Pharmacological interventions for the prevention of bleeding in people undergoing elective hip or knee surgery: a systematic review and network meta-analysis.

BACKGROUND: Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery. Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care. OBJECTIVES: To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology. SEARCH METHODS: We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included RCTs of people undergoing elective hip or knee surgery only. We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator. Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants. DATA COLLECTION AND ANALYSIS: We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet. We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received. MAIN RESULTS: We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%). In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence). Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion. We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported. In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence). We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network. There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials). AUTHORS' CONCLUSIONS: We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review.

Radiochromic film dosimetry in radiotherapy: a survey of current practice in the United Kingdom.

OBJECTIVES: To establish the variation in film dosimetry usage in radiotherapy centres across the United Kingdom. To identify consensus and highlight areas of potential improvement to enhance radiotherapy dosimetry verification with film. METHODS: A survey questionnaire was designed by members of the Institute of Physics and Engineering in Medicine Interdepartmental Dosimetry Audit Group via Microsoft Forms and distributed to all Heads of Radiotherapy Physics in the United Kingdom. The survey was open from June 19, 2023, to July 31, 2023. RESULTS: Forty responses were received from the 62 radiotherapy centres in the United Kingdom, of which 58% were currently using film dosimetry and a further 7 were keen to commence use. Many reported film use had decreased in recent years but was still valuable particularly for commissioning and implementing new techniques. The variation and consensus of methods for film dosimetry calibration, measurement, and application was established. A review of barriers to implementation and methods to reduce uncertainty were included in the assessment. CONCLUSIONS: A comprehensive assessment of film dosimetry usage in radiotherapy in the United Kingdom has been collated, which demonstrates a wide variation in methods, across typical clinical users, but maintains film as a valuable dosimetry option. ADVANCES IN KNOWLEDGE: This research provides a snapshot of current film dosimetry use across the United Kingdom. It examines the variation and consensus of practice to which individual users can compare their systems, and identifies opportunities to improvement in the accuracy of film dosimetry.

Frequent microbiological profile changes are seen in subsequent-revision hip and knee arthroplasty for prosthetic joint infection.

A proportion of patients with hip and knee prosthetic joint infection (PJI) undergo multiple revisions with the aim of eradicating infection and improving quality of life. The aim of this study was to describe the microbiology cultured from multiply revised hip and knee replacement procedures to guide antimicrobial therapy at the time of surgery. Patients and methods: Consecutive patients were retrospectively identified from databases at two specialist orthopaedic centres in the United Kingdom between 2011 and 2019. Patient were included who had undergone repeat-revision total knee replacement (TKR) or total hip replacement (THR) for infection, following an initial failed revision for infection. Results: A total of 106 patients were identified. Of these patients, 74 underwent revision TKR and 32 underwent revision THR. The mean age at first revision was 67 years (SD 10). The Charlson comorbidity index was ≤ 2 for 31 patients, 3-4 for 57 patients, and ≥ 5 for 18 patients. All patients underwent at least two revisions, 73 patients received three, 47 patients received four, 31 patients received five, and 21 patients received at least six. After six revisions, 90 % of patients had different organisms cultured compared with the initial revision, and 53 % of organisms were multidrug resistant. The most frequent organisms at each revision were coagulase-negative Staphylococcus (36 %) and Staphylococcus aureus (19 %). Fungus was cultured from 3 % of revisions, and 21 % of infections were polymicrobial. Conclusion: Patients undergoing multiple revisions for PJI are highly likely to experience a change in organism, with 90 % of patients having a different organism cultured by their sixth revision. It is therefore important to administer empirical antibiotics at each subsequent revision, taking into account known drug resistance from previous cultures. Our results do not support the routine use of empirical antifungals.

Epidemiology of revision hip replacement surgery in the UK over the past 15 years-an analysis from the National Joint Registry.

OBJECTIVES: To investigate trends in the incidence rate and main indication for revision hip replacement (rHR) over the past 15 years in the UK. DESIGN: Repeated national cross-sectional study from 2006 to 2020. SETTING/PARTICIPANTS: rHR procedures were identified from the National Joint Registry for England, Wales, Northern Ireland, the Isle of Man and the States of Guernsey. Population statistics were obtained from the Office for National Statistics. MAIN OUTCOME MEASURES: Crude incidence rates of rHR. RESULTS: The incidence rate of rHR doubled from 11 per 100 000 adults in 2006 (95% CI 10.7 to 11.3) to a peak of 22 per 100 000 adults (95% CI 22 to 23) in 2012, before falling to 17 per 100 000 adults in 2019 (95% CI 16 to 17) (24.5% decrease from peak). The incidence rate of rHR reduced by 39% in 2020 compared with 2019 (during the COVID-19 pandemic). The most frequent indications for rHR between 2006 and 2019 were loosening/lysis (27.8%), unexplained pain (15.1%) and dislocation/instability (14.7%). There were incremental increases in the annual number and incidence rates of rHR for fracture, infection, dislocation/instability and a decrease in rHR for aseptic loosening/lysis. CONCLUSIONS: The incidence rate of rHR doubled from 2006 to 2012, likely due to high early failure rates of metal-on-metal hip replacements. The incidence of rHR then decreased by approximately 25% from 2012 to 2019, followed by a large decrease during the COVID-19 pandemic. The decrease in the number of rHR performed for aseptic loosening/lysis may reflect improved wear and implant longevity. Increased healthcare resource will be required to care for the increasing numbers of patients undergoing rHR for fracture and infection.

Cell salvage for minimising perioperative allogeneic blood transfusion in adults undergoing elective surgery.

BACKGROUND: Concerns regarding the safety and availability of transfused donor blood have prompted research into a range of techniques to minimise allogeneic transfusion requirements. Cell salvage (CS) describes the recovery of blood from the surgical field, either during or after surgery, for reinfusion back to the patient. OBJECTIVES: To examine the effectiveness of CS in minimising perioperative allogeneic red blood cell transfusion and on other clinical outcomes in adults undergoing elective or non-urgent surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases and two clinical trials registers for randomised controlled trials (RCTs) and systematic reviews from 2009 (date of previous search) to 19 January 2023, without restrictions on language or publication status. SELECTION CRITERIA: We included RCTs assessing the use of CS compared to no CS in adults (participants aged 18 or over, or using the study's definition of adult) undergoing elective (non-urgent) surgery only. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 106 RCTs, incorporating data from 14,528 participants, reported in studies conducted in 24 countries. Results were published between 1978 and 2021. We analysed all data according to a single comparison: CS versus no CS. We separated analyses by type of surgery. The certainty of the evidence varied from very low certainty to high certainty. Reasons for downgrading the certainty included imprecision (small sample sizes below the optimal information size required to detect a difference, and wide confidence intervals), inconsistency (high statistical heterogeneity), and risk of bias (high risk from domains including sequence generation, blinding, and baseline imbalances). Aggregate analysis (all surgeries combined: primary outcome only) Very low-certainty evidence means we are uncertain if there is a reduction in the risk of allogeneic transfusion with CS (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.59 to 0.72; 82 RCTs, 12,520 participants). Cancer: 2 RCTs (79 participants) Very low-certainty evidence means we are uncertain whether there is a difference for mortality, blood loss, infection, or deep vein thrombosis (DVT). There were no analysable data reported for the remaining outcomes. Cardiovascular (vascular): 6 RCTs (384 participants) Very low- to low-certainty evidence means we are uncertain whether there is a difference for most outcomes. No data were reported for major adverse cardiovascular events (MACE). Cardiovascular (no bypass): 6 RCTs (372 participants) Moderate-certainty evidence suggests there is probably a reduction in risk of allogeneic transfusion with CS (RR 0.82, 95% CI 0.69 to 0.97; 3 RCTs, 169 participants). Very low- to low-certainty evidence means we are uncertain whether there is a difference for volume transfused, blood loss, mortality, re-operation for bleeding, infection, wound complication, myocardial infarction (MI), stroke, and hospital length of stay (LOS). There were no analysable data reported for thrombosis, DVT, pulmonary embolism (PE), and MACE. Cardiovascular (with bypass): 29 RCTs (2936 participants) Low-certainty evidence suggests there may be a reduction in the risk of allogeneic transfusion with CS, and suggests there may be no difference in risk of infection and hospital LOS. Very low- to moderate-certainty evidence means we are uncertain whether there is a reduction in volume transfused because of CS, or if there is any difference for mortality, blood loss, re-operation for bleeding, wound complication, thrombosis, DVT, PE, MACE, and MI, and probably no difference in risk of stroke. Obstetrics: 1 RCT (1356 participants) High-certainty evidence shows there is no difference between groups for mean volume of allogeneic blood transfused (mean difference (MD) -0.02 units, 95% CI -0.08 to 0.04; 1 RCT, 1349 participants). Low-certainty evidence suggests there may be no difference for risk of allogeneic transfusion. There were no analysable data reported for the remaining outcomes. Orthopaedic (hip only): 17 RCTs (2055 participants) Very low-certainty evidence means we are uncertain if CS reduces the risk of allogeneic transfusion, and the volume transfused, or if there is any difference between groups for mortality, blood loss, re-operation for bleeding, infection, wound complication, prosthetic joint infection (PJI), thrombosis, DVT, PE, stroke, and hospital LOS. There were no analysable data reported for MACE and MI. Orthopaedic (knee only): 26 RCTs (2568 participants) Very low- to low-certainty evidence means we are uncertain if CS reduces the risk of allogeneic transfusion, and the volume transfused, and whether there is a difference for blood loss, re-operation for bleeding, infection, wound complication, PJI, DVT, PE, MI, MACE, stroke, and hospital LOS. There were no analysable data reported for mortality and thrombosis. Orthopaedic (spine only): 6 RCTs (404 participants) Moderate-certainty evidence suggests there is probably a reduction in the need for allogeneic transfusion with CS (RR 0.44, 95% CI 0.31 to 0.63; 3 RCTs, 194 participants). Very low- to moderate-certainty evidence suggests there may be no difference for volume transfused, blood loss, infection, wound complication, and PE. There were no analysable data reported for mortality, re-operation for bleeding, PJI, thrombosis, DVT, MACE, MI, stroke, and hospital LOS. Orthopaedic (mixed): 14 RCTs (4374 participants) Very low- to low-certainty evidence means we are uncertain if there is a reduction in the need for allogeneic transfusion with CS, or if there is any difference between groups for volume transfused, mortality, blood loss, infection, wound complication, PJI, thrombosis, DVT, MI, and hospital LOS. There were no analysable data reported for re-operation for bleeding, MACE, and stroke. AUTHORS' CONCLUSIONS: In some types of elective surgery, cell salvage may reduce the need for and volume of allogeneic transfusion, alongside evidence of no difference in adverse events, when compared to no cell salvage. Further research is required to establish why other surgeries show no benefit from CS, through further analysis of the current evidence. More large RCTs in under-reported specialities are needed to expand the evidence base for exploring the impact of CS.

Patient-Relevant Outcomes Following First Revision Total Knee Arthroplasty, by Diagnosis: An Analysis of Implant Survivorship, Mortality, Serious Medical Complications, and Patient-Reported Outcome Measures Utilizing the National Joint Registry Data Set.

BACKGROUND: The purpose of this study was to investigate patient-relevant outcomes following first revision total knee arthroplasties (rTKAs) performed for different indications. METHODS: This population-based cohort study utilized data from the United Kingdom National Joint Registry, Hospital Episode Statistics Admitted Patient Care, National Health Service Patient-Reported Outcome Measures, and the Civil Registrations of Death. Patients undergoing a first rTKA between January 1, 2009, and June 30, 2019, were included in our data set. Patient-relevant outcomes included implant survivorship (up to 11 years postoperatively), mortality and serious medical complications (up to 90 days postoperatively), and patient-reported outcome measures (at 6 months postoperatively). RESULTS: A total of 24,540 first rTKAs were analyzed. The patient population was 54% female and 62% White, with a mean age at the first rTKA of 69 years. At 2 years postoperatively, the cumulative incidence of re-revision surgery ranged from 2.7% (95% confidence interval [CI], 1.9% to 3.4%) following rTKA for progressive arthritis to 16.3% (95% CI, 15.2% to 17.4%) following rTKA for infection. The mortality rate at 90 days was highest following rTKA for fracture (3.6% [95% CI, 2.5% to 5.1%]) and for infection (1.8% [95% CI, 1.5% to 2.2%]) but was <0.5% for other indications. The rate of serious medical complications requiring hospital admission within 90 days was highest for patients treated for fracture (21.8% [95% CI, 17.9% to 26.3%]) or infection (12.5% [95% CI, 11.2% to 13.9%]) and was lowest for those treated for progressive arthritis (4.3% [95% CI, 3.3% to 5.5%]). Patients who underwent rTKA for stiffness or unexplained pain had some of the poorest postoperative joint function (mean Oxford Knee Score, 24 and 25 points, respectively) and had the lowest proportion of responders (48% and 55%, respectively). CONCLUSIONS: This study found large differences in patient-relevant outcomes among different indications for first rTKA. The rate of complications was highest following rTKA for fracture or infection. Although rTKA resulted in large improvements in joint function for most patients, those who underwent surgery for stiffness and unexplained pain had worse outcomes. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Evaluation of a new radiochromic film dosimeter, Gafchomic EBT4, for VMAT, SABR and HDR treatment delivery verification.

Objective.To evaluate a new film for radiotherapy dosimetry, Gafchromic EBT4, compared to the current EBT3. To evaluate dose-response and verify test cases in MV external beam and HDR brachytherapy.Approach. Three lots (batches) of EBT4 and three lots of EBT3 films were calibrated at 6 MV over 0-1200 cGy range, using FilmQAPro software. Signal-to-noise of pixel value, reported dose (RD), and factors affecting dosimetry accuracy were evaluated (rotation of the film at scanning, energy response and post-exposure darkening). Both films were exposed to clinical treatment plans (VMAT prostate, SABR lung, single HDR source dwell, and 'pseudo' 3-channel HDR cervix brachytherapy). Film-RD was compared to TPS-calculated dose.Main results.EBT4 calibration curves had characteristics more favourable than EBT3 for radiation dosimetry, with improved signal to noise in film-RD of EBT4 compared to EBT3 (increase of average 46% in red and green channels at 500 cGy). Film rotation at scanning and post-exposure darkening was similar for the two films. The energy response of EBT4 is similar to EBT3. For all clinical case studies, EBT4 provided better agreement with the TPS-planned doses than EBT3. VMAT prostate gamma 3%/3 mm passing rate, EBT4 100.0% compared to EBT3 97.9%; SABR lung gamma 2%/2 mm, EBT4 99.6% and EBT3 97.9%; HDR cervix gamma 3%/2 mm, EBT4 97.7% and EBT3 95.0%.Significance.These results show EBT4 is superior to EBT3 for radiotherapy dosimetry validation of TPS plan delivery. Fundamental improvements in noise profile and calibration curve are reported for EBT4. All clinical test cases showed EBT4 provided equivalent or smaller difference in measured dose to TPS calculated dose than EBT3. Baseline data is presented on the achievable accuracy of film dosimetry in radiotherapy using the new Gafchromic EBT4 film.

Pharmacological interventions for the prevention of bleeding in people undergoing definitive fixation or joint replacement for hip, pelvic and long bone fractures.

BACKGROUND: Pelvic, hip, and long bone fractures can result in significant bleeding at the time of injury, with further blood loss if they are treated with surgical fixation. People undergoing surgery are therefore at risk of requiring a blood transfusion and may be at risk of peri-operative anaemia. Pharmacological interventions for blood conservation may reduce the risk of requiring an allogeneic blood transfusion and associated complications. OBJECTIVES: To assess the effectiveness of different pharmacological interventions for reducing blood loss in definitive surgical fixation of the hip, pelvic, and long bones. SEARCH METHODS: We used a predefined search strategy to search CENTRAL, MEDLINE, PubMed, Embase, CINAHL, Transfusion Evidence Library, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) from inception to 7 April 2022, without restrictions on language, year, or publication status. We handsearched reference lists of included trials to identify further relevant trials. We contacted authors of ongoing trials to acquire any unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people who underwent trauma (non-elective) surgery for definitive fixation of hip, pelvic, and long bone (pelvis, tibia, femur, humerus, radius, ulna and clavicle) fractures only. There were no restrictions on gender, ethnicity, or age. We excluded planned (elective) procedures (e.g. scheduled total hip arthroplasty), and studies published since 2010 that had not been prospectively registered. Eligible interventions included: antifibrinolytics (tranexamic acid, aprotinin, epsilon-aminocaproic acid), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. We did not perform a network meta-analysis due to lack of data. MAIN RESULTS: We included 13 RCTs (929 participants), published between 2005 and 2021. Three trials did not report any of our predefined outcomes and so were not included in quantitative analyses (all were tranexamic acid versus placebo). We identified three comparisons of interest: intravenous tranexamic acid versus placebo; topical tranexamic acid versus placebo; and recombinant factor VIIa versus placebo. We rated the certainty of evidence as very low to low across all outcomes. Comparison 1. Intravenous tranexamic acid versus placebo Intravenous tranexamic acid compared to placebo may reduce the risk of requiring an allogeneic blood transfusion up to 30 days (RR 0.48, 95% CI 0.34 to 0.69; 6 RCTs, 457 participants; low-certainty evidence) and may result in little to no difference in all-cause mortality (Peto odds ratio (Peto OR) 0.38, 95% CI 0.05 to 2.77; 2 RCTs, 147 participants; low-certainty evidence).  It may result in little to no difference in risk of participants experiencing myocardial infarction (risk difference (RD) 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 199 participants; low-certainty evidence), and cerebrovascular accident/stroke (RD 0.00, 95% CI -0.02 to 0.02; 3 RCTs, 324 participants; low-certainty evidence).  We are uncertain if there is a difference between groups for risk of deep vein thrombosis (Peto OR 2.15, 95% CI 0.22 to 21.35; 4 RCTs, 329 participants, very low-certainty evidence), pulmonary embolism (Peto OR 1.08, 95% CI 0.07 to 17.66; 4 RCTs, 329 participants; very low-certainty evidence), and suspected serious drug reactions (RD 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 185 participants; very low-certainty evidence). No data were available for number of red blood cell units transfused, reoperation, or acute transfusion reaction. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures), and upgraded the evidence for transfusion requirement for a large effect.  Comparison 2. Topical tranexamic acid versus placebo We are uncertain if there is a difference between topical tranexamic acid and placebo for risk of requiring an allogeneic blood transfusion (RR 0.31, 95% CI 0.08 to 1.22; 2 RCTs, 101 participants), all-cause mortality (RD 0.00, 95% CI -0.10 to 0.10; 1 RCT, 36 participants), risk of participants experiencing myocardial infarction (Peto OR 0.15, 95% CI 0.00 to 7.62; 1 RCT, 36 participants), cerebrovascular accident/stroke (RD 0.00, 95% CI -0.06 to 0.06; 1 RCT, 65 participants); and deep vein thrombosis (Peto OR 1.11, 95% CI 0.07 to 17.77; 2 RCTs, 101 participants).  All outcomes reported were very low-certainty evidence. No data were available for number of red blood cell units transfused, reoperation, incidence of pulmonary embolism, acute transfusion reaction, or suspected serious drug reactions. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), inconsistency (moderate heterogeneity), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures, and high risk of attrition and reporting biases in one trial). Comparison 3. Recombinant factor VIIa versus placebo   Only one RCT of 48 participants reported data for recombinant factor VIIa versus placebo, so we have not presented the results here. AUTHORS' CONCLUSIONS: We cannot draw conclusions from the current evidence due to lack of data. Most published studies included in our analyses assessed the use of tranexamic acid (compared to placebo, or using different routes of administration).  We identified 27 prospectively registered ongoing RCTs (total target recruitment of 4177 participants by end of 2023). The ongoing trials create six new comparisons: tranexamic acid (tablet + injection) versus placebo; intravenous tranexamic acid versus oral tranexamic acid; topical tranexamic acid versus oral tranexamic acid; different intravenous tranexamic acid dosing regimes; topical tranexamic acid versus topical fibrin glue; and fibrinogen (injection) versus placebo.

The Outcomes of Hip and Knee Fungal Periprosthetic Joint Infections: A Retrospective Cohort Study.

BACKGROUND: Fungal infections are a rare cause of periprosthetic joint infection (PJI), identified in 1% of all of these cases. Outcomes are not well-established due to small cohort sizes in the published literature. The aims of this study were to establish the patient demographics and infection-free survival of patients presenting to 2 high-volume revision arthroplasty centers who had fungal infection of either a hip or knee arthroplasty. We sought to identify risk factors for poor outcomes. METHODS: A retrospective analysis was performed of patients at 2 high-volume revision arthroplasty centers who had confirmed fungal PJI of the total hip arthroplasty (THA) and total knee arthroplasty (TKA). Consecutive patients treated between 2010 and 2019 were included. Patient outcomes were classified as infection eradication or persistence. A total of 67 patients who had 69 fungal PJI cases were identified. There were 47 cases involving the knee and 22 of the hip. Mean age at presentation was 68 years (THA mean 67, range 46 to 86) (TKA mean 69, range, 45 to 88). A history of sinus or open wound was present in 60 cases (89%) (THA 21 cases, TKA 39 cases). The median number of operations prior to the procedure at which fungal PJI was identified was 4 (range, 0 to 9), THA 5 (range, 3 to 9), and TKA 3 (range, 0 to 9). RESULTS: At a mean follow-up 34 months (range, 2 to 121), remission rates were 11 of 24 (45%) and 22 of 45 (49%) for hip and knee, respectively. There were 7 TKA (16%) and 1 THA cases (4%) that failed treatment resulting in amputations. During the study period, 7 THA and 6 TKA patients had died. Two deaths were directly attributable to PJI. Patient outcome was not associated with the number of prior procedures, patient comorbidities, or organisms. CONCLUSION: Eradication of fungal PJI is achieved in less than half of patients, and outcomes are comparable for TKA and THA. The majority of patients who have fungal PJI present with an open wound or sinus. No factors were identified that increase the risk of persistent infection. Patients who have fungal PJI should be informed of the poor outcomes.

Systematic review highlights high risk of bias of clinical prediction models for blood transfusion in patients undergoing elective surgery.

BACKGROUND: Blood transfusion can be a lifesaving intervention after perioperative blood loss. Many prediction models have been developed to identify patients most likely to require blood transfusion during elective surgery, but it is unclear whether any are suitable for clinical practice. STUDY DESIGN AND SETTING: We conducted a systematic review, searching MEDLINE, Embase, PubMed, The Cochrane Library, Transfusion Evidence Library, Scopus, and Web of Science databases for studies reporting the development or validation of a blood transfusion prediction model in elective surgery patients between January 1, 2000 and June 30, 2021. We extracted study characteristics, discrimination performance (c-statistics) of final models, and data, which we used to perform risk of bias assessment using the Prediction model risk of bias assessment tool (PROBAST). RESULTS: We reviewed 66 studies (72 developed and 48 externally validated models). Pooled c-statistics of externally validated models ranged from 0.67 to 0.78. Most developed and validated models were at high risk of bias due to handling of predictors, validation methods, and too small sample sizes. CONCLUSION: Most blood transfusion prediction models are at high risk of bias and suffer from poor reporting and methodological quality, which must be addressed before they can be safely used in clinical practice.

Coronal-plane leg alignment in adolescence and the effects of activity: A full leg length MRI study.

The aim of this study was to explore the association between developing coronal-plane leg alignment and activity levels during adolescence. We performed a cross-sectional cohort study with individuals from soccer club academies and an age-matched control population. Outcome measures were the hip knee angle (HKA), medial proximal tibial physeal angle (MPTPhyA), lateral distal femoral physeal angle (LDFPhyA) on full leg length magnetic reasonance imagine scans, and the physical activity questionnaire (PAQ) score. The cohort comprised 57 elite male soccer players, 34 male and 34 female controls aged 11-21 years. Mean HKA became more varus with age, with little change after 16 years or skeletal maturity. Skeletally mature elite male soccer players were significantly more varus than male controls with a HKA 2.28° less than male controls (p < 0.001). Skeletally mature male controls had a HKA 1.34° less than female controls (p < 0.001). A negative correlation existed between HKA and PAQ score (coefficient -0.24, p = 0.029). A positive correlation existed between HKA and MPTPhyA (coefficient 0.32, p = 0.008). In conclusion, high activity levels during adolescence are associated with the development of varus leg alignment. Mean HKA becomes more varus with age until skeletal maturity. The development of varus alignment may represent a physiological adaptation to load at the proximal tibial physis. Clinical Significance: A time period may exist for intervention before the development of varus leg alignment in young athletes, such as training load modification or proximal tibial morphology monitoring.

Overcoming pubic arch interference in prostate brachytherapy using steerable needles.

Purpose: A proportion of patients are not directly eligible for prostate brachytherapy (BT) due to pubic arch interference (PAI). Constraints in positioning sources behind the pubic arch due to linear, horizontal needle paths, may hamper effective irradiation of the target volume. This work evaluated the effect of prostate volume (Vp) and patient posture change on the amount of PAI, and demonstrated that steerable needles may broaden the inclusion criteria for patients with enlarged prostates and observed PAI. Material and methods: Twenty-seven patients (Vp > 60 cc) were included in this study. Access obstruction to the prostate was evaluated using diagnostic magnetic resonance imaging (MRI) scans, after six upward rotations of the pelvis and the prostate in 5 degree steps, to indicate the effect of patient posture change from supine to lithotomy position. For patients with PAI, we evaluated if the steerable needle could access the obstructed volume of the prostate. Results: The data showed no clear relation between Vp and PAI. In 23 of the 27 patients, in which PAI was observed, 14 showed obstruction of the prostate of ≥ 10 mm in the supine position (mean PAI ± standard deviation: 15.2 ±3.8 mm). Anatomical rotation reduced PAI by 4.8 mm after every 10 degrees of upward rotation, still resulting in obstructions of 8.1 ±2.4 mm in 10 of the 14 cases after 15 degree rotation. The steerable needle enabled access to all the required coordinates of the prostate. Conclusions: The ability to steer along curved paths enables prostate BT in patients with enlarged prostates and PAI, and reduces the change of needing to abandon treatment.

Improving the quality of head and neck radiotherapy CT images using a second image reconstruction set.

PURPOSE: To improve the quality of radiotherapy head and neck CT images through use of an additional image set reconstructed from the raw data of the primary scan, thus allowing parameters such as reconstruction field-of-view (FOV) and kernel to be optimised without impacting on the images used for treatment planning dose calculations. METHODS: Using a Catphan image quality phantom and a Toshiba Aquilion LB CT scanner, qualitative and quantitative measurements were made for different reconstruction kernels and FOV diameters. The preferred FOV diameter and kernels were selected. Clinical images from six patients were reconstructed using those kernels (FC13, FC41, FC44, FC64) and the chosen FOV, 200 mm. The images were ranked to choose the kernel which gave best image quality for organ delineation. The scanner workflow was adjusted to produce for every scan a second image set using the chosen kernel and FOV. Finally, for 10 patient scans, image quality was compared for the two reconstructed images. RESULTS: The second image set was produced using kernel FC44 and 200 mm FOV. The primary image set using 550 mm FOV and FC13 was unchanged and contours from the second image set merged onto the first. Oncologists reported increased confidence in contouring in all cases using the new procedure. CONCLUSION: Production of a second image set, using a reduced reconstruction FOV and a kernel which optimises contrast and sharpness, significantly improves the quality of head and neck CT images for contouring, and avoids any dose increase.

Suitability of propagated contours for adaptive replanning for head and neck radiotherapy.

PURPOSE: Adaptive radiotherapy relies on rapid recontouring for replanning. Contour propagation offers workflow efficiencies, but the impact of using unedited propagated OAR contours directly during re-optimisation is unclear. METHODS: Plans for ten head and neck patients were created on the planning CT scan. OAR contours for the spinal cord, brainstem, parotids and larynx were then propagated to five shading-corrected CBCTs equally spaced throughout treatment using five commercial packages. Two reference contours were created on the CBCTs by (1) a clinician and (2) a geometric consensus from the propagated contours. Treatment plans were re-optimised on each CBCT for each set of contours, and the DVH statistic differences to the reference contours were calculated. The spread of DVH statistic differences between the 5th and 95th percentiles was quantified. RESULTS: The spread of DVH statistic differences was 3.7 Gy compared to the clinician contour and 3.3 Gy compared to the consensus contour for the brainstem (and PRV) and 2.4 Gy and 2 Gy for the spinal cord (and PRV), across all 5 auto-contouring solutions. The parotids and larynx showed differences of 3.7 Gy compared to the clinician and 0.9 Gy to the consensus contour, with the larger difference for the clinician possibly caused by uncertainty in the clinician standard due to poor image quality on the CBCTs. CONCLUSIONS: Propagated OAR contours can be used safely for adaptive radiotherapy replanning, however, where organ doses are close to clinical tolerance then the contours should be reviewed for accuracy regardless of the propagation software used.

Comparing the Results of Total Ankle Arthroplasty Vs Tibiotalar Fusion (Ankle Arthrodesis) in Patients with Ankle Osteoarthritis since 2006 to 2020- A Systematic Review.

Background: This study compares the outcomes of patients undergoing total ankle arthroplasty (TAA) and tibiotalar fusion (ankle arthrodesis) in patients with end-stage osteoarthritis. The primary outcome assessed was Patient Reported Outcome Measures (PROMS); secondary outcomes included the incidence of revision, re-operation, and complications. Methods: A systematic review of studies examining the outcomes of patients undergoing TAA and/or tibiotalar fusion from 2006 to 2020 was conducted. Individual cohort studies and randomized control trials were included. Outcomes were assessed at two and five years. Results: 21 studies were included: 16 arthroplasty (2,016 patients) and 5 arthrodesis (256 patients) studies. No significant difference in PROMS was evident two years post-surgery - American Orthopaedic Foot and Ankle Society (AOFAS) scores were 78.8 (95% CI-confidence interval: 76.6-80.8; n=1548) and 80.8 (95% CI: 80.1-81.5; n=206 patients) for the arthroplasty and arthrodesis groups respectively. Two years post-surgery the revision rates for the arthroplasty and arthrodesis groups were similar - 3.5% (n=9) and 3.7% (n=61) respectively (OR-odds ratio: 1.05; 95% CI: 0.51-2.13); however, the re-operation rate was 2.5 times higher for the arthroplasty group (12.2%) in comparison to the arthrodesis group (5.1%) (OR: 2.57; 95% CI: 1.43-4.62). Documented complications in the arthroplasty group were half those documented in the arthrodesis group two years post-surgery (OR: 0.53; 95% CI: 0.37-0.77). No arthrodesis studies were found which contained mean 5-year follow-up data within the study period. Conclusion: Despite recent developments in TAA design, we found no clear evidence as to their superiority over ankle arthrodesis when considering patient outcomes two years postoperatively. However, this conclusion could be debatable in some types of patients such as diabetic patients, posttraumatic patients and patients with stiff hindfoot and midfoot.

The geometric and dosimetric effect of algorithm choice on propagated contours from CT to cone beam CTs.

PURPOSE: Adaptive radiotherapy relies of rapid re-contouring, online more so than offline. Intra-patient contour propagation via non-rigid registration offers a solution but can be of limited accuracy. However, the dosimetric significance of the inaccuracies is unknown. Here we evaluate the dosimetric reliability of contours generated by different commercially-available software packages. METHOD: Planning CT contours for ten head and neck cancer patients were propagated via five commercial packages to five CBCT scans acquired throughout treatment. The treatment plan was recalculated on each of the CBCTs for each set of propagated contours, and DVH parameters extracted for the spinal cord, brainstem, parotids and larynx. The propagated contours were compared to two gold standard contours: contours manually outlined and a consensus STAPLE contours generated from the propagated contours. Geometrical similarity was evaluated using mean distance to agreement (mDTA), Hausdorff distance, centroid agreement and Dice similarity coefficient. Dosimetric reliability was assessed against clinical constraints and comparing via the intraclass correlation coefficient (ICC). RESULTS: All propagated contours were similar to the STAPLE (mDTA < 1.0 mm) whilst larger differences were seen for the manual contours (mDTA < 3.0 mm). The dosimetric comparison showed that the propagated contours gave excellent dose estimates for most organs. The spinal cord reliability was moderate (ICC > 0.66). CONCLUSIONS: Large differences in geometric metrics rarely had a statistically significant impact on DVH parameters for the OARs studied. For that reason, propagated contours on treatment CBCT images are suitable for estimating dose to the OARs.

Utility of pre-operative haemoglobin concentration to guide peri-operative blood tests for hip and knee arthroplasty: A decision curve analysis.

OBJECTIVE: Assess the prognostic value of pre-operative haemoglobin concentration (Hb) for identifying patients who develop severe post-operative anaemia or require blood transfusion following primary total hip or knee, or unicompartmental knee arthroplasty (THA, TKA, UKA). BACKGROUND: Pre-operative group and save (G&S), and post-operative Hb measurement may be unnecessary for many patients undergoing hip and knee arthroplasty provided individuals at greatest risk of severe post-operative anaemia can be identified. METHODS AND MATERIALS: Patients undergoing THA, TKA, or UKA between 2011 and 2018 were included. Outcomes were post-operative Hb below 70 and 80 g/L, and peri-operative blood transfusion. Logistic regression assessed the association between pre-operative Hb and each outcome. Decision curve analysis compared strategies for selecting patients for G&S and post-operative Hb measurement. RESULTS: 10 015 THA, TKA and UKA procedures were performed in 8582 patients. The incidence of blood transfusion (4.5%) decreased during the study. Using procedure specific Hb thresholds to select patients for pre-operative G&S and post-operative Hb testing had a greater net benefit than selecting all patients, no patients, or patients with pre-operative anaemia. CONCLUSIONS: Pre-operative G&S and post-operative Hb measurement may not be indicated for UKA or TKA when adopting restrictive transfusion thresholds, provided clinicians accept a 0.1% risk of patients developing severe undiagnosed post-operative anaemia (Hb < 70 g/L). The decision to perform these blood tests for THA patients should be based on local institutional data and selection of acceptable risk thresholds.

Association between hip joint impingement and lumbar disc disease in elite rowers.

OBJECTIVES: Lumbar disc disease is a known cause of back pain. Increasingly it is thought that cam morphology of the hip may have a causal role in development of lumbar disc disease. The aim of this study was to describe the morphology of the hip and investigate the association of cam morphology with lumbar disc disease observed on MRI in elite rowers. METHODS: Cross-sectional observational study of 20 elite rowers (12 male, 8 female, mean age 24.45, SD 2.1). Assessment included clinical examination, questionnaires, 3T MRI scans of the hips and lumbar spine. Alpha angle of the hips and Pfirrmann score of lumbar discs were measured. RESULTS: 85% of rowers had a cam morphology in at least one hip. Alpha angle was greatest at the 1 o'clock position ((bone 70.9 (SD 16.9), cartilage 71.4 (16.3)). 95% of the group were noted to have labral tears, but only 50% of the group had history of groin pain. 85% of rowers had at least one disc with a Pfirrmann score of 3 or more and 95% had a history of back pain. A positive correlation was observed between the alpha angle and radiological degenerative disc disease (correlation coefficient=3.13, p=0.012). A negative correlation was observed between hip joint internal rotation and radiological degenerative disc disease (correlation coefficient=-2.60, p=0.018). CONCLUSIONS: Rowers have a high prevalence of labral tears, cam morphology and lumbar disc disease. There is a possible association between cam morphology and radiological lumbar degenerative disc disease, however, further investigation is required.

Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis.

Importance: Intravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. Objective: To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. Study Selection: Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. Data Extraction and Synthesis: Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. Main Outcomes and Measures: The primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences. Results: A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. Conclusions and Relevance: In this large systematic review and meta-analysis, intravenous iron was associated with an increased risk of infection. Well-designed studies, using standardized definitions of infection, are required to understand the balance between this risk and the potential benefits.

The role of intraoperative cell salvage for musculoskeletal sarcoma surgery.

BACKGROUND: The efficacy and safety of cell salvage for musculoskeletal sarcoma surgery have not been reported, and concerns over re-infusion of tumour cells remain. This study aims to i) describe the intra-operative blood loss and cell salvage reinfusion volumes for lower limb sarcoma and pelvic sarcoma procedures ii) and explore whether there is evidence of tumour cells in reinfused blood. METHODS: Retrospective analysis of 109 consecutive surgical procedures for biopsy-proven sarcoma or bone metastasis performed between 1 July 2015 and 30 October 2019. Salvaged blood was processed and reinfused when intraoperative blood loss exceeded 500 ml. Primary bone tumour (n = 86(79%)) and metastasis (n = 23(21%) constituted the study group and surgeries were classified under hemipelvectomy (n = 43(39%)), lower limb endoprosthesis replacement (LLE) (n = 50(46%)) and wide excision surgery (WE) (n = 16(15%)). Microscopic examination of imprint cytology of leuco-depletion(LD) filters, and peripheral smear examination was performed for reinfused blood. RESULTS: Median (IQR) intra-operative blood loss was 1750 (600-3000) ml for hemipelvectomy, 850 (600-1200) ml for LLE, and 1000 (550-2000) ml for WE. Salvaged blood was re-infused in 102 of 109 (94%) patients. The mean (SD) volume of re-infusion was 445(4 2 5) ml for hemipelvectomy, 206(1 3 1) ml for LLE, and 184(1 0 6) ml for WE. In total, 64 of 109 (59%) patients received an allogeneic red blood transfusion within 72 h of surgery. Cytology analysis of imprints taken from the filtered blood available in 95(87%) patients and peripheral smear examination of reinfused blood available in 32(29%) patients did not reveal evidence of tumour cells on microscopic examination of any samples. CONCLUSION: Our study demonstrates that musculoskeletal sarcoma surgery is associated with significant blood loss, and cell salvage permits reinfusion of autologous blood in most patients. The cytological analysis did not reveal evidence of tumour cells in reinfused blood, consistent with other studies where cell salvage is used for cancer surgery.