The characteristics and predictors of mortality in periprosthetic fractures around the knee.

Aims: Periprosthetic fractures (PPFs) around the knee are challenging injuries. This study aims to describe the characteristics of knee PPFs and the impact of patient demographics, fracture types, and management modalities on in-hospital mortality. Methods: Using a multicentre study design, independent of registry data, we included adult patients sustaining a PPF around a knee arthroplasty between 1 January 2010 and 31 December 2019. Univariate, then multivariable, logistic regression analyses were performed to study the impact of patient, fracture, and treatment on mortality. Results: Out of a total of 1,667 patients in the PPF study database, 420 patients were included. The in-hospital mortality rate was 6.4%. Multivariable analyses suggested that American Society of Anesthesiologists (ASA) grade, history of peripheral vascular disease (PVD), history of rheumatic disease, fracture around a loose implant, and cerebrovascular accident (CVA) during hospital stay were each independently associated with mortality. Each point increase in ASA grade independently correlated with a four-fold greater mortality risk (odds ratio (OR) 4.1 (95% confidence interval (CI) 1.19 to 14.06); p = 0.026). Patients with PVD have a nine-fold increase in mortality risk (OR 9.1 (95% CI 1.25 to 66.47); p = 0.030) and patients with rheumatic disease have a 6.8-fold increase in mortality risk (OR 6.8 (95% CI 1.32 to 34.68); p = 0.022). Patients with a fracture around a loose implant (Unified Classification System (UCS) B2) have a 20-fold increase in mortality, compared to UCS A1 (OR 20.9 (95% CI 1.61 to 271.38); p = 0.020). Mode of management was not a significant predictor of mortality. Patients managed with revision arthroplasty had a significantly longer length of stay (median 16 days; p = 0.029) and higher rates of return to theatre, compared to patients treated nonoperatively or with fixation. Conclusion: The mortality rate in PPFs around the knee is similar to that for native distal femur and neck of femur fragility fractures. Patients with certain modifiable risk factors should be optimized. A national PPF database and standardized management guidelines are currently required to understand these complex injuries and to improve patient outcomes.

The Impact of the COVID-19 Pandemic on Orthopaedic Trauma Surgery in a District General Hospital in the United Kingdom.

Introduction The 2020 COVID-19 pandemic led to a national lockdown and a major reorganization of healthcare services in the United Kingdom. The center where the study was done was one of the worst affected hospitals in the United Kingdom at the outset of the pandemic. Our study evaluates the impact of the pandemic and national lockdown on the outcomes for patients undergoing orthopedic trauma surgery. Methods We prospectively identified all patients undergoing orthopedic trauma surgery in the unit from 1st March 2020 to 31st May 2020. We recorded demographics, diagnoses, COVID-19 infection status, length of stay, and mortality. This was compared with a comparative group in the same period in 2018 and 2019. Results There was a significant reduction in the number of orthopedic trauma surgery cases (318) performed in 2020 compared to 2019 (423 cases, p<0.001) and 2018 (444 cases, p<0.001). The mean time from injury to presentation was 3.6 days, with 40 patients (12.6%) presenting more than one week after injury. The 30-day mortality was 8.2%, and the six-month mortality was 15.1%, with both significantly higher than in 2018 (p<0.001) and 2019 (p<0.001). COVID-19 testing was positive in 39% of patients, with 30-day mortality in this group at 37%, rising to a 53% six-month mortality. No patients under the age of 50 years old died. The majority of admissions (51%) were due to falls at home. The second most common mechanism was Do-It-Yourself (DIY) injuries. Road traffic accidents accounted for 2%. Conclusion There were significantly fewer cases of orthopedic trauma surgery during the first wave of the COVID-19 pandemic compared to the same period in previous years. The type of trauma also showed low numbers of high-energy and sporting injuries as a result of the national lockdown. Patients undergoing orthopedic trauma surgery who tested positive for COVID-19 had significantly higher 30-day mortality than those without COVID-19, and this increased mortality persisted to six months post-operatively. However, patients under 50 years old appear to be at low risk of death.

Predictors of mortality in periprosthetic fractures of the hip: Results from the national PPF study.

INTRODUCTION: Periprosthetic fractures (PPFs) around the hip joint are increasing in prevalence. In this collaborative study, we aimed to investigate the impact of patient demographics, fracture characteristics, and modes of management on in-hospital mortality of PPFs involving the hip. METHODS: Using a multi-centre cohort study design, we retrospectively identified adults presenting with a PPF around the hip over a 10-year period. Univariate and multivariable logistic regression analyses were performed to study the independent correlation between patient, fracture, and treatment factors on mortality. RESULTS: A total of 1,109 patients were included. The in-hospital mortality rate was 5.3%. Multivariable analyses suggested that age, male sex, abbreviated mental test score (AMTS), pneumonia, renal failure, history of peripheral vascular disease (PVD) and deep surgical site infection were each independently associated with mortality. Each yearly increase in age independently correlates with a 7% increase in mortality (OR 1.07, p=0.019). The odds of mortality was 2.99 times higher for patients diagnosed with pneumonia during their hospital stay [OR 2.99 (95% CI 1.07-8.37) p=0.037], and 7.25 times higher for patients that developed renal failure during their stay [OR 7.25 (95% CI 1.85-28.47) p=0.005]. Patients with history of PVD have a six-fold greater mortality risk (OR 6.06, p=0.003). Mode of treatment was not a significant predictor of mortality. CONCLUSION: The in-hospital mortality rate of PPFs around the hip exceeds 5%. The fracture subtype and mode of management are not independent predictors of mortality, while patient factors such as age, AMTS, history of PVD, pneumonia, and renal failure can independently predict mortality. Peri-operative optimisation of modifiable risk factors such as lung and kidney function in patients with PPFs around the hip during their hospital stay is of utmost importance.

The British Orthopaedic Oncology Management (BOOM) audit.

Aims: Most patients with advanced malignancy suffer bone metastases, which pose a significant challenge to orthopaedic services and burden to the health economy. This study aimed to assess adherence to the British Orthopaedic Oncology Society (BOOS)/British Orthopaedic Association (BOA) guidelines on patients with metastatic bone disease (MBD) in the UK. Methods: A prospective, multicentre, national collaborative audit was designed and delivered by a trainee-led collaborative group. Data were collected over three months (1 April 2021 to 30 June 2021) for all patients presenting with MBD. A data collection tool allowed investigators at each hospital to compare practice against guidelines. Data were collated and analyzed centrally to quantify compliance from 84 hospitals in the UK for a total of 1,137 patients who were eligible for inclusion. Results: A total of 846 patients with pelvic and appendicular MBD were analyzed, after excluding those with only spinal metastatic disease. A designated MBD lead was not present in 39% of centres (33/84). Adequate radiographs were not performed in 19% of patients (160/846), and 29% (247/846) did not have an up-to-date CT of thorax, abdomen, and pelvis to stage their disease. Compliance was low obtaining an oncological opinion (69%; 584/846) and prognosis estimations (38%; 223/846). Surgery was performed in 38% of patients (319/846), with the rates of up-to-date radiological investigations and oncology input with prognosis below the expected standard. Of the 25% (215/846) presenting with a solitary metastasis, a tertiary opinion from a MBD centre and biopsy was sought in 60% (130/215). Conclusion: Current practice in the UK does not comply with national guidelines, especially regarding investigations prior to surgery and for patients with solitary metastases. This study highlights the need for investment and improvement in care. The recent publication of British Orthopaedic Association Standards for Trauma (BOAST) defines auditable standards to drive these improvements for this vulnerable patient group.

Medial patellofemoral ligament reconstruction and tibial tuberosity transfer can be used to successfully manage patellofemoral instability in the setting of trochlea dysplasia.

BACKGROUND: Management of patella instability remains a challenge particularly in the presence of trochlea dysplasia. The aim of this study is to assess the recurrence rates of those with patellar instability who have undergone a combined tibial tuberosity transfer (TTT) and medial patellofemoral ligament reconstruction (MPFLR) in the setting of trochlea dysplasia. METHODS: All skeletally mature patients who underwent combined TTT and MPFLR for recurrent patella instability were identified between January 2009 and December 2019. A retrospective review was conducted, with information regarding re-dislocation/subluxation and complications collected. RESULTS: Seventy patients with a mean age 25.3 years were identified and evaluated. Thirteen patients were found to have low-grade dysplasia (Dejour A), with 57 patients having high-grade dysplasia (Dejour B/C/D). No patients in the low,grade dysplasia group suffered a recurrence of their symptoms, with four in the high-grade group suffering episodes of re-dislocation/subluxation. Three patients subsequently underwent a trochleoplasty, with the other patient managed successfully non-operatively. There were a total of 13 complications in 11 patients. CONCLUSIONS: A combined procedure of MPFLR and TTT can be used to manage patellofemoral instability even in the setting of trochlea dysplasia with a low rate of recurrence. Trochlea dysplasia, however, remains an anatomical risk factor for recurrence and patients should be counselled accordingly. The anatomical risk factors should be assessed in all patients to allow for the development of the most appropriate management plan, of which this combined procedure represents a potentially successful option. LEVEL OF EVIDENCE: IV (Case Series).

Clinical Audit Platform for Students (CAPS): a pilot study.

BACKGROUND: A clinical audit measures specific clinical outcomes or processes against a predefined standard. However, many clinicians are unable to carry out audits given their time constraints. Alternatively, medical students may often wish to complete audits early in their career to strengthen their portfolios. As such, the student clinical audit platform was designed to connect willing supervisors and these medical students. METHODS: Project supervisors were members of a regional trainee-led network. Interested students were familiarised with the various aspects of an audit and allocated to supervisors with similar interests. There was regular communication to track progress and anonymised feedback forms were distributed to all students and supervisors after a year. RESULTS: A total of 17 responses were received from the 19 students who were involved in a project. Based on a 5-point Likert scale, students displayed a mean improvement in their understanding of a clinical audit (1.18±1.07, p<0.001), the confidence to approach a supervisor (1.29±1.21, p<0.001) and the ability to conduct an audit by themselves in the future (1.77±1.15, p<0.001). Of the seven affiliated supervisors, five provided feedback with 80% indicating they had projects which remained inactive and all happy with the quality of work produced by their students. CONCLUSION: Despite limitations to this programme, the platform produced projects which were disseminated both locally and nationally, demonstrating positive collaboration between medical students and clinicians. We present our findings and evaluations to encourage similar audit platforms to be adopted at other locations.

Two stage cementation and screw augmentation of large acetabular defects in low demand patients: Early results and surgical technique.

INTRODUCTION: The reconstruction of large acetabular defects in revision hip arthroplasty represents a challenge to the surgeon and increases the complexity of the case. There are different options to overcome the problem of acetabular deficiency. In the elderly low demand patients, the main objective of revision surgery is to provide pain relief, allow immediate full weight bearing, and an early return to function. METHODS: This article presents our experience in acetabular revision surgery using a novel technique of two stage cementation and screw augmentation in low demand patients. We report on the surgical technique and present the early results in 10 patients. RESULTS: There were 6 females and 4 males with average age of 83.8 years. Patients were followed up for an average of 18.1 months. All patients were pain free and full weight bearing at the time of the final follow up with radiographs showing maintenance of implant position. None of the patients underwent revision surgery and there were no radiographic signs of failure detected in the early follow-up period. CONCLUSION: This is a suitable technique in the management of large acetabular defects in revision hip arthroplasty, especially in the low demand patient population. It is a simple cost-effective technique that reduces the complexity of the acetabular revision, operative time, and morbidity associated with prolonged complex revision surgery.

TLR2 Plays a Pivotal Role in Mediating Mucosal Serotonin Production in the Gut.

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that mediates various physiological processes in the gut. Enterochromaffin (EC) cells in the mucosal layer of the gut are the main source of 5-HT in the body and are situated in close proximity to the gut microbiota. In this study, we identify a pivotal role of TLR2 in 5-HT production in the gut. Antibiotic treatment reduces EC cell numbers and 5-HT levels in naive C57BL/6 mice, which is associated with downregulation of TLR2 expression but not TLR1 or TLR4. TLR2-deficient (Tlr2 -/-) and Myd88 -/- mice express lower EC cell numbers and 5-HT levels, whereas treatment with TLR2/1 agonist upregulates 5-HT production in irradiated C57BL/6 mice, which are reconstituted with Tlr2 -/- bone marrow cells, and in germ-free mice. Human EC cell line (BON-1 cells) release higher 5-HT upon TLR2/1 agonist via NF-κB pathway. Tlr2 -/- mice and anti-TLR2 Ab-treated mice infected with enteric parasite, Trichuris muris, exhibited attenuated 5-HT production, compared with infected wild-type mice. Moreover, excretory-secretory products from T. muris induce higher 5-HT production in BON-1 cells via TLR2 in a dose-dependent manner, whereby the effect of excretory-secretory products is abrogated by TLR2 antagonist. These findings not only suggest an important role of TLR2 in mucosal 5-HT production in the gut by resident microbiota as well as by a nematode parasite but also provide, to our knowledge, novel information on the potential benefits of targeting TLR2 in various gut disorders that exhibit aberrant 5-HT signaling.

Is the routine use of magnetic resonance imaging indicated in patients with scoliosis?

BACKGROUND: To assess the reliability of the indicators for performing magnetic resonance imaging in patients with scoliosis and assess the incidence of neural axis anomalies in a population with scoliosis referred to a specialist centre. METHODS: A retrospective review of magnetic resonance imaging (MRI) reports of all patients under the age of 18 who underwent a pre-operative MRI for investigation of their scoliosis between 2009 and 2014 at a single institution was performed. RESULTS: There were 851 patients who underwent an MRI scan of their whole spine with a mean age of 14.08 years. There were 211 males and 640 females. One hundred and fourteen neural axis abnormalities (NAA) were identified. The presence of a left sided thoracic curve, a double thoracic curve, being male nor being diagnosed before the age of 10 were found to be statistically significant for the presence of a NAA. Furthermore, 2.34% of patients were also found to have an incidental finding (IF) of an extraspinal abnormality. CONCLUSIONS: From our series, the reported indications for performing an MRI scan in the presence of scoliosis are not reliable for the presence of an underlying NAA. We have demonstrated that there is a number of intra and extra dural anomalies found on MRI without clinical symptoms and signs. This acts as normative information for this group. KEYWORDS: Scoliosis; magnetic resonance imaging (MRI); neural axis abnormalities (NAA); adolescent idiopathic scoliosis (AIS).

The 3-dot circle: A reliable method for safe and efficient digital templating of the acetabular component.

BACKGROUND: Templating for preoperative planning of joint arthroplasty has followed the evolution of digital templating software. OBJECTIVE: This study aims to provide a safe, reliable and reproducible method for prediction of acetabular component size based on measurement of the radiographic femoral head diameter, with the aid of templating software. METHODS: A defined methodology for femoral head measurement was applied to 97 consecutive, calibrated digital pelvic radiographs. Based on radiographic femoral head diameter, the minimum acetabular shell diameter was calculated and then compared to the size of the implanted acetabular shells. RESULTS: This method predicted safe minimum acetabular component size with an accuracy of 95.9% with a high inter-observer reliability of 97.6%. CONCLUSIONS: This study presents a simple, reproducible and accurate method for templating of the minimum safest acetabular component diameter.

Functional results following high tibial osteotomy: a review of the literature.

INTRODUCTION: High tibial osteotomy (HTO) is an operation used to treat patients with medial compartment knee osteoarthritis. The United Kingdom Knee Osteotomy Registry (UKKOR) has been set up to gather contemporaneous data on HTO throughout the patient journey. UKKOR uses a variety of patient-reported outcome measures (PROMs) to gauge the surgical outcome. AIM: The aim of this review is to analyse the published literature that has used PROMs to assess the outcomes following HTO. METHODOLOGY: Two searches of the literature were performed and compiled highlighting 95 articles of interest. After screening and manual additions, 23 manuscripts were reviewed and appraised using the appropriate Critical Appraisal Skills Programme Checklist (Kai et al. in PLoS Med 4(11):1766-1775, 2007). RESULTS AND DISCUSSION: There is a variety of published literature on HTO with a varied approach to the use of PROMs. Their use has increased recently, and studies have demonstrated that they are appropriate assessment tools for monitoring outcomes following HTO. In all of the studies that compared pre-operative to post-operative PROMs, there have been significant improvements. However, the data are varied due to differing study designs which in some instances have significant limitations. CONCLUSION: PROMs are effective ways to measure outcomes following HTO. They can also be useful in predicting outcome. The heterogeneity of the data and limitations of the study designs limit the transferability of the data. It is therefore important to analyse data from a multi-surgeon, multi-centre source that uses robust and constant pre- and post-operative PROMs.

Discovery of Small Molecules as Multi-Toll-like Receptor Agonists with Proinflammatory and Anticancer Activities.

Therapies based on activation of multiple Toll-like receptors (TLRs) may offer superior therapeutic profiles than that of single TLR activation. To discover new small molecules that could activate multiple TLRs, we performed a cell-based high-throughput screening of a small-molecule library based on TLR3-mediated NF-κB activation. Subsequent structural optimization and counterscreening of other TLRs produced the first small molecule 17e (CU-CPT17e) capable of simultaneously activating TLRs 3, 8, and 9. Biochemical studies demonstrated that 17e could induce a strong immune response via the production of various cytokines in human monocytic THP-1 cells. Furthermore, 17e inhibited the proliferation of HeLa cancer cells by triggering apoptosis and arresting the cell cycle at the S phase. These results showcase potential therapeutic applications of 17e in both vaccine adjuvants and anticancer therapies based on multi-TLR activation.

HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia.

Infectious and sterile inflammatory diseases are correlated with increased levels of high mobility group box 1 (HMGB1) in tissues and serum. Extracellular HMGB1 is known to activate Toll-like receptors (TLRs) 2 and 4 and RAGE (receptor for advanced glycation endproducts) in inflammatory conditions. Here, we find that TLR5 is also an HMGB1 receptor that was previously overlooked due to lack of functional expression in the cell lines usually used for studying TLR signaling. HMGB1 binding to TLR5 initiates the activation of NF-κB signaling pathway in a MyD88-dependent manner, resulting in proinflammatory cytokine production and pain enhancement in vivo. Biophysical and in vitro results highlight an essential role for the C-terminal tail region of HMGB1 in facilitating interactions with TLR5. These results suggest that HMGB1-modulated TLR5 signaling is responsible for pain hypersensitivity.

Role of aminoacyl-tRNA synthetases in infectious diseases and targets for therapeutic development.

Aminoacyl-tRNA synthetases (AARSs) play a pivotal role in protein synthesis and cell viability. These 22 "housekeeping" enzymes (1 for each standard amino acid plus pyrrolysine and o-phosphoserine) are specifically involved in recognizing and aminoacylating their cognate tRNAs in the cellular pool with the correct amino acid prior to delivery of the charged tRNA to the protein synthesis machinery. Besides serving this canonical function, higher eukaryotic AARSs, some of which are organized in the cytoplasm as a multisynthetase complex of nine enzymes plus additional cellular factors, have also been implicated in a variety of non-canonical roles. AARSs are involved in the regulation of transcription, translation, and various signaling pathways, thereby ensuring cell survival. Based in part on their versatility, AARSs have been recruited by viruses to perform essential functions. For example, host synthetases are packaged into some retroviruses and are required for their replication. Other viruses mimic tRNA-like structures in their genomes, and these motifs are aminoacylated by the host synthetase as part of the viral replication cycle. More recently, it has been shown that certain large DNA viruses infecting animals and other diverse unicellular eukaryotes encode tRNAs, AARSs, and additional components of the protein-synthesis machinery. This chapter will review our current understanding of the role of host AARSs and tRNA-like structures in viruses and discuss their potential as anti-viral drug targets. The identification and development of compounds that target bacterial AARSs, thereby serving as novel antibiotics, will also be discussed. Particular attention will be given to recent work on a number of tRNA-dependent AARS inhibitors and to advances in a new class of natural "pro-drug" antibiotics called Trojan Horse inhibitors. Finally, we will explore how bacteria that naturally produce AARS-targeting antibiotics must protect themselves against cell suicide using naturally antibiotic resistant AARSs, and how horizontal gene transfer of these AARS genes to pathogens may threaten the future use of this class of antibiotics.

Dual role for motif 1 residues of human lysyl-tRNA synthetase in dimerization and packaging into HIV-1.

The primer for reverse transcription in human immunodeficiency virus type 1, human tRNA(Lys,3), is selectively packaged into the virion along with tRNA(Lys1,2). Human lysyl-tRNA synthetase (hLysRS), the only cellular factor known to interact specifically with all three tRNA(Lys) isoacceptors, is also selectively packaged into HIV-1. We have previously defined a tRNA(Lys) packaging complex that includes the tRNA(Lys) isoacceptors, LysRS, HIV-1 Gag, GagPol, and viral RNA. Numerous studies support the hypothesis that during tRNA(Lys) packaging, a Gag·GagPol complex interacts with a tRNA(Lys)·LysRS complex, with Gag interacting specifically with the catalytic domain of LysRS, and GagPol interacting with both Gag and tRNA(Lys). In this work, we have identified residues along one face of the motif 1 dimerization helix (H7) of hLysRS that are critical for packaging of the synthetase into virions. Mutation of these residues affects binding to Gag in vitro, as well as the oligomerization state and aminoacylation activity of the synthetase. Taken together, these data suggest that H7 of LysRS has a dual function. In its canonical role it maintains the synthetase dimer interface, whereas in its function in tRNA primer recruitment, it bridges interactions with HIV-1 Gag.

Prognostic and survival factors in myxofibrosarcomas.

Aim. Our study aimed to determine prognostic factors for survival and recurrence in myxofibrosarcomas based on the experience of a single institution. Methods. Patients who had been diagnosed with a myxofibrosarcoma were identified from our database. Survival and recurrence were evaluated with Kaplan Meier survival curves for univariate and cox regression for multivariate analysis. Results. 174 patients with a diagnosis of myxofibrosarcoma were identified. Two patients were excluded due to incomplete information, leaving 172 patients with a mean age of 67 years. Surgery was undertaken in all but 6 patients. Five-year survival was better for myxofibrosarcomas when compared to other soft tissue sarcomas (63% versus 57%). Size, grade of tumour, age, and metastases were all found to be prognostic factors. Local recurrence occurred in 29 patients (17%) with an overall risk of 15% at 5 years. Previous inadvertent excision significantly raised this risk to 45%. Wide surgical margins and depth of tumour, however, had no impact on recurrence. Conclusion. Factors previously identified as prognostic did not demonstrate such a relationship in our study, highlighting the unpredictable nature of myxofibrosarcomas. Future treatment may lie in developing an understanding molecular basis of the tumour and directing therapies accordingly.

Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction.

The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) plays a critical role in the viral life cycle. The C-terminal domain (CTD) of CA binds to human lysyl-tRNA synthetase (hLysRS), and this interaction facilitates packaging of host cell tRNA(Lys,3), which serves as the primer for reverse transcription. Here, we report the library synthesis, high-throughput screening, and identification of cyclic peptides (CPs) that bind HIV-1 CA. Scrambling or single-residue changes of the selected peptide sequences eliminated binding, suggesting a sequence-specific mode of interaction. Two peptides (CP2 and CP4) subjected to detailed analysis also inhibited hLysRS/CA interaction in vitro. Nuclear magnetic resonance spectroscopy and mutagenesis studies revealed that both CPs bind to a site proximal to helix 4 of the CA-CTD, which is the known site of hLysRS interaction. These results extend the current repertoire of CA-binding molecules to a new class of peptides targeting a novel site with potential for development into novel antiviral agents.

Hybrid open-endovascular repair of a contained suprarenal mycotic aneurysm using femoral vein.

Mycotic aneurysms have a high mortality rate, predominantly driven by sepsis. We present a 61-year-old patient who was treated with a hybrid open-endovascular repair using autologous femoral vein as a single channel revascularization. This provided a practical and innovative approach to a high-risk situation.