A Comparison of the Surgical Practice of Potential Revision Outlier Joint Replacement Surgeons With Non-outliers: A Case Control Study From the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

BACKGROUND: The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) has monitored the performance of consultant surgeons performing primary total hip (THR) or knee replacements (KR) since 2007. The aims of this study were: 1) To describe the surgical practice of consultant hip and knee replacement surgeons in the National Joint Registry for England and Wales (NJR), stratified by potential outlier status for revisions. 2) To compare the practice of revision outlier and non-outlier surgeons. METHODS: We combined NJR primary THR and KR data from 2008-2017 separately with relevant anonymised NJR outlier notification records. We described the surgical practice of outliers and non-outliers by surgical workload, implant choice, and patients' clinical and demographic characteristics. We explored associations between surgeon-level factors and outlier status with conditional logistic regression models. RESULTS: We included 764,888 primary THRs by 3213 surgeons and 889,954 primary KRs by 3084 surgeons performed between 2008-2017. One hundred and eleven (3.5%) THR and 114 (3.7%) KR consultant surgeons were potential revision outliers. Surgeons who used more types of implant had increased odds of being an outlier (KR: OR/additional implant = 1.35, 95%CI 1.17-1.55; THR: OR = 1.12, 95%CI 1.06-1.18). CONCLUSIONS: The use of more types of implant is associated with increased risk of being a potential revision outlier. Further research is required to understand why surgeons use many different implants and to what extent this is responsible for the effects observed here.

The Uptake of New Knee Replacement Implants in the UK: Analysis of the National Joint Registry for England and Wales.

BACKGROUND: Knee replacement (KR) surgery is one of the most common elective procedures in the UK. A large number of different KR implant brands are in use in the UK, which may contribute to variation in uptake and patient outcomes. METHODS: A cohort of 722,178 primary KRs performed for osteoarthritis (with or without other indications) by 2675 consultant surgeons between 2008 and 2017 in England and Wales from the National Joint Registry was examined. We described the uptake of new (first use >2008) KR implant brands, and variation in uptake by consultant surgeons (primary objectives). We explored consultant-level/patient-level factors associated with use/receipt of new implant brands with multilevel logistic regression models (secondary objectives). RESULTS: Sixty-five new KR implant brands were used in 22,134 KRs (3.1%) by 759 consultants (28.4%) between 2008 and 2017. Consultants used a median of 1 new brand (interquartile range = 1-2, max = 8) in 4.1% (interquartile range = 1.1%-12.3%) of their KRs. Younger patients (<55 vs 55-80, odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.54-1.72) and women (OR = 1.17, 95% CI = 1.13-1.22) had higher odds of receiving a new rather than established brand. Consultants who used more different implant brands had higher odds of using new brands (OR/additional implant/year = 2.57, 95% CI = 2.37-2.79). CONCLUSION: A large number of new KR implant brands have been introduced in the National Joint Registry since 2008. A quarter of consultants have tried a new implant brand but have used them in only a small proportion of primary KRs in this period. Younger, healthier patients are more likely to receive new implant brands, and they are more likely to be used by surgeons who use many different implant brands.

Depressive symptoms in relation to overall survival in people with head and neck cancer: A longitudinal cohort study.

OBJECTIVE: The objective of the study is to investigate the relation between pretreatment depressive symptoms (DS) and the course of DS during the first year after cancer diagnosis, and overall survival among people with head and neck cancer (HNC). METHODS: Data from the Head and Neck 5000 prospective clinical cohort study were used. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) pretreatment, at 4 and 12-month follow-up. Also, socio-demographic, clinical, lifestyle, and mortality data were collected. The association between before start of treatment DS (HADS-depression > 7) and course (never DS, recovered from DS, or persistent/recurrent/late DS at 12-month follow-up) and survival was investigated using Cox regression. Unadjusted and adjusted analyses were performed. RESULTS: In total, 384 of the 2144 persons (18%) reported pretreatment DS. Regarding DS course, 63% never had DS, 16% recovered, and 20% had persistent/recurrent/late DS. People with pretreatment DS had a higher risk of earlier death than people without DS (hazard ratio (HR) = 1.65; 95% confidence interval (CI) 1.33-2.05), but this decreased after correcting for socio-demographic, clinical, and lifestyle-related factors (HR = 1.21; 95% CI 0.97-1.52). Regarding the course of DS, people with persistent/recurrent/late DS had a higher risk of earlier death (HR = 2.04; 95% CI 1.36-3.05), while people who recovered had a comparable risk (HR = 1.12; 95% CI 0.66-1.90) as the reference group who never experienced DS. After correcting for socio-demographic and clinical factors, people with persistent/recurrent/late DS still had a higher risk of earlier death (HR = 1.66; 95% CI 1.09-2.53). CONCLUSIONS: Pretreatment DS and persistent/recurrent/late DS were associated with worse survival among people with HNC.

Physical activity, alcohol consumption, BMI and smoking status before and after prostate cancer diagnosis in the ProtecT trial: opportunities for lifestyle modification.

Associations between certain lifestyle characteristics and prostate cancer risk have been reported, and continuation post-diagnosis can adversely affect prognosis. We explored whether men make spontaneous changes to their physical activity and alcohol intake, body mass index (BMI) and smoking status, following a diagnosis of localised prostate cancer. A detailed diet, health and lifestyle questionnaire was completed by 511 participants within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial, both before and 9 months after a diagnosis of prostate cancer. Of 177 men who were insufficiently active before their diagnosis (median 0 activity units/week; IQR 0-9), 40.7% had increased their activity by a median of 22 U week(-1) (IQR 15-35) 9 months later, and there was weak evidence that men were more active after diagnosis than before (p = 0.07). Men categorised as "working" occupational social class and who were insufficiently active before diagnosis were 2.03 (95%, CI = 1.03-3.99, p = 0.04) times more likely to have increased their physical activity levels compared to men classified as "managerial or professional." Similarly, men who were insufficiently active pre-diagnosis and with T-stage 2 compared with T-stage 1 prostate cancer were 2.47 (95%, CI = 1.29-4.71, p = 0.006) times more likely to be sufficiently active post-diagnosis. Following diagnosis, there was an overall reduction in alcohol intake (p = 0.03) and the proportion of current smokers (p = 0.09), but no overall change in BMI. We conclude that some men spontaneously change certain lifestyle behaviours on receiving a diagnosis of prostate cancer. For many men, however, additional support through lifestyle interventions is probably required to facilitate and maintain these changes.

Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000.

BACKGROUND: Head and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors. METHODS: We are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires. DISCUSSION: This large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research.

Additional Roles Reimbursement Scheme commissioning 2020-2023: associations with patient experience and QOF.

BACKGROUND: The Additional Roles Reimbursement Scheme (ARRS) was introduced by NHS England in 2020 alongside Primary Care Networks (PCNs) with aims of increasing the workforce and improving patient outcomes. AIM: Describe the uptake of direct-patient care (DPC)-ARRS roles and its impact on patients' experiences. DESIGN AND SETTING: Ecological study using 2020-2023 PCN and Practice workforce data, registered patient characteristics, the General Practice Patient Survey, and the Quality and Outcomes Framework (QOF). METHODS: Descriptive statistics with associations examined using quantile and linear regression. RESULTS: By March 2023, 17,714 FTE DPC-ARRS roles were commissioned by 1,223 PCNs. PCNs with fewer constituent practices had more DPC-ARRS roles per population (p<0.001) as did PCNs with more FTE GPs per population (p=0.012). DPC-ARRS commissioning did not vary with age, proportion female or deprivation of practice populations. DPC-ARRS roles were associated with small increases in patient satisfaction (0.8 percentage points increase in patients satisfied per one DPC-ARRS FTE) and perceptions of access (0.7 percentage points increase in patients reporting 'good' experience of making an appointment per one DPC-ARRS FTE), but not with overall QOF achievement. CONCLUSIONS: The commissioning of DPC-ARRS roles was associated with small increases in patient satisfaction and perceptions of access, but not with QOF achievement. DPC-ARRS roles were employed in areas with more GPs rather than compensating for a shortage of doctors. Single practice PCNs commissioned more roles per registered population, which may be advantageous to single practice PCNs. Further evaluation of the scheme is warranted.

REST: a preoperative tailored sleep intervention for patients undergoing total knee replacement - feasibility study for a randomised controlled trial.

OBJECTIVES: To test the feasibility of a randomised controlled trial (RCT) of a novel preoperative tailored sleep intervention for patients undergoing total knee replacement. DESIGN: Feasibility two-arm two-centre RCT using 1:1 randomisation with an embedded qualitative study. SETTING: Two National Health Service (NHS) secondary care hospitals in England and Wales. PARTICIPANTS: Preoperative adult patients identified from total knee replacement waiting lists with disturbed sleep, defined as a score of 0-28 on the Sleep Condition Indicator questionnaire. INTERVENTION: The REST intervention is a preoperative tailored sleep assessment and behavioural intervention package delivered by an Extended Scope Practitioner (ESP), with a follow-up phone call 4 weeks postintervention. All participants received usual care as provided by the participating NHS hospitals. OUTCOME MEASURES: The primary aim was to assess the feasibility of conducting a full trial. Patient-reported outcomes were assessed at baseline, 1-week presurgery, and 3 months postsurgery. Data collected to determine feasibility included the number of eligible patients, recruitment rates and intervention adherence. Qualitative work explored the acceptability of the study processes and intervention delivery through interviews with ESPs and patients. RESULTS: Screening packs were posted to 378 patients and 57 patients were randomised. Of those randomised, 20 had surgery within the study timelines. An appointment was attended by 25/28 (89%) of participants randomised to the intervention. Follow-up outcomes measures were completed by 40/57 (70%) of participants presurgery and 15/57 (26%) postsurgery. Where outcome measures were completed, data completion rates were 80% or higher for outcomes at all time points, apart from the painDETECT: 86% complete at baseline, 72% at presurgery and 67% postsurgery. Interviews indicated that most participants found the study processes and intervention acceptable. CONCLUSIONS: This feasibility study has demonstrated that with some amendments to processes and design, an RCT to evaluate the clinical and cost-effectiveness of the REST intervention is feasible. TRIAL REGISTRATION NUMBER: ISRCTN14233189.

Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations.

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.

Impact of pausing elective hip and knee replacement surgery during 2017 on subsequent service provision at a major NHS Trust: a descriptive observational study using interrupted time series.

OBJECTIVES: To explore the impact of a temporary cancellation of elective surgery in winter 2017 on trends in primary hip and knee replacement at a major National Health Service (NHS) Trust, and whether lessons can be learnt about efficient surgery provision. DESIGN AND SETTING: Observational descriptive study using interrupted time series analysis of hospital records to explore trends in primary hip and knee replacement surgery at a major NHS Trust, as well as patient characteristics, 2016-2019. INTERVENTION: A temporary cancellation of elective services for 2 months in winter 2017. OUTCOMES: NHS-funded hospital admissions for primary hip or knee replacement, length of stay and bed occupancy. Additionally, we explored the ratio of elective to emergency admissions at the Trust as a measure of elective capacity, and the ratio of public to private provision of NHS-funded hip and knee surgery. RESULTS: After winter 2017, there was a sustained reduction in the number of knee replacements, a decrease in the proportion of most deprived people having knee replacements and an increase in average age for knee replacement and comorbidity for both types of surgery. The ratio of public to private provision dropped after winter 2017, and elective capacity generally has reduced over time. There was clear seasonality in provision of elective surgery, with less complex patients admitted during winter. CONCLUSIONS: Declining elective capacity and seasonality has a marked effect on the provision of joint replacement, despite efficiency improvements in hospital treatment. The Trust has outsourced less complex patients to independent providers, and/or treated them during winter when capacity is most limited. There is a need to explore whether these are strategies that could be used explicitly to maximise the use of limited elective capacity, provide benefit to patients and value for money for taxpayers.

The impact of restricted provision of publicly funded elective hip and knee joints replacement during the COVID-19 pandemic in England.

AIMS: Elective hip and knee replacement operations were suspended in April 2020 due to the COVID-19 pandemic. The impact of this suspension and continued disruption to the delivery of joint replacement surgery is still emerging. We describe the impact of the pandemic on the provision of publicly funded elective hip and knee replacement surgery at one teaching hospital in England and on which patients had surgery. METHODS: We included all elective primary and revision hip and knee replacements performed at one hospital between January 2016 and June 2021. Using data for the years 2016-2019, we estimated the expected number of operations and beds occupied per month in January 2020 to June 2021 using time series linear models (adjusting for season and trend). We compared the predictions with the real data for January 2020 to June 2021 to assess the impact of the pandemic on the provision of elective hip and knee replacements. We compared the length of stay and characteristics (age, gender, number of comorbidities, index of multiple deprivation) of patients who had surgery before the pandemic with those who had surgery during the pandemic. RESULTS: We included 6,964 elective primary and revision hip and knee replacements between January 2016 and June 2021. Between January 2020 and June 2021 primary hip replacement volume was 59% of predicted, and 47% for primary knee replacements. Revision hip replacement volume was 77% of predicted, and 42% for revision knee replacement. Median length of stay was one day shorter for primary (4 vs 3 days) and revision (6 vs 5 days) operations during the pandemic compared with before. Patients operated on during the pandemic were younger and had slightly more comorbidities than those operated on before the pandemic. CONCLUSIONS: The restricted provision of elective hip and knee replacements during the COVID-19 pandemic changed the patient casemix, but did not introduce new inequalities in access to these operations. Patients were younger, had more comorbidities, and stayed in hospital for less time than those treated before the pandemic. Approximately half the number of operations were performed during the pandemic than would have been expected and the effect was greatest for revision knee replacements.

Development and application of simulation modelling for orthopaedic elective resource planning in England.

OBJECTIVES: This study aimed to develop a simulation model to support orthopaedic elective capacity planning. METHODS: An open-source, generalisable discrete-event simulation was developed, including a web-based application. The model used anonymised patient records between 2016 and 2019 of elective orthopaedic procedures from a National Health Service (NHS) Trust in England. In this paper, it is used to investigate scenarios including resourcing (beds and theatres) and productivity (lengths of stay, delayed discharges and theatre activity) to support planning for meeting new NHS targets aimed at reducing elective orthopaedic surgical backlogs in a proposed ring-fenced orthopaedic surgical facility. The simulation is interactive and intended for use by health service planners and clinicians. RESULTS: A higher number of beds (65-70) than the proposed number (40 beds) will be required if lengths of stay and delayed discharge rates remain unchanged. Reducing lengths of stay in line with national benchmarks reduces bed utilisation to an estimated 60%, allowing for additional theatre activity such as weekend working. Further, reducing the proportion of patients with a delayed discharge by 75% reduces bed utilisation to below 40%, even with weekend working. A range of other scenarios can also be investigated directly by NHS planners using the interactive web app. CONCLUSIONS: The simulation model is intended to support capacity planning of orthopaedic elective services by identifying a balance of capacity across theatres and beds and predicting the impact of productivity measures on capacity requirements. It is applicable beyond the study site and can be adapted for other specialties.

Temporal trends in comorbidity in adult elective hip and knee arthroplasty patients in England : a national population-based cohort study from the National Joint Registry.

AIMS: Our main aim was to describe the trend in the comorbidities of patients undergoing elective total hip arthroplasties (THAs) and knee arthroplasties (KAs) between 1 January 2005 and 31 December 2018 in England. METHODS: We combined data from the National Joint Registry (NJR) on primary elective hip and knee arthroplasties performed between 2005 and 2018 with pre-existing conditions recorded at the time of their primary operation from Hospital Episodes Statistics. We described the temporal trend in the number of comorbidities identified using the Charlson Comorbidity Index, and how this varied by age, sex, American Society of Anesthesiologists (ASA) grade, index of multiple deprivation, and type of KA. RESULTS: We included 696,504 and 833,745 elective primary THAs and KAs respectively, performed for any indication. Between 2005 and 2018, the proportion of elective THA and KA patients with one or more comorbidity at the time of their operation increased substantially (THA: 20% to 38%, KA: 22% to 41%). This was driven by increases in four conditions: chronic obstructive pulmonary disease (COPD) (2018: ~17%), diabetes without complications (2018: THA 10%, KA 14%), myocardial infarction (2018: 4%), and renal disease (2018: ~8%). Notably, renal disease prevalence increased from < 1% in 2005 to ~8% in 2018. CONCLUSION: Between 2005 and 2018 there were significant changes in the number of comorbidities recorded in patients having elective primary THAs and KAs. Renal disease is now one of the most prevalent comorbidities in this patient population. Future research should explore whether this comorbidity trend has increased the burden on other medical specialities to optimize these patients before surgery and to provide additional postoperative care.Cite this article: Bone Joint J 2022;104-B(9):1052-1059.

Identification of risk factors associated with prolonged hospital stay following primary knee replacement surgery: a retrospective, longitudinal observational study.

OBJECTIVES: To identify risk factors associated with prolonged length of hospital stay and staying in hospital longer than medically necessary following primary knee replacement surgery. DESIGN: Retrospective, longitudinal observational study. SETTING: Elective knee replacement surgeries between 2016 and 2019 were identified using routinely collected data from an NHS Trust in England. PARTICIPANTS: There were 2295 knee replacement patients with complete data included in analysis. The mean age was 68 (SD 11) and 60% were female. OUTCOME MEASURES: We assessed a binary length of stay outcome (>7 days), a continuous length of stay outcome (≤30 days) and a binary measure of whether patients remained in hospital when they were medically fit for discharge. RESULTS: The mean length of stay was 5.0 days (SD 3.9), 15.4% of patients were in hospital for >7 days and 7.1% remained in hospital when they were medically fit for discharge. Longer length of stay was associated with older age (b=0.08, 95% CI 0.07 to 0.09), female sex (b=0.36, 95% CI 0.06 to 0.67), high deprivation (b=0.98, 95% CI 0.47 to 1.48) and more comorbidities (b=2.48, 95% CI 0.15 to 4.81). Remaining in hospital beyond being medically fit for discharge was associated with older age (OR=1.07, 95% CI 1.05 to 1.09), female sex (OR=1.71, 95% CI 1.19 to 2.47) and high deprivation (OR=2.27, 95% CI 1.27 to 4.06). CONCLUSIONS: The regression models could be used to identify which patients are likely to occupy hospital beds for longer. This could be helpful in scheduling operations to aid hospital efficiency by planning these patients' operations for when the hospital is less busy.

Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma.

The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.

Ten-Year Results of the Triathlon Knee Replacement: A Cohort Study.

Introduction Studies evaluating the outcomes of different brands of knee prostheses are important to monitor patient outcomes and generate evidence to aid decisions around the choice of implant. The Triathlon® prosthesis (Stryker, Limerick, Ireland), one of the most commonly used total condylar knee prosthesis, is designed to provide greater knee motion and the potential for longer implant survivorship. The aim of this cohort study was to evaluate outcomes and survivorship of the Triathlon total knee replacement (TKR) up to 10 years post-operative. Methods Two-hundred sixty-six (266) patients listed for a Triathlon TKR in one orthopaedic hospital were recruited. Assessments were conducted preoperatively and then at three months and one, two, three, five, seven, and 10 years after surgery. Outcomes assessed included pain, function, knee-related quality of life (QoL), satisfaction, kneeling ability, activity levels, American Knee Society Score, complications, and survivorship. Results Large improvements in patient-reported outcomes were observed in the first three months after surgery, followed by small improvement up to one year post-operative, and then outcomes plateaued up to 10 years post-operative. Satisfaction with overall outcome ranged from 79%-94% over the duration of follow-up. Activity levels and kneeling ability were similar before and after surgery. There was a large improvement in the median American Knee Society score in the first three months post-operative, followed by a small but gradual improvement to 10 years post-operative. Survivorship was 95.4% (95% confidence interval 91.8-97.5%) at 10 years post-operative. Conclusions This study found that the Triathlon TKR results in excellent outcomes and survivorship to 10 years post-operative.

A comparison of comorbidity measures for predicting mortality after elective hip and knee replacement: A cohort study of data from the National Joint Registry in England and Wales.

BACKGROUND: The risk of mortality following elective total hip (THR) and knee replacements (KR) may be influenced by patients' pre-existing comorbidities. There are a variety of scores derived from individual comorbidities that can be used in an attempt to quantify this. The aims of this study were to a) identify which comorbidity score best predicts risk of mortality within 90 days or b) determine which comorbidity score best predicts risk of mortality at other relevant timepoints (30, 45, 120 and 365 days). PATIENTS AND METHODS: We linked data from the National Joint Registry (NJR) on primary elective hip and knee replacements performed between 2011-2015 with pre-existing conditions recorded in the Hospital Episodes Statistics. We derived comorbidity scores (Charlson Comorbidity Index-CCI, Elixhauser, Hospital Frailty Risk Score-HFRS). We used binary logistic regression models of all-cause mortality within 90-days and within 30, 45, 120 and 365-days of the primary operation using, adjusted for age and gender. We compared the performance of these models in predicting all-cause mortality using the area under the Receiver-operator characteristics curve (AUROC) and the Index of Prediction Accuracy (IPA). RESULTS: We included 276,594 elective primary THRs and 338,287 elective primary KRs for any indication. Mortality within 90-days was 0.34% (N = 939) after THR and 0.26% (N = 865) after KR. The AUROC for the CCI and Elixhauser scores in models of mortality ranged from 0.78-0.81 after THR and KR, which slightly outperformed models with ASA grade (AUROC = 0.77-0.78). HFRS performed similarly to ASA grade (AUROC = 0.76-0.78). The inclusion of comorbidities prior to the primary operation offers no improvement beyond models with comorbidities at the time of the primary. The discriminative ability of all prediction models was best for mortality within 30 days and worst for mortality within 365 days. CONCLUSIONS: Comorbidity scores add little improvement beyond simpler models with age, gender and ASA grade for predicting mortality within one year after elective hip or knee replacement. The additional patient-specific information required to construct comorbidity scores must be balanced against their prediction gain when considering their utility.

Tracing the emergence of primordial germ cells from bilaminar disc rabbit embryos and pluripotent stem cells.

Rabbit embryos develop as bilaminar discs at gastrulation as in humans and most other mammals, whereas rodents develop as egg cylinders. Primordial germ cells (PGCs) appear to originate during gastrulation according to many systematic studies on mammalian embryos. Here, we show that rabbit PGC (rbPGC) specification occurs at the posterior epiblast at the onset of gastrulation. Using newly derived rabbit pluripotent stem cells, we show robust and rapid induction of rbPGC-like cells in vitro with WNT and BMP morphogens, which reveals SOX17 as the critical regulator of rbPGC fate as in several non-rodent mammals. We posit that development as a bilaminar disc is a crucial determinant of the PGC regulators, regardless of the highly diverse development of extraembryonic tissues, including the amnion. We propose that investigations on rabbits with short gestation, large litters, and where gastrulation precedes implantation can contribute significantly to advances in early mammalian development.

Liver steatosis is a risk factor for hepatotoxicity in inflammatory bowel disease patients treated with azathioprine.

BACKGROUND AND AIMS: The literature demonstrates that hepatic steatosis reduces the tolerance of immunosuppression in people with inflammatory bowel disease. It also shows that elevated methylmercaptopurine may be responsible for thiopurine-induced hepatitis. This exploratory study investigates the relationship between hepatic steatosis, methylmercaptopurine and alanine transaminase. METHODS: We performed a retrospective review of patients started on azathioprine treatment at University Hospitals Bristol NHS Foundation Trust between 2014 and 2017. There were 600 patients in total. Ninety-one patients met our inclusion criteria which were at least one ultrasound scan commenting on the appearance of the liver, liver function tests at commencement of azathioprine and liver function tests and a methylmercaptopurine level between 6 and 8 weeks after starting treatment. RESULTS: Of 91 patients included in our study, 32 patients (32%) were identified as having radiological hepatic steatosis on ultrasound imaging and 59 patients had no evidence of steatosis. We found a positive association between methylmercaptopurine levels and change in alanine transaminase in patients with hepatic steatosis (P < 0.001) but not in those with a normal liver on ultrasound imaging. CONCLUSION: We conclude that the higher levels of methylmercaptopurine may be a risk factor for hepatitis in patients with hepatic steatosis but not in those with a normal liver.

Factors associated with early postoperative feeding: An observational study in a colorectal surgery population.

BACKGROUND AND AIMS: Early post-operative feeding is recommended within enhanced recovery after surgery programmes. This study aimed to describe post-operative feeding patterns and associated factors among patients following colorectal surgery, using a post-hoc analysis of observational data from a previous RCT on chewing gum after surgery. METHODS: Data from 301 participants (59% male, median age 67 years) were included. Amounts of meals consumed on post-operative days (POD) 1-5 were recorded as: none, a quarter, half, three-quarters, all. 'Early' consumers were those who ate ≥a quarter of a meal on POD1. 'Early' tolerance was the consumption of at least half of three meals on POD1 or 2 without vomiting. Exploration of selected peri-operative factors with early feeding and tolerance were assessed using logistic regression. RESULTS: 222 people (73.8%) consumed solid food early, and 109 people (36.2%) tolerated solid food early. Several factors were associated with postoperative feeding: provision of pre-operative bowel preparation was associated with delayed consumption [odds ratio (OR) 0.34, 95% confidence interval (CI) 0.14-0.83] and tolerance (OR 0.35, 95% CI 0.16-0.81) of food; and laparoscopic/laparoscopic assisted (vs. open/converted to open surgery) was associated with early tolerance of food (OR 1.99, 95% CI 1.17-3.39). CONCLUSIONS: While three-quarters of the study population ate solid food early, only one-third tolerated solid food early. Findings suggest that bowel preparation and surgery type are factors warranting further investigation in future studies to improve uptake of early post-operative feeding.

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer.

BACKGROUND: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival. RESULTS: Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10-05). CONCLUSIONS: Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.