Short-term outcomes with routine use of size ≥40 femoral heads in THA: A retrospective cohort study.

Background: Using larger femoral heads during total hip arthroplasty (THA) may result in a more stable hip. Greater volumetric wear and frictional torque, however, may result in increased postoperative complications. The purpose of this study was to compare outcomes of patients with femoral head size ≥40 mm compared to those with femoral head size <40 mm. Materials and methods: A retrospective chart review of 504 THAs performed by a single surgeon at a single institution from 2009 to 2016 was conducted. Following exclusions, 131 THAs were identified with femoral heads ≥40 mm and 348 THAs were identified with femoral heads <40 mm. In addition to demographic data, all postoperative complications were recorded. Plain radiographs were used to rule out/in periprosthetic osteolysis and/or acetabular loosening. Chi-square tests and Student's t-tests were used to compare categorical and continuous variables, respectively. Results: Mean follow-up period for the entire cohort was 5.5 years. Complications with ≥40 mm femoral heads included 1 superficial infection and 1 deep periprosthetic joint infection (PJI). There were no cases of dislocation, osteolysis, acetabular loosening, or trunnionosis. In contrast, complications with <40 mm femoral heads included 9 dislocations and 7 PJIs. Conclusion: The routine use of large femoral heads (≥40-mm) during THA appears to be a safe option for patients at short-term clinical follow-up. Notably, 0 patients had a clinical course complicated by dislocation, osteolysis, acetabular loosening, or trunnionosis. Level of evidence: Level III Retrospective Cohort Study.

Patellar resurfacing in contemporary total knee arthroplasty: Frequency of complications in a matched cohort.

Introduction: Optimum patient selection and outcomes following patellar resurfacing are ongoing debates amongst the arthroplasty community. This study compared the outcomes of patients who had a total knee arthroplasty (TKA) with patellar resurfacing to those left with their native patella. Methods: A retrospective review of 1941 TKAs performed between 2016 and 2020 was conducted. 41 TKAs without patellar resurfacing and with 2-years of minimum follow-up were identified. Of these, 38 TKAs were matched on age (exact), sex (exact), and body mass index (±10) to 38 TKAs that had patellar resurfacing. The indications for patella resurfacing were subjective based upon the surgeon preference and assessment of cartilage quality. Paired t-tests and chi-square tests were used for analysis. Results: There was 1 major patellofemoral complication in both the resurfaced group (patellar fracture) and the non-resurfaced group (patellar tendon tear), requiring nonoperative management and revision surgery, respectively. However, in the non-resurfaced group there were 4 cases of subjective patellofemoral pain compared to none in the resurfaced group (p = 0.37). Additionally, 3 non-resurfaced patients required manipulation under anesthesia (MUA) compared to none in the resurfaced group (p = 0.44). Discussion: There was no difference in the frequency of major patella-specific complications between the groups. However, there was a non-statistically significant trend towards increased patellofemoral pain and MUA in the non-resurfaced group. Based on this study both methods of treatment remain viable options, but the trend towards increased pain and stiffness should continue to be closely evaluated.

Actin-driven nanotopography promotes stable integrin adhesion formation in developing tissue.

Morphogenesis requires building stable macromolecular structures from highly dynamic proteins. Muscles are anchored by long-lasting integrin adhesions to resist contractile force. However, the mechanisms governing integrin diffusion, immobilization, and activation within developing tissues remain elusive. Here, we show that actin polymerization-driven membrane protrusions form nanotopographies that enable strong adhesion at Drosophila muscle attachment sites (MASs). Super-resolution microscopy reveals that integrins assemble adhesive belts around Arp2/3-dependent actin protrusions, forming invadosome-like structures with membrane nanotopographies. Single protein tracking shows that, during MAS development, integrins become immobile and confined within diffusion traps formed by the membrane nanotopographies. Actin filaments also display restricted motion and confinement, indicating strong mechanical connection with integrins. Using isolated muscle cells, we show that substrate nanotopography, rather than rigidity, drives adhesion maturation by regulating actin protrusion, integrin diffusion and immobilization. These results thus demonstrate that actin-polymerization-driven membrane protrusions are essential for the formation of strong integrin adhesions sites in the developing embryo, and highlight the important contribution of geometry to morphogenesis.

TET2 promotes tumor antigen presentation and T cell IFN-γ which is enhanced by vitamin C.

Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a co-factor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell-derived IFNγ-induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen-presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity which is augmented by high-dose VC therapy.

Design of linked-domain protein inhibitors of UBE2D as tools to study cellular ubiquitination.

Ubiquitin (Ub) is a post-translational modification that largely controls proteostasis through mechanisms spanning transcription, translation, and notably, protein degradation. Ub conjugation occurs through a hierarchical cascade of three enzyme classes (E1, E2, and E3s) involving >1000 proteins that regulate the ubiquitination of proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized, partly due to a lack of inhibitors. For example, the cellular roles of the promiscuous E2 UBE2D/UBCH5 are not well described. Here, we develop a highly selective, multivalent, engineered protein inhibitor for the UBE2D family that simultaneously targets the RING- and backside-binding sites. In HeLa cells, these inhibitors phenocopy knockdown of UBE2D by reducing the IC50 to cisplatin and whole-cell proteomics reveal an increased abundance of ~20% of the identified proteins, consistent with reduced Ub degradation and proteotoxic stress. These precision tools will enable new studies probing UBE2D's central role in proteome management.

USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination.

The CMG helicase (CDC45-MCM2-7-GINS) unwinds DNA as a component of eukaryotic replisomes. Replisome (dis)assembly is tightly coordinated with cell cycle progression to ensure genome stability. However, factors that prevent premature CMG unloading and replisome disassembly are poorly described. Since disassembly is catalyzed by ubiquitination, deubiquitinases (DUBs) represent attractive candidates for safeguarding against untimely and deleterious CMG unloading. We combined a targeted loss-of-function screen with quantitative, single-cell analysis to identify human USP37 as a key DUB preventing replisome disassembly. We demonstrate that USP37 maintains active replisomes on S-phase chromatin and promotes normal cell cycle progression. Proteomics and enzyme assays revealed USP37 interacts with the CMG complex to deubiquitinate MCM7, thus antagonizing replisome disassembly. Significantly, USP37 protects normal epithelial cells from oncoprotein-induced replication stress. Our findings reveal USP37 to be critical to the maintenance of replisomes in S-phase and suggest USP37-targeting as a potential strategy for treating malignancies with defective DNA replication control.

A cross-sectional study assessing the role of interventional radiology services in regional and remote Australia.

INTRODUCTION: It is estimated that 8% of hospitalised patients require treatment from Interventional Radiology (IR). However, little is known about the potential impact of IR on regional and remote Australians, including Indigenous patients. This study aimed to assess treatments performed by IRs on regional/remote patients to predict future IR workforce and governance needs. METHODS: Single-centre cross-sectional study at a tertiary Victorian hospital. Patients were identified when they had an advanced IR treatment between 1 January 2022 and 2024. Basic procedures such as biopsy and drain insertion were not included. The primary outcome was the type and volume of IR treatments performed on patients who were transferred from a regional or remote home location for treatment. RESULTS: Of 3485 advanced IR interventions, 908 procedures (26.0%) from patients who lived in a regional or remote location were included with 36.5% female, of mean age 55.6 years (SD 17.9). 1.4% identified as Indigenous which is similar to the Indigenous population incidence in Victoria of 1.0%. Of this group, 350 (38.5%) were either a day procedure, overnight elective admission, or simple inpatient procedure which could have been performed in a regional centre, which included 1.1% Indigenous patients. CONCLUSION: There is an unmet need for IR services in regional and remote Australia, with many patients being transferred to our metropolitan centre for treatment that could be performed in regional IR hubs. This data will be important to drive government and hospital planning including capital infrastructure, workforce modelling and future recognition of IR as a new specialty in Australia.

Ninety-Day Outcomes in Primary Hypercoagulable Disease Patients Undergoing Total Joint Arthroplasty Vs Normal: A Matched Case-Control Series.

Background: Perioperative complications of deep vein thrombosis are well described in the total joint arthroplasty (TJA) literature. Few studies have investigated short-term perioperative outcomes of patients with primary hypercoagulable diseases (PHDs). Optimal perioperative management of PHD patients remains unknown, and they are often referred to tertiary centers for care. We investigated the influence perioperative hematology consultation and anti-coagulation use had on PHD patient outcomes following TJA surgery within the 90-day postoperative period. Methods: This retrospective cohort study examined perioperative outcomes of PHD patients undergoing TJA. Thirty-eight PHD patients were identified and compared to a 3:1 matched control group in a consecutive series of 6568 cases (2007-2019). Perioperative hematology consultations, use of anticoagulants (AC) or antiplatelet therapy, emergency department (ED) visits, readmissions, and complications within 90 days of surgery were determined. Results: The PHD cohort exhibited more frequent hematology consultations (odds ratio 5.88, 95% confidence interval: 2.59-16.63) and AC use (odds ratio 7.9, 95% confidence interval: 3.38-23.80) than controls. PHD patients did not show significantly greater rates of deep vein thrombosis, transfusion, infection, ED visits, or need for operative intervention. Similarly, AC vs antiplatelet therapy yielded comparable ED visits and readmissions within 90 days postoperatively (11.0% vs 9.7%, P = .85 and 5.5% vs 5.5%, P = 1, respectively). Conclusions: These findings suggest that despite increased hematology consultation and AC use, PHD patients do not demonstrate significantly elevated perioperative risks post-TJA, favoring careful preoperative workup and outpatient postoperative follow-up.

A survey of experts to identify methods to detect problematic studies: stage 1 of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews project.

BACKGROUND AND OBJECTIVE: Randomized controlled trials (RCTs) inform health-care decisions. Unfortunately, some published RCTs contain false data, and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesize all RCTs which have been conducted on a given topic. This means that any of these 'problematic studies' are likely to be included, but there are no agreed methods for identifying them. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is developing a tool to identify problematic RCTs in systematic reviews of health care-related interventions. The tool will guide the user through a series of 'checks' to determine a study's authenticity. The first objective in the development process is to assemble a comprehensive list of checks to consider for inclusion. METHODS: We assembled an initial list of checks for assessing the authenticity of research studies, with no restriction to RCTs, and categorized these into five domains: Inspecting results in the paper; Inspecting the research team; Inspecting conduct, governance, and transparency; Inspecting text and publication details; Inspecting the individual participant data. We implemented this list as an online survey, and invited people with expertise and experience of assessing potentially problematic studies to participate through professional networks and online forums. Participants were invited to provide feedback on the checks on the list, and were asked to describe any additional checks they knew of, which were not featured in the list. RESULTS: Extensive feedback on an initial list of 102 checks was provided by 71 participants based in 16 countries across five continents. Fourteen new checks were proposed across the five domains, and suggestions were made to reword checks on the initial list. An updated list of checks was constructed, comprising 116 checks. Many participants expressed a lack of familiarity with statistical checks, and emphasized the importance of feasibility of the tool. CONCLUSION: A comprehensive list of trustworthiness checks has been produced. The checks will be evaluated to determine which should be included in the INSPECT-SR tool. PLAIN LANGUAGE SUMMARY: Systematic reviews draw upon evidence from randomized controlled trials (RCTs) to find out whether treatments are safe and effective. The conclusions from systematic reviews are often very influential, and inform both health-care policy and individual treatment decisions. However, it is now clear that the results of many published RCTs are not genuine. In some cases, the entire study may have been fabricated. It is not usual for the veracity of RCTs to be questioned during the process of compiling a systematic review. As a consequence, these "problematic studies" go unnoticed, and are allowed to contribute to the conclusions of influential systematic reviews, thereby influencing patient care. This prompts the question of how these problematic studies could be identified. In this study, we created an extensive list of checks that could be performed to try to identify these studies. We started by assembling a list of checks identified in previous research, and conducting a survey of experts to ask whether they were aware of any additional methods, and to give feedback on the list. As a result, a list of 116 potential "trustworthiness checks" was created. In subsequent research, we will evaluate these checks to see which should be included in a tool, INveStigating ProblEmatic Clinical Trials in Systematic Reviews, which can be used to detect problematic studies.

The Viability and Success of Noncemented Kinematic Total Knee Arthroplasty.

BACKGROUND: The prevalence of noncemented total knee arthroplasty (TKA) is increasing as personalized knee alignment strategies deviate from implanting components on a strict mechanical axis. This retrospective study evaluated the outcomes of 74 consecutive noncemented unrestricted kinematic TKA procedures. METHODS: This study included 74 consecutive noncemented kinematic TKAs performed by one surgeon at a tertiary academic medical center from 2021 to 2023. The technique used was unrestricted femur-first caliper kinematic TKA. The outcomes included revision, pain scores, and radiographic measurements. RESULTS: Of the 74 procedures performed, there were no revisions or readmissions for problems related to TKA. The mean follow-up was 17.6 months, with 74% of patients being followed up for more than 1 year postoperatively. On the day of surgery, postoperative measurements showed that the average tibial mechanical, distal femoral, and anatomic tibiofemoral angles were 3.3°, 7.7°, and 5.8°, respectively. 5 knees were observed initially with signs of radiolucency, which all resolved by the most recent appointment. None of the knees was radiographically loose. Of the patients, 65%, 19%, and 16% reported no pain, minimal pain, and some pain, respectively, at the 6-week follow-up visit. This improved to 78%, 19%, and 3% at the most recent follow-up. CONCLUSION: Combining kinematic alignment with noncemented fixation showed excellent clinical and radiographic outcomes with short-term survivorship. Although the use of both kinematic alignment and noncemented TKAs has been controversial, these early data suggest that noncemented kinematic TKA is safe and effective.

Prediction of biochemical recurrence after radical prostatectomy from primary tumour characteristics.

OBJECTIVES: To construct and externally calibrate a predictive model for early biochemical recurrence (BCR) after radical prostatectomy (RP) incorporating clinical and modern imaging characteristics of the primary tumour. PATIENTS AND METHODS: Patients who underwent RP following multiparametric magnetic resonance imaging, prostate biopsy and prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT), from two centres in Australia and the Netherlands. The primary outcome was biochemical recurrence-free survival (BRFS), where BCR was defined as a rising PSA level of ≥0.2 ng/mL or initiation of postoperative treatment per clinician discretion. Proportional hazards models to predict time to event were developed in the Australian sample using relevant pre- and post-surgical parameters and primary tumour maximum standardised uptake value (SUVmax) on diagnostic PSMA-PET/CT. Calibration was assessed in an external dataset from the Netherlands with the same inclusion criteria. RESULTS: Data from 846 patients were used to develop the models. Tumour SUVmax was associated with worse predicted 3-year BRFS for both pre- and post-surgical models. SUVmax change from 4 to 16 lessened the predicted 3-year BRFS from 66% to 42% for a patient aged 65 years with typical pre-surgical parameters (PSA level 8 ng/mL, Prostate Imaging-Reporting and Data System score 4/5 and biopsy Gleason score ≥4 + 5). Considering post-surgical variables, a patient with the same age and PSA level but pathological stage pT3a, RP Gleason score ≥4 + 5 and negative margins, SUVmax change from 4 to 16 lessened the predicted 3-year BRFS from 76% to 61%. Calibration on an external sample (n = 464) showed reasonable performance; however, a tendency to overestimate survival in patients with good prognostic factors was observed. CONCLUSION: Tumour SUVmax on diagnostic PSMA-PET/CT has utility additional to commonly recognised variables for prediction of BRFS after RP.

Injury epidemiology in male and female competitive diving athletes: A four-year observational study.

OBJECTIVES: To describe the incidence, severity, burden and sport specific characteristics of injuries reported in elite diving athletes. DESIGN: Descriptive epidemiology study. METHODS: Medical attention and time-loss injuries from 63 (43 female, 20 male) Australian national diving programme athletes were prospectively collected over four seasons (September 2018-August 2022). Injury incidence rates and burden were calculated, standardised per 365 athlete days, and compared across groups using negative binomial generalised linear models. RESULTS: In total 421 injuries were reported (female = 292, male = 129) at an injury incidence rate of 2.36 (95 % confidence interval = 2.14-2.60) per 365 athlete days. Annual injury prevalence ranged from 70.0 to 85.1 %. Approximately two-thirds of injuries (67.2 %) resulted in a period of time-loss. The overall injury burden was 91 days of absence (95 % confidence interval = 81-102) per 365 athlete days. Stress fractures in springboard diving athletes incurred the largest mean days of time-loss compared to other injured tissue types. The majority of injuries were reported to occur during training (79.3 %) as opposed to competition (2.4 %), with more than half (55.3 %) of all reported injuries occurring during pool training sessions. Water entry (30.4 %) or take-off (27.8 %) were the most frequently reported mechanism of injury. CONCLUSIONS: Annual injury prevalence reported in competitive Australian diving athletes was found to be high. Contrary to existing literature, competitive diving injuries were reported to occur within the daily training environment, with few injuries occurring during competition. Notable injury differences between springboard and platform athletes were observed.

Outcomes of Regional Block in Revision Total Joint Arthroplasty for Prosthetic Joint Infection.

INTRODUCTION: Infection is among the most common reasons for revision after a total joint arthroplasty (TJA) and is associated with notable morbidity and mortality rates. As the demand for TJA increases, a concurrent increase in the prevalence of periprosthetic joint infection (PJI) is also expected to rise. While previous studies have explored differences in postoperative outcomes between general and spinal anesthesia, there is limited data on the use of regional blocks in patients undergoing revision joint arthroplasty for PJI. This study evaluated the postoperative outcomes of patients undergoing revision TJA for PJI using regional blocks. METHODS: Data from 518 patients were retrospectively collected. Patients included in the study had undergone revision TJA for PJI from January 2004 to January 2023 at a single institution. Patients undergoing same-day bilateral revisions, above-knee amputations, and aseptic revisions were excluded. Postoperative complications investigated included local complications, postoperative transfusion, wound complication, readmission, sepsis, systemic infection, spinal infection, death, persistent PJI, periprosthetic fracture, and unplanned revision surgery. Chi-square analysis was used to compare postoperative complications between procedures that used spinal or general anesthesia with regional blocks and those with spinal or general anesthesia without regional blocks. RESULTS: Of the 518 patients who underwent revision TJA, 63 (12.2%) used a regional block. After surgery, 12.7% (n = 8) of patients with regional block and 23.5% (n = 107) of patients without regional block experienced persistent PJI (P = 0.076). No significant differences in wound complication (P = 0.333), readmission (P = 0.998), revision surgery (P = 0.783), and death (P = 0.588) were found between those with and without regional block use. Sepsis (P = 0.224), systemic infection (P = 0.220), and spinal infection (P = 0.998) rates within 1 year after revision TJA for PJI surgery were comparable between the two groups. No local infections were observed at the block site. A subanalysis comparing spinal and general anesthesia demonstrated comparable persistent PJI postoperatively and complication rates; however, spinal anesthesia use was associated with shorter length of stay (P = 0.003) and lower transfusion rates (P = 0.002). CONCLUSION: The results of this study suggest that the use of regional block is not associated with an increased probability of postoperative persistent PJI, local wound complication, readmission, spinal/systemic/other infections, death, or revision surgery. Surgeons can comfortably choose regional block as a safe option for revision surgery for PJI. Consistent with previous research, patients who received spinal anesthesia had shorter hospital stays and lower transfusion rates when compared with those who received general anesthesia.

Fixing science means an end to gaming the system.

During the last decade, there has been a substantial acceleration in the open science movement. Most people would probably hope to have seen signs of positive change in that time, yet it seems that the process of improving the practice of science is moving at a glacial pace.

Sustained intestinal epithelial monolayer wound closure after transient application of a FAK-activating small molecule.

M64HCl, which has drug-like properties, is a water-soluble Focal Adhesion Kinase (FAK) activator that promotes murine mucosal healing after ischemic or NSAID-induced injury. Since M64HCl has a short plasma half-life in vivo (less than two hours), it has been administered as a continuous infusion with osmotic minipumps in previous animal studies. However, the effects of more transient exposure to M64HCl on monolayer wound closure remained unclear. Herein, we compared the effects of shorter M64HCl treatment in vitro to continuous treatment for 24 hours on monolayer wound closure. We then investigated how long FAK activation and downstream ERK1/2 activation persist after two hours of M64HCl treatment in Caco-2 cells. M64HCl concentrations immediately after washing measured by mass spectrometry confirmed that M64HCl had been completely removed from the medium while intracellular concentrations had been reduced by 95%. Three-hour and four-hour M64HCl (100 nM) treatment promoted epithelial sheet migration over 24 hours similar to continuous 24-hour exposure. 100nM M64HCl did not increase cell number. Exposing cells twice with 2-hr exposures of M64HCl during a 24-hour period had a similar effect. Both FAK inhibitor PF-573228 (10 µM) and ERK kinase (MEK) inhibitor PD98059 (20 µM) reduced basal wound closure in the absence of M64HCl, and each completely prevented any stimulation of wound closure by M64HCl. Rho kinase inhibitor Y-27632 (20 µM) stimulated Caco-2 monolayer wound closure but no further increase was seen with M64HCl in the presence of Y-27632. M64HCl (100 nM) treatment for 3 hours stimulated Rho kinase activity. M64HCl decreased F-actin in Caco-2 cells. Furthermore, a two-hour treatment with M64HCl (100 nM) stimulated sustained FAK activation and ERK1/2 activation for up to 16 and hours 24 hours, respectively. These results suggest that transient M64HCl treatment promotes prolonged intestinal epithelial monolayer wound closure by stimulating sustained activation of the FAK/ERK1/2 pathway. Such molecules may be useful to promote gastrointestinal mucosal repair even with a relatively short half-life.

Characterizing electron-collecting CdTe for use in a 77†ns burst-rate imager.

The Keck-PAD (pixel array detector) was developed at Cornell as a burst-rate imager capable of recording images from successive electron bunches (153 ns period) from the Advanced Photon Source (APS). Both Si and hole-collecting Schottky CdTe have been successfully bonded to this ASIC (application-specific integrated circuit) and used with this frame rate. The facility upgrades at the APS will lower the bunch period to 77 ns, which will require modifications to the Keck-PAD electronics to image properly at this reduced period. In addition, operation at high X-ray energies will require a different sensor material having a shorter charge collection time. For the target energy of 40 keV for this project, simulations have shown that electron-collecting CdTe should allow >90% charge collection within 35 ns. This collection time will be sufficient to sample the signal from one frame and prepare for the next. 750 µm-thick electron-collecting Schottky CdTe has been obtained from Acrorad and bonded to two different charge-integrating ASICs developed at Cornell, the Keck-PAD and the CU-APS-PAD. Carrier mobility has been investigated using the detector response to single X-ray bunches at the Cornell High Energy Synchrotron Source and to a pulsed optical laser. The tests indicate that the collection time will meet the requirements for 77 ns imaging.

Influence of Contralateral Hip Status on Pelvic Tilt After Total Hip Arthroplasty.

Background: Every degree of change in pelvic tilt (PT) leads to a 0.7° change in anteversion and a 0.3° change in inclination. This study aimed to determine the significance of contralateral hip arthritis on changes in PT using preoperative and postoperative anteroposterior radiographs. Methods: There were 193 primary total hip arthroplasties done by 2 surgeons at a single academic tertiary referral center reviewed between September 2021 and January 2023. PT was calculated as Tilt = -(ln[(B/A) × (1/0.483)]) / 0.051. Value A is the distance from the base of the SI joint to the superior margin of the obturator foramen; value B is the height of the obturator foramen. After exclusions, contralateral hips were identified as being normal (n = 75), arthritic (n = 39) (Tönnis grade 3/4), replaced (n = 34), or having undergone simultaneous bilateral total hip arthroplasty (n = 5) on postoperative films. Difference in PT was measured between preoperative and postoperative films taken 1-3 months after surgery. Analyses for statistical significance were calculated using t-tests and one-way analysis of variance. Results: Average change in PT in patients with normal contralateral hips was -5.2° with an absolute mean difference of 7.6°, -1.5° for arthritic contralateral hips with an absolute mean difference of 5.0°, -1.6° for replaced contralateral hips with a mean absolute difference of 4.3°, and 2.2° for bilateral hips with a mean absolute difference of 2.6° (P < .01). Conclusions: Differences in postoperative PT changes between healthy, arthritic, and replaced contralateral hip study groups were significant. Changes in preoperative to postoperative tilt may have implications for optimal cup placement.

The 'Prostate Embolisation AS first-line therapY compAred to meDication in treatment naïVe men with prostAte eNlargement, a randomised ControllEd trial' (P-EASY ADVANCE): a randomised controlled trial of prostate embolisation vs medication for BPH.

OBJECTIVE: To compare prostate artery embolisation (PAE) to the combination of tamsulosin and dutasteride therapy as a potential first-line therapy for obstructive benign prostatic hyperplasia (BPH) in treatment-naïve patients in the 'Prostate Embolisation AS first-line therapY compAred to meDication in treatment naïVe men with prostAte eNlargement, a randomised ControllEd trial' (P-EASY ADVANCE). PATIENTS AND METHODS: A total of 39 men with enlarged prostates, moderate-severe lower urinary tract symptoms (LUTS) and obstructed/equivocal urodynamic studies (UDS), and who had no prior treatment for BPH, were randomised to receive either combined medical therapy with tamsulosin and dutasteride (medication) or PAE. Follow-up UDS, International Prostate Symptom Score (IPSS), uroflowmetry and ultrasound were performed at short- to medium-term intervals following interventions and compared to baseline. RESULTS: The medication and PAE treatment groups had similar baseline characteristics, including prostate volumes (87.8 and 85.4 mL respectively), maximum urinary flow rate (Qmax; 6.5 and 6.6 mL/s, respectively), IPSS (19.5 and 21, respectively) and obstructed UDS (79% and 74%, respectively). Both interventions improved voiding and bladder outflow obstruction from baseline, with more patients unobstructed after PAE (63%) compared to medication (28%) (P = 0.03). PAE patients had significantly greater reductions in prostate size (P < 0.001), incomplete emptying (P = 0.002), total IPSS (P = 0.032), Qmax (P = 0.006) and quality of life (P = 0.001). Altered ejaculation, erectile dysfunction and nausea were more common in the medication group. CONCLUSION: Prostate artery embolisation was more effective than combined medical therapy at reducing urinary obstruction, decreasing prostate volume and improving LUTS in patients with BPH who had not previously been treated. This is the first randomised control study to compare PAE and combined medical therapy in exclusively treatment-naïve patients and raises the potential of PAE as an alternative early treatment option for BPH. Further randomised comparative trials are planned to further validate the role of PAE in mitigating obstructive BPH.

Recruitment of FBXO22 for targeted degradation of NSD2.

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.