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Kennedy research Professor Irina Udalova has joined the Wellcome Trust’s Immune System in Health and Disease Expert Review Group from 1 October 2018.
A prenatal skin atlas reveals immune regulation of human skin morphogenesis.
Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.
Threaded rods versus arthrodesis nail as a static spacer for two-stage revision total knee arthroplasty.
INTRODUCTION: A spacer is required to maintain limb length and alignment and to provide a stable limb for mobilisation in two-stage revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI). Static spacers are indicated in cases of massive bone loss, compromised soft tissues, and ligamentous and/or extensor mechanism insufficiency. The aim of this study was to compare the use of Ilizarov rods to arthrodesis nails for static spacer constructs in first-stage rTKA for PJI. METHODS: This was a retrospective cohort study of 40 patients who underwent two-stage rTKA for PJI between 2019 and 2022. Static spacers were used in all cases, constructed from Ilizarov rods 20 patients and nails in 20 patients. Data collected included number of previous revisions, patient age at first revision, comorbidities and identified organisms. Groups were compared based on outcome measures including complications, reoperations, length of stay and re-revision rates. RESULTS: The use of Ilizarov rods showed higher rates of intraoperative complications (5% vs. 0%), readmissions (55% vs. 5%), and interstage re-operations (50% vs. 10%). Spacer-related complications occurred in 10 of 20 cases (50%) in the Ilizarov rod group, all due to spacer fractures, compared to none in the nail group (0%) (p
External femoral rotation of 2 degrees is associated with the lowest stuffing rates around the femur in functionally aligned TKA.
PURPOSE: Modifying femoral morphology after total knee arthroplasty (TKA) poses a potential risk for ligament-imbalances and patella mal-tracking. The purpose of this study was primarily to quantify TKA-induced stuffing around the femur and secondarily assess the effect of femoral rotation (FR) on trochlear and condylar anatomy-changes. METHODS: Knee anatomy-modification was quantified in 69 robotic-assisted TKAs utilising tibia-based functional alignment (FA). Caliper-measurements were performed on the medial (Med), central (Ctr), and lateral (Lat) sides of the following resection planes: anterior trochlea (AT), oblique trochlea (OT), distal condyles (DC), posterior condyles (PC) and tibia (TIB). The same caliper-measurements were performed on the femoral components used to calculate bone-implant differences and analyse possible patterns of postoperative trochlear anatomy-modifications (TAM) and condylar anatomy-modifications (CAM). Over- or understuffing analysis for different FRs and regression analysis were conducted to assess the effect of FR on CAM and TAM. RESULTS: TAM results were Lat-AT -3.2 mm ([95% confidence interval [CI]: -3.71 to -2.63], p 2 mm in 60.9%, 39.1%, and 39.1%, respectively. CAM results were Med-DC -3.6 mm ([95%CI: -4.14 to -3.05], p 0.001) with stuffing > 2 mm in 78.3% and 63.8%. FR (3.8 ± 2.6°, range: -1.6° to 8.5°) affected mostly the anterior (r = -0.40, p 2 mm and ≥ 4 mm. CONCLUSIONS: FA-typical modification-pattern was a TAM with lateral facet understuffing, and CAM with medial distal understuffing and lateral posterior overstuffing. Trochlear groove height was non-significantly affected by FR. FA with the current off-the-shelf implant induces the lowest stuffing rates when set in 2° external femoral rotation. LEVEL OF EVIDENCE: Level II.
Low confidence in the cumulative evidence for the existence of a volume-outcome relationship after revision total knee replacement: A systematic review and meta-analysis.
PURPOSE: This systematic review and meta-analysis aimed to establish the relationship between the number of procedures a hospital or surgeon performs with outcomes following revision knee replacement (RevKR). METHODS: MEDLINE and Embase were searched using Ovid silver platter up to December 2024 for randomised controlled trials and cohort studies that reported RevKR volumes, in at least two categories, performed by hospitals and surgeons and their relationship to patient and provider level outcomes. The primary outcome was re-revision rate. Secondary outcomes included mortality, post-operative complications, patient-reported outcomes measures (PROMs), emergency readmissions and hospital length of stay. The effect estimates were pooled and plotted using a random-effects, non-linear dose-response meta-analysis (DRMA). Where limitations in the data prohibited DRMA, a narrative approach was utilised. ROBINS-I and the GRADE approach were used to assess the risk of bias and the confidence in the cumulative evidence, respectively. RESULTS: A total of 10 cohort studies with data from 1993 to 2021 were included. The confidence in the cumulative evidence exploring the relationship between surgeon/hospital volume and all outcomes after RevKR was very low. An inconsistent relationship was seen between hospital and surgeon volume and re-revision at any point. There was a non-linear dose-response relationship between higher hospital volume and lower odds of adverse post-operative events (p
Indications for lateral unicompartmental knee arthroplasty - A systematic review.
BACKGROUND: While evidence-based indications are established for medial UKA, the optimal indications for lateral UKA have not received as much attention. There exists significant anatomical, osteoarthritis phenotype, kinematic, and surgical technique differences between medial and lateral UKA. The indications for the two procedures may therefore not be identical. Hence, this review aims to access the indications and contraindications in published cohort studies on lateral UKA, to assess if consensus exists. METHODS: In May 2024, a systematic review was carried out following the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Cohort studies on lateral UKA with a clear report of indications were included. Data on indications and contraindications were extracted to evaluate consensus. Furthermore, outcomes related to expanding or testing indications for lateral UKA were obtained. RESULTS: 38 studies were included. Lateral UKA was mostly performed for primary lateral osteoarthritis. The most reported indications were moderate to severe lateral osteoarthritis, with full-thickness cartilage in the medial compartment, intact ligaments, a correctable valgus deformity, and a flexion contracture
Higher hospital volume reduces early failure rates in single-stage revision TKR for infection: An analysis of the United Kingdom National Joint Registry and National Administrative Databases.
PURPOSE: Revision knee replacement (RevKR) for infection is rare but increasing. It is hypothesised that higher hospital volume reduces adverse outcomes. The aim was to estimate the association of surgical unit volume with outcomes following first, single-stage RevKR for infection. METHODS: This population-based cohort study merged data from the United Kingdom National Joint Registry, Hospital Episode Statistics, National Patient Reported Outcome Measures and the Civil Registrations of Death. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. Early outcomes were chosen to reflect the quality of the surgical provision and included re-revision at 2 years, mortality, serious medical complications, length of stay and patient-reported outcome measures (PROMs). Adjusted fixed effect multivariable regression models were used to examine the association between surgical unit mean annual caseload and the risk of adverse outcomes. RESULTS: A total of 1477 patients underwent first-time single-stage RevKRs for infection across 267 surgical units and 716 surgeons. Following adjustment for age, gender, American Society of Anaesthesiologists grade, surgeon volume, year of surgery and operation funder and modelling surgical unit volume with restricted cubic spline, a greater mean annual volume was associated with a lower risk of re-revision at 2 years. The odds of re-revision in hospitals performing fewer than or equal to 12 cases per year was 2.53 (95% confidence interval = 1.50-4.31) times more likely than hospitals performing three to four cases per month. Annual variation in surgical unit volume was not associated with mortality and serious medical complications within 90 days. Only 99 out of 1477 (7%) of patients had linked PROMs which precluded subsequent analysis. CONCLUSION: Overall, higher volume surgical units had lower rates of early re-revision following the first RevKR for infection. We were unable to provide recommended specific volume thresholds for units; however, the probability of re-revision appears to be lowest in the highest volume units. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.
'Obviously, because it's a tear it won't necessarily mend itself': a qualitative study of patient experiences and expectations of treatment for a meniscal tear.
OBJECTIVES: There is a paucity of qualitative research exploring the patient experience of living with a meniscal tear, vital to effective patient management. The aim of this study was to explore the experiences and expectations of treatment of patients aged 18-55 years with a meniscal tear of the knee. DESIGN: Qualitative study involving semistructured interviews. SETTING: Participants were selected from nine secondary care centres in England. PARTICIPANTS: 10 participants diagnosed with a meniscal tear were recruited from the Meniscal Tear Outcome cohort study using a purposive sampling strategy until data saturation was achieved. Semistructured interviews were conducted between April and May 2021 and thematic analysis was used to identify key patient experiences. RESULTS: Themes identified relate to the broad areas of symptoms, clinical consultation and experience of treatment. Meniscal tears have a profound impact on pain and many patients experience effects on their family and financial life in addition to physical symptoms. Participants expected most of their management to occur in secondary care and most thought surgery would be a definitive treatment, while they believed the effectiveness of physiotherapy could not be guaranteed as it would not fix the physical tear. CONCLUSION: This study is one of the first to explore patient experiences of a meniscal tear and their perceptions of treatment options. Patient experiences and perceptions are important for clinicians to understand in order to provide the best possible care. It is important to elicit these experiences, listen to the patient, discuss their perspectives and build these experiences and expectations into clinical care. TRIAL REGISTRATION NUMBER: ISRCTN11534691.
FRCS Trauma and Orthopaedics Viva
Based on the highly successful Oxford revision course, this book helps candidates prepare for the viva section of the FRCS Trauma and Orthopaedics exam.
Glial-immune interactions in barrier organs.
Neuro-immune interactions within barrier organs, such as lung, gut, and skin, are crucial in regulating tissue homeostasis, inflammatory responses, and host defence. Our rapidly advancing understanding of peripheral neuroimmunology is transforming the field of barrier tissue immunology, offering a fresh perspective for developing therapies for complex chronic inflammatory disorders affecting barrier organs. However, most studies have primarily examined interactions between the peripheral nervous system and the immune system from a neuron-focused perspective, while glial cells, the nonneuronal cells of the nervous system, have received less attention. Glial cells were long considered as mere bystanders, only supporting their neuronal neighbours, but recent discoveries mainly on enteric glial cells in the intestine have implicated these cells in immune-regulation and inflammatory disease pathogenesis. In this review, we will highlight the bi-directional interactions between peripheral glial cells and the immune system and discuss the emerging immune regulatory functions of glial cells in barrier organs.
Higher surgeon volume reduces early failure in first time revision of non-infected total knee arthroplasty: An analysis using data from the United Kingdom National Joint Registry.
PURPOSE: Revision total knee replacement (RevKR) is an increasingly common procedure. It is hypothesised that higher surgical volume is linked to lower levels of adverse outcomes. The aim was to estimate the association of surgical volume on patient outcomes following first single-stage RevKR for non-infected indications. METHODS: This population-based cohort study used data from the United Kingdom National Joint Registry, Hospital Episode Statistics and National Patient Reported Outcome Measures. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. The primary outcome measure was re-revision within 2 years; chosen to reflect the quality of the surgical provision. Fixed effect multivariable regression models were used to examine the association between surgeon and surgical unit annual caseload and the risk of adverse outcomes. RESULTS: A total of 8695 patients underwent first time single stage revision for aseptic loosening, instability, or malalignment across 389 surgical units and 1204 surgeons. Following adjustment for age, gender, ASA grade, year of surgery and operation funder, higher surgeon volume was associated with a lower risk of re-revision at 2 years. The risk of re-revision decreased amongst surgeons performing ≥9 annual revisions (OR 0.77, 95% CI 0.62-0.95, p-value = 0.02) compared to those performing <9 annual revisions. CONCLUSIONS: Annual surgeon case volume of ≥9 first single-stage RevKR for non-infected indications is independently associated with reductions in early re-revision. This evidence supports the setting of minimum volume targets to improve outcomes for patients. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.
What is the impact of longer patient travel distances and times on perioperative outcomes following revision knee replacement: a retrospective observational study using data for England from Hospital Episode Statistics.
OBJECTIVES: Patients undergoing revision total knee replacement (RevKR) surgery often have difficulties mobilising and increasingly rely on family support. Evolving practice in England aims to manage these patients in specialised centres with the intention of improving outcomes. This practice will result in longer travel distances and times in this frailer group of patients. We want to examine the types of distances and travel times patients can be expected to travel for this complex orthopaedic surgery and to explore concerns of how these impact patient outcomes. DESIGN: Retrospective observational study from the Hospital Episode Statistics. Multivariable adjusted logistic regression models were used to investigate the relationship between patient travel distances and times with perioperative outcomes. SETTING: Patients presenting to tertiary referral centres between 1 January 2016 and 31 December 2019. A tertiary referral centre was defined as a trust performing >49 revisions in the year prior. PARTICIPANTS: Adult patients undergoing RevKR procedures for any reason between 1 January 2016 ando 31 December 2019. EXPOSURE: The shortest patient level travel distance and time was calculated using the Department of Health Journey Time Statistics using Transport Accessibility and Connectivity Calculator software and Dijkstra's algorithm. MAIN OUTCOME MEASURES: The primary outcome is emergency readmission within 30 days. Secondary outcomes are mortality within 90 days and length of inpatient stay. RESULTS: 6880 patients underwent RevKR at 36 tertiary referral centres. There was a weak correlation between social deprivation and travel distance, with patients from the most deprived areas travelling longer distances. Overall, 30-day readmission was not statistically associated with longer driving distance (OR 1.00 95% CI 0.99 to 1.02) or peak driving times (OR 1.00 95% CI 0.99 to 1.01). CONCLUSIONS: There was no association between increasing travel distance and time on perioperative outcomes for RevKR patients.
The risk of revision surgery after trainee-led primary total hip replacement.
INTRODUCTION: The aim of this study was to determine the impact of operating surgeon grade and level of supervision on the incidence of one-year patient mortality and all-cause revision following elective primary total hip replacement (THR). METHODS: National Joint Registry data from 2005 to 2020 for a single University Teaching Hospital were used, with analysis performed on the 15-year dataset divided into 5-year block periods (B1, 2005-2010; B2, 2010-2015; B3, 2015-2020). Outcome measures were mortality and revision surgery at one year, in relation to lead surgeon grade, and level of supervision for trainee-led (TL) operations. RESULTS: A total of 9,999 eligible primary THRs were performed, of which 5,526 (55.3%) were consultant-led (CL), and 4,473 (44.7%) TL. Of TL, 2,404 (53.7%) were nonconsultant-supervised (TU) and 2,069 (46.3%) consultant-supervised (TS). The incidence of one-year patient mortality was 2.05% (n=205), and all-cause revision was 1.11% (n=111). There was no difference in one-year mortality between TL and CL operations (p=0.20, odds ratio (OR) 0.78, confidence interval (CI) 0.55-1.10). The incidence of one-year revision was not different for TL and CL operations (p=0.15, OR 1.37, CI 0.89-2.09). Overall, there was no temporal change for either outcome measure between TL or CL operations. A significant increase in revision within one-year was observed in B3 between TU compared with CL operations (p=0.005, OR 2.81, CI 1.35-5.87). CONCLUSIONS: We found no difference in overall one-year mortality or all-cause revision rate between TL and CL primary THR. Despite a reduction in unsupervised THR in the latest five-year period (2015-2020), unsupervised TL THR resulted in an increased risk of early revision.
Roadmap for alleviating the manifestations of ageing in the cardiovascular system.
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
Hypercoagulation after Hospital Discharge in Acute Severe Ulcerative Colitis: A Prospective Study.
BACKGROUND & AIMS: Venous thromboembolism is a serious complication during and following hospitalization with acute severe ulcerative colitis (ASUC). We evaluated serial thrombotic profiles of patients with ASUC from the point of hospitalization up to 12 weeks postdischarge and compared these with control patients with quiescent ulcerative colitis. METHODS: Twenty-seven patients with ASUC and 25 control patients with quiescent ulcerative colitis were recruited. Thrombin generation (endogenous thrombin potential), rotational thromboelastometry (EXTEM and FIBTEM maximum clot firmness), procoagulant factors, anticoagulant factors, and fibrinolytic markers were assessed for those with ASUC on admission (Day 1), Day 5, 4 weeks, and at 8-12 weeks. These assessments were performed on a single occasion for control patients. RESULTS: Endogenous thrombin potential and maximum clot firmness were significantly elevated in patients with ASUC compared with control subjects and remained significantly elevated for 4 weeks and for 8-12 weeks after admission (P < .05), respectively. Von Willebrand factor antigen, factor VIII, Clauss fibrinogen concentration, and platelet count were significantly increased from presentation to 8-12 weeks and are likely to account for changes in the global hemostatic profile. CONCLUSIONS: Global measures of hemostasis demonstrated that patients with ASUC were prothrombotic compared with control subjects with quiescent colitis. This difference was maintained 8-12 weeks after the initial presentation, supporting clinical observations that patients with ASUC have an elevated risk of venous thromboembolism after hospital discharge.
The role and uses of antibodies in COVID-19 infections: a living review.
Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity.
