyses were performed to assess component positioning. Functional outcome was determined using the Oxford Knee Score (OKS). PSI guides could not be used in three cases due to concerns regarding accuracy and registration onto native anatomy, particularly on the tibial side. In general, similar component alignment and positioning was achieved using the two systems (n.s. for coronal/sagittal alignment and tibial coverage). The PSI group had greater tibial slope (p = 0.029). The control group had a higher number of optimum size meniscal bearing inserted (95 vs 52%; p = 0.001). There were no differences in OKS improvements (n.s). Component positioning for the two groups was similar for the femur but less accurate on the tibial side using PSI, often with some unnecessarily deep resections of the tibial plateau. Although PSI was comparable to conventional instrumentation based on OKS improvements at 12 months, we continue to use conventional instrumentation for UKA at our institution until further improvements to the PSI guides can be demonstrated. Therapeutic, Level I.

Journal ArticleDOI
01 Feb 2018-Pain
TL;DR: Overall, it is found that pain and pain-related outcomes were no different for those undergoing ABM compared with placebo training or no training when tested immediately after training or 3 months later.
Abstract: Attention bias for pain-related information is theorised to maintain chronic pain, indicating that changing this bias could improve pain-related outcomes. Modifying attention biases in adolescents, when chronic pain often first emerges, may be particularly beneficial. We report here a random

Journal ArticleDOI
TL;DR: Higher diet quality across adulthood is associated with better physical performance in older age, suggesting potential for improvements in diet in early older age.
Abstract: © The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. Background: Current evidence that links "healthier" dietary patterns to better measured physical performance is mainly from older populations; little is known about the role of earlier diet. We examined adult diet quality in relation to physical performance at age 60-64 years. Methods Diet quality was defined using principal component analysis of dietary data collected at age 36, 43, 53, and 60-64. Throughout adulthood, diets of higher quality were characterized by higher consumption of fruit, vegetables, and wholegrain bread. Diet quality scores calculated at each age indicated compliance with this pattern. Physical performance was assessed using chair rise, timed-up-and-go, and standing balance tests at age 60-64. The analysis sample included 969 men and women. Results In gender-adjusted analyses, higher diet quality at each age was associated with better measured physical performance (all p <.01 for each test), although some associations were attenuated after adjustment for covariates. Diet quality scores were highly correlated in adulthood (0.44 ≤ r ≤ 0.67). However, conditional models showed that higher diet quality at age 60-64 (than expected from scores at younger ages), was associated with faster chair rise speed and with longer standing balance time (adjusted: 0.08 [95% CI: 0.02, 0.15] and 0.07 [0.01, 0.14] SD increase in chair rise speed and balance time, respectively, per SD increase in conditional diet quality; both p <.05). Conclusions Higher diet quality across adulthood is associated with better physical performance in older age. Current diet quality may be particularly important for physical performance, suggesting potential for improvements in diet in early older age.

Journal ArticleDOI
TL;DR: This international survey infers the need for a consensus definition of FRI and provides insight into the clinical parameters seen by an international community of trauma surgeons as being critical for defining FRI.
Abstract: Introduction Fracture-related infection (FRI) is one of the most challenging musculoskeletal complications in orthopaedic-trauma surgery. Although the orthopaedic community has developed and adopted a consensus definition of prosthetic joint infections (PJI), it still remains unclear how the trauma surgery community defines FRI in daily clinical practice or in performing clinical research studies. The central aim of this study was to survey the opinions of a global network of trauma surgeons on the definitions and criteria they routinely use, and their opinion on the need for a unified definition of FRI. The secondary aims were to survey their opinion on the utility of currently used definitions that may be at least partially applicable for FRI, and finally their opinion on the important clinical parameters that should be considered as diagnostic criteria for FRI. Methods An 11-item questionnaire was developed to cover the above-mentioned aims. The questionnaire was administered by SurveyMonkey and was sent via blast email to all registered users of AO Trauma (Davos, Switzerland). Results Out of the 26'563 recipients who opened the email, 2'327 (8.8%) completed the questionnaire. Nearly 90% of respondents agreed that a consensus-derived definition for FRI is required and 66% of the surgeons also agreed that PJI and FRI are not equal with respect to diagnosis, treatment and outcome. Furthermore, “positive cultures from microbiology testing”, “elevation of CRP”, “purulent drainage” and “local clinical signs of infection” were voted the most important diagnostic parameters for FRI. Conclusion This international survey infers the need for a consensus definition of FRI and provides insight into the clinical parameters seen by an international community of trauma surgeons as being critical for defining FRI.

18 May 2018
TL;DR: In this article, the authors investigated the value of quantitative histological analysis in the diagnosis of fracture-related infection (FRI) in 156 surgically treated non-unions.
Abstract: Aim The aim was to investigate the value of quantitative histological analysis in the diagnosis of fracture-related infection (FRI). Patients and Methods The clinical features, microbiology culture results and histological analysis in 156 surgically treated non-unions were used to stratify the likelihood of associated infection. There were 64 confirmed infected non-unions (≥1 confirmatory criteria; pus, sinus and bacterial growth in ≥2 samples), 66 aseptic non-unions (no confirmatory criteria) and 26 possibly infected (pathogen identified from a single specimen and no confirmatory criteria). The histological inflammatory response was assessed by average neutrophil polymorphs (NPs) counts per high power field (HPF) and compared to the established diagnosis. Results Assuming a cut-off of >5NPs/HPF for positive histological diagnosis, there was 80% sensitivity and 100% specificity (accuracy 90%). Using a cut-off of any NPs/HPF (>0) for negative histological diagnosis there was a sensitivity of 98% and a spec...

Journal ArticleDOI
10 Aug 2018
TL;DR: Scientific evidence on sonication fluid and tissue sampling, including culture, molecular techniques and histopathology for the diagnosis of FRI is scarce and it is imperative that laboratory protocols become standardized and uniform diagnostic criteria be implemented.
Abstract: Introduction: Intraoperatively obtained peri-implant tissue cultures remain the standard for diagnosis of fracture-related infection (FRI), although culture-negative cases may complicate treatment decisions. This paper reviews the evidence on sonication fluid and tissue sampling for the diagnosis of FRI. Methods: A comprehensive search in Pubmed, Embase and Web-of-Science was carried out on April 5, 2018, to identify diagnostic validation studies regarding sonication fluid and tissue sampling for FRI. Results: Out of 2624 studies, nine fulfilled the predefined inclusion criteria. Five studies focused on sonication fluid culture, two on PCR and two on histopathology. One additional histopathology study was found after screening of reference lists. There is limited evidence that sonication fluid culture may be a useful adjunct to conventional tissue culture, but no strong evidence that it is superior or can replace tissue culture. Regarding molecular techniques and histopathology the evidence is even less clear. Overall, studies had variable 'gold standard' criteria for comparison and poorly reported culture methods. Conclusions: Scientific evidence on sonication fluid and tissue sampling, including culture, molecular techniques and histopathology for the diagnosis of FRI is scarce. It is imperative that laboratory protocols become standardized and uniform diagnostic criteria, as recently published in a consensus definition, be implemented.

Journal ArticleDOI
01 Dec 2018-Knee
TL;DR: The cementless OUKR is a safe and reproducible procedure with excellent 10-year survival and clinical results in the hands of both designer and independent surgeons.
Abstract: Background Cementless fixation is an alternative to cemented unicompartmental knee replacement (UKR), with several advantages over cementation. This study reports the ten-year survival and seven-year clinical outcome of cementless Oxford unicompartmental knee replacement (OUKR). Methods This prospective study describes the clinical outcome and survival of the first 1000 consecutive cementless medial OUKRs implanted at two centres for recommended indications. Results The 10-year survival was 97% (CI 95%: 92–100%), with 25 knees being revised. The commonest reason for revision was progression of arthritis laterally, which occurred in nine knees, followed by primary dislocation of the bearing, which occurred in six knees. There were two dislocations secondary to trauma and a ruptured ACL, and two tibial plateau fractures. Although there were no definite cases of aseptic loosening, two early revisions were related to tibial fixation: one for pain and a radiolucent line and one for incomplete seating of the component with a radiolucent line. There were four revisions for pain, but the cause of the pain was uncertain: in one there was tibial overhang and in two there was patellofemoral degeneration, which possibly contributed to the pain. There were no deep infections. The mean OKS improved from 23 (SD 8) to 42 (SD 7) at a mean follow-up of 7.0 years (p Conclusions The cementless OUKR is a safe and reproducible procedure with excellent 10-year survival and clinical results in the hands of both designer and independent surgeons.