Weightbearing versus non-weight bearing in geriatric distal femoral fractures: a systematic review and meta-analysis.

BACKGROUND: Demographics of patients who sustain geriatric distal femoral fractures (DFF) match those of patients with neck-of-femur fractures but have limited evidence with which to support post-operative weightbearing protocols. PURPOSE: This systematic review sought to identify any difference in outcomes for elderly patients with DFF who were allowed early versus delayed weightbearing postoperatively. METHODS: DATA SOURCES: PubMed, Medline, Embase and The Cochrane Library, reference lists of retrieved articles. STUDY SELECTION: English language papers published between January 2010 and February 2023 with AO-OTA type 33A, B and C femoral fractures as well as Lewis and Rorabeck Type I and II periprosthetic DFF surgically treated with either a lateral locking plate or retrograde intramedullary nail and an average patient age of ≥ 60 years. DATA EXTRACTION: Studies were assessed for inclusion by two authors and quality was assessed using the MINORS tool. DATA SYNTHESIS: Sixteen studies were included, Meta-analysis of non-union, malunion, infection, delayed union and implant complications was performed using Microsoft Excel and the MetaXL extension. The data on return to mobility were presented in narrative form. The analyses demonstrated no difference between the early and delayed weightbearing groups. CONCLUSIONS: There are no significant differences in complication rates between early versus delayed weightbearing after surgery for DFF in an elderly population. The study results are limited by high heterogeneity and low-quality studies. High quality, prospective studies are needed to determine the ideal postoperative weightbearing protocol. LEVEL OF EVIDENCE: Level III, Systematic Review and Meta-analysis of Level III studies. International Prospective Register of Systematic Reviews registration-Prospero CRD42022371460.

Surgical evacuation with intraoperative ultrasound (SEE U): A randomised controlled trial.

OBJECTIVES: To test whether intraoperative ultrasound can reduce the incidence of early and late complications following surgical removal of products of conception. DESIGN: This was a prospective, multicentre, randomised, open clinical trial to assess feasibility. It was performed in two University Teaching hospitals in the West Midlands, England. The population consisted of women aged 16 years or over who were referred for surgical management of miscarriage. Patients were randomised to surgical management of miscarriage with either continuous intraoperative ultrasound or without intraoperative ultrasound. Process outcomes included the proportion of eligible women screened and proportion of eligible women randomised, attrition rates, evaluation of outcome measurement tools and acceptability. The primary clinical outcome was a composite outcome of unsuccessful procedure or a complication. RESULTS: Fifty-nine women requiring surgical management of miscarriage were randomised. The conversion rate for entry into the trial was 59/79(75 %; 95 %CI = 64-84 %). The composite clinical outcome was attained in 5/27(19 %) patients who had surgery without ultrasound and 7/28(25 %) patients who had surgery with ultrasound (RR = 0.74;95 %CI = 0.26, 2.10). When we excluded the patients that could not attend their hysteroscopy appointment, due to COVID-19 pandemic, 5/27(19 %) of patients who had surgery without ultrasound and 5/25(20 %) of patients who had surgery with ultrasound attained the composite clinical outcome (RR = 0.93;95 %CI = 0.30, 2.90). CONCLUSIONS: This multicentre pilot study showed that a large RCT comparing surgical management of miscarriage with and without intraoperative ultrasound is feasible.

Astringency and its sub-qualities: a review of astringency mechanisms and methods for measuring saliva lubrication.

Astringency is an important mouthfeel attribute that influences the sensory experiences of many food and beverage products. While salivary lubricity loss and increased oral friction were previously believed to be the only astringency mechanisms, recent research has demonstrated that nontactile oral receptors can trigger astringency by responding to astringents without mechanical stimulation. Various human factors have also been identified that affect individual responses to astringents. This article presents a critical review of the key research milestones contributing to the current understanding of astringency mechanisms and the instrumental approaches used to quantify perceived astringency intensity. Although various chemical assays or physical measures mimic in-mouth processes involved in astringent mouthfeel, this review highlights how one chemical or physical approach can only provide a single measure of astringency determined by a specific mechanism. Subsequently, using a single measurement to predict astringency perception is overly idealistic. Astringency has not been quantified beyond the loss of saliva lubrication; therefore, nontactile receptor-based responses must also be explored. An important question remains about whether astringency is a single perception or involves distinct sub-qualities such as pucker, drying, and roughness. Although these sub-quality lexicons have been frequently cited, most studies currently view astringency as a single perception rather than dividing it into sub-qualities and investigating the potentially independent mechanisms of each. Addressing these knowledge gaps should be an important priority for future research.

Overcoming osimertinib resistance with AKT inhibition in EGFRm-driven Non-Small-Cell-Lung-Cancer with PIK3CA/PTEN alterations.

PURPOSE: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR engineered NSCLC cell lines and PXD models support a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. RESULTS: These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be re-sensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alteration, and in these double mutant models capivasertib and osimertinib combination elicits an improved anti-tumor effect versus osimertinib alone. CONCLUSIONS: Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC that have a sub-optimal response, or develop resistance, to osimertinib through PIK3CA/AKT/PTEN alterations.

Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.

Intra-articular Vancomycin Reduces Prosthetic Infection in Primary Hip and Knee Arthroplasty.

Background: Intravenous antibiotic infusion has been the standard prophylaxis for total joint arthroplasty surgery. However, infection rates still occur at 1%-2% in many series. Single-dose intra-articular antibiotics (IAAs) present a safe and potentially more effective prophylactic regime in total joint arthroplasty. This study aimed to assess the outcomes of a single-dose IAA injection on PJI rates in a single surgeon series of hip and knee arthroplasty. Methods: We reviewed the data of all patients operated on for a primary hip or knee replacement from 2010 to 2021. From January 2018, 1 gm of vancomycin in 10 ml of saline was injected into every total joint replacement after fascial closure. A comparison was made with PJI referencing the Australian National Joint Replacement Registry data on revision for the 2 periods: 2010-2017 and 2018-2021. Results: During the period without IAA (2010-2017) for TKR, 6 of 489 (1.2%), and for THR, 5 of 694 (0.7%) had PJI requiring revision surgery. In the period with IAA (2018-2021) for TKR, 0 of 214 (0%, P = .11), and for THR, 1 of 517 (0.2%, P = .19) PJI required revision surgery, but the overall incidence of PJI for TKR and THR was significantly reduced (P = .03). Conclusions: A single dose of intra-articular vancomycin 1 gm injected into the total joint replacement following fascial closure reduced the incidence of deep PJI requiring a revision surgery in a single-surgeon series. These results demonstrate significant benefits to this technique which merit further larger trials.

Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrom macroglobulinaemia.

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.

Accurate additive manufacturing of lightweight and elastic carbons using plastic precursors.

Despite groundbreaking advances in the additive manufacturing of polymers, metals, and ceramics, scaled and accurate production of structured carbons remains largely underdeveloped. This work reports a simple method to produce complex carbon materials with very low dimensional shrinkage from printed to carbonized state (less than 4%), using commercially available polypropylene precursors and a fused filament fabrication-based process. The control of macrostructural retention is enabled by the inclusion of fiber fillers regardless of the crosslinking degree of the polypropylene matrix, providing a significant advantage to directly control the density, porosity, and mechanical properties of 3D printed carbons. Using the same printed plastic precursors, different mechanical responses of derived carbons can be obtained, notably from stiff to highly compressible. This report harnesses the power of additive manufacturing for producing carbons with accurately controlled structure and properties, while enabling great opportunities for various applications.

Aseptic loosening around total joint replacement in humans is regulated by miR-1246 and miR-6089 via the Wnt signalling pathway.

BACKGROUND: Total joint replacement for osteoarthritis is one of the most successful surgical procedures in modern medicine. However, aseptic loosening continues to be a leading cause of revision arthroplasty. The diagnosis of aseptic loosening remains a challenge as patients are often asymptomatic until the late stages. MicroRNA (miRNA) has been demonstrated to be a useful diagnostic tool and has been successfully used in the diagnosis of other diseases. We aimed to identify differentially expressed miRNA in the plasma of patients with aseptic loosening. METHODS: Adult patients undergoing revision arthroplasty for aseptic loosening and age- and gender-matched controls were recruited. Samples of bone, tissue and blood were collected, and RNA sequencing was performed in 24 patients with aseptic loosening and 26 controls. Differentially expressed miRNA in plasma was matched to differentially expressed mRNA in periprosthetic bone and tissue. Western blot was used to validate protein expression. RESULTS: Seven miRNA was differentially expressed in the plasma of patients with osteolysis (logFC >|2|, adj-P < 0.05). Three thousand six hundred and eighty mRNA genes in bone and 427 mRNA genes in tissue samples of osteolysis patients were differentially expressed (logFC >|2|, adj-P < 0.05). Gene enrichment analysis and pathway analysis revealed two miRNA (miR-1246 and miR-6089) had multiple gene targets in the Wnt signalling pathway in the local bone and tissues which regulate bone metabolism. CONCLUSION: These results suggest that aseptic loosening may be regulated by miR-1246 and miR-6089 via the Wnt signalling pathway.

Union and Complication Rates After Total Wrist Arthrodesis: A Systematic Review and Meta-Analysis.

PURPOSE: Total wrist arthrodesis (TWA) has been performed using various techniques. We aimed to provide pooled prevalence estimates of union and complications of TWA by technique. A secondary aim was to provide estimates of union and complication rates by treatment of the carpometacarpal joint (CMCJ) in TWA using plates. Given the widespread adoption of wrist arthrodesis plates (WAP), we hypothesized that these implants would result in higher union and lower complication rates. We also hypothesized that TWA with CMCJ arthrodesis would improve these outcomes. METHODS: Online databases including PubMed, Medline, Embase, and Cochrane were searched. Studies reporting union and/or complication rates of 10 or more TWA performed with a similar technique (analyzed as bone graft only, bone graft with minimal fixation, intramedullary, augmented intramedullary, plate, WAP, and other) were included. Studies with fewer than 10 TWA, studies reporting TWA where union or complications could not be analyzed separately, and studies without union and complication rates were excluded. Data extraction was performed independently by two English-speaking reviewers with a translator where required. Pooled prevalence estimates were made using a random-effects meta-analysis model and presented as a percent prevalence with 95% confidence and prediction intervals. RESULTS: One hundred and thirty-six studies with a total of 3,517 patients and 3,969 TWA were analyzed. No differences in union and complication prevalence were observed between TWA techniques and in TWA with different treatments of the CMCJ using plates and WAP. CONCLUSION: Using meta-analysis, we found no difference in union and complication prevalence between TWA techniques and TWA with different treatments of the CMCJ with plates and WAP. It must be acknowledged that this research included low-quality studies with high heterogeneity, and confidence in the precision of the estimates is low. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

The use of intra-articular vancomycin is safe in primary hip and knee arthroplasty.

Background: The use of a single dose of intra-articular antibiotic (IAA) has been reported in reducing the rate of prosthetic joint injection after total hip and knee arthroplasty. We examine the safety of IAA in primary hip and knee replacement surgery and the blood levels and joint fluid levels of vancomycin utilising this technique. Methods: From August to October 2021, 68 patients undergoing primary total joint arthroplasty (THA & TKA) were given 1g vancomycin intra-articularly (IA)after closure of the fascia. All patients received 2g cefazolin intravenously (IV) 30 min prior to the procedure as is our standard prophylaxis, and 21 of the patients (IA + IV) were also administered an additional 1 gm vancomycin IV. Post-operative blood vancomycin, creatinine land eGFR level monitoring was performed d1 and d3. To determine the post-operative intra-articular vancomycin levels, surgical drain fluid was sampled at day 1 and 2, in 10 patients. Results: All patients had serum vancomycin levels measured on day 1 and 3. In the group where vancomycin was injected after fascial closure, the average blood vancomycin level day 1 was 5.2 µg/ml (range 2.0-10.9) and day 3 was <1.4 µg/ml. The average pre-op creatinine levels were 69.4 µmol/L (56.1-82.6) compared to 70.2 µmol/L (57.0-83.4) on day 1 and 66.1 µmol/L (52.6-79.6) on day 3, (p = 0.663). The average pre-op eGFR levels (ml/min/1.73 m2) were 82.2 (76.0-88.3) compared to 81.7 (75.6-87.8) on day 1 and 83.0 (76.8-89.2) on day 3 (p = 0.736). Samples of joint fluid aspirated from surgical drains on day 1 and day 2 showed average vancomycin levels of 224 µg/ml and 51 µg/ml respectively, significantly higher than the MIC for Staph aureus. Conclusions: The use of intra-articular vancomycin is safe in primary TJA, with no renal damage and delivers levels within the joint which are highly therapeutic for at least 48 h post injection.

LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Patient experiences of outpatient hysteroscopy.

OBJECTIVES: Patient perspectives have an important role in improving the quality of outpatient hysteroscopy (OPH) services. Understanding women's experiences can help provide important insights regarding the OPH journey. The purpose of this paper is to share perspectives and reflect on the experiences of women that participated in a national benchmarking OPH survey. In addition, we explore the correlation between women's experience of OPH and reported pain scores. MATERIAL AND METHODS: Over a two-month period, 5151 women took part in the national OPH survey. Free text comments relating to women's OPH experience, collected as part of the survey, were subjected to qualitative analysis using NVivo 12 software to provide a better understanding of the OPH journey. In addition, correlations were drawn between the qualitative and quantitative data collected for pain scores and satisfaction using SPSS software. RESULTS: 1720 (33.3%) women provided comments on their OPH experience. Qualitative thematic analysis generated themes that were divided into positive (82%) and negative (7%) experiences of care. Potential areas of improvement in relation to the OPH service were highlighted in 11% of themes. Most women regarded OPH as a safe, tolerable, and well delivered outpatient service. Quantitative analysis showed that 1829 (35.5%) women reported procedural pain between 70 and 100 mm. These women reported equivalent quality of care on a 10 cm visual analogue scale (9.71 [SD1.04] vs. 9.76 [0.73]; P = 0.06) but were more likely to decline having the procedure done in the same way again (19.4% vs. 3.1%; RR 6.30, 95% CI 5.06 to 7.83) compared to women with pain scores < 70 mm. CONCLUSION: Qualitative data supports the usefulness, safety, tolerability, and acceptance of hysteroscopy in an outpatient setting by most women. However, the reasons for high procedural pain, poor tolerability and negative experiences warrant review and exploration of both individual patient and relevant institutional factors including training, equipment, and local processes.

BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors.

BACKGROUND: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. METHODS: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. RESULTS: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. CONCLUSIONS: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

Novel method for highly multiplexed gene expression profiling of circulating tumor cells (CTCs) captured from the blood of women with metastatic breast cancer.

BACKGROUND: Enumeration of circulating tumor cells (CTCs) has proven clinical significance for monitoring patients with metastatic cancers. Multiplexed gene expression profiling of CTCs is a potential tool for assessing disease status and monitoring treatment response. The Parsortix® technology enables the capture and harvest of CTCs from blood based on cell size and deformability. The HyCEAD™ (Hybrid Capture Enrichment Amplification and Detection) assay enables simultaneous amplification of short amplicons for up to 100 mRNA targets, and the Ziplex™ instrument quantifies the amplicons for highly sensitive gene expression profiling down to single cell levels. The aim of the study was to functionally assess this system. METHODS: The HyCEAD/Ziplex platform was used to quantify the expression levels for 72 genes using as little as 20 pg of total RNA or a single cultured tumor cell. Assay performance was evaluated using cells or total RNA spiked into Parsortix harvests of healthy donor blood. The assay was also evaluated using total RNA obtained from Parsortix harvests of blood from metastatic breast cancer (MBC) patients or healthy volunteers (HVs). RESULTS: Using genes with low expression in WBC RNA and/or in unspiked Parsortix harvests from HVs, the assay distinguished between the different breast cancer and ovarian cancer cell lines with as little as 20 pg of total RNA (equivalent to a single cell) in the presence of 1 ng of WBC RNA. Single cultured cells spiked into Parsortix harvests from 10 mL of HV blood were also detected and distinguished from each other. CVs from repeatability experiments were less than 20%. Hierarchical clustering of clinical samples differentiated most MBC patients from HVs. CONCLUSION: HyCEAD/Ziplex provided sensitive quantification of expression of 72 genes from 20 pg of total RNA from cultured tumor cell lines or from single cultured tumor cells spiked into lysates from Parsortix harvests of HV blood. The HyCEAD/Ziplex platform enables the quantification of selected genes in the presence of residual nucleated blood cells in Parsortix harvests. The HyCEAD/Ziplex platform is an effective tool for multiplexed molecular characterization of mRNA in small numbers of tumor cells harvested from blood.

Transcriptome Profiling of Circulating Tumor Cells to Predict Clinical Outcomes in Metastatic Castration-Resistant Prostate Cancer.

The clinical utility of circulating tumor cells (CTC) as a non-invasive multipurpose biomarker is broadly recognized. The earliest methods for enriching CTCs from whole blood rely on antibody-based positive selection. The prognostic utility of CTC enumeration using positive selection with the FDA-approved CellSearchTM system has been demonstrated in numerous studies. The capture of cells with specific protein phenotypes does not fully represent cancer heterogeneity and therefore does not realize the prognostic potential of CTC liquid biopsies. To avoid this selection bias, CTC enrichment based on size and deformability may provide better fidelity, i.e., facilitate the characterization of CTCs with any phenotype. In this study, the recently FDA-approved Parsortix® technology was used to enrich CTCs from prostate cancer (PCa) patients for transcriptome analysis using HyCEADTM technology. A tailored PCa gene panel allowed us to stratify metastatic castration-resistant prostate cancer (mCRPC) patients with clinical outcomes. In addition, our findings suggest that targeted CTC transcriptome profiling may be predictive of therapy response.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Diabetes mellitus is a potential risk factor for aseptic loosening around hip and knee arthroplasty.

BACKGROUND: Aseptic loosening is a leading cause of revision following total hip and knee arthroplasty which is caused by chronic inflammation around the prosthesis. Diabetes mellitus causes systemic inflammatory changes which could increase the risk of aseptic loosening. This study investigated the association between diabetes mellitus and aseptic loosening around hip and knee arthroplasty. METHODS: A case-control study was conducted at a single arthroplasty centre over the seven-year period of January 2015 to December 2021. Cases were defined as any adult patient undergoing revision hip or knee arthroplasty for aseptic loosening. Controls were randomly selected patients undergoing primary total hip or knee arthroplasty during the same period at a 1:4 ratio. Risk factors were compared between the two groups. RESULTS: A total of 440 patients were included in our study - 88 in the aseptic loosening group and 352 patients in the control group. The odds of having diabetes mellitus in the aseptic loosening group was 2.78 (95%CI 1.31-5.92, P = 0.01). Other risk factors were not significantly different between the two groups. CONCLUSIONS: The incidence of diabetes mellitus is significantly greater in patients undergoing revision arthroplasty for aseptic loosening. Further research is required to explore whether this association is indeed causative.

Laparoscopic removal of Essure device techniques, perioperative findings and evaluation of patient's satisfaction: A case series.

OBJECTIVE: To evaluate perioperative outcomes and symptom resolution in women undergoing Essure removal. METHODS: Single centre cohort study at a large University Teaching Hospital in the UK. Symptoms and Quality of life (QoL) were assessed using a standardised questionnaire administered at 6-months and up to 10-years following removal of Essure® devices. RESULTS: 61 women underwent surgical removal of Essure® devices representing 61/1087 (5.6%) of all women undergoing this hysteroscopic form of sterilization. Patients who had Essure® removal were more likely to have a previous caesarean section [38% vs 18%; OR 0.4, 95% CI 0.2-0.6; P <0.001]. The main indication for removal was pelvic pain (49/61, 80%). Removal was achieved by laparoscopic bilateral salpingectomy/cornuectomy (44/61,71%) or hysterectomy (17/61, 28%). At surgery, perforated device was seen in 4/61 (7%) cases. 26/61 (43%) of patients had concomitant pelvic pathology; 12/26 (46%) had fibrous adhesions, 8/26 (31%) endometriosis, 4/26 (15%) adenomyosis, and 2/26 (8%) had endometriosis and adenomyosis. 10 patients underwent further procedure following removal for ongoing symptoms. 55/61 women (90%) responded to the post removal symptom questionnaire. Most respondents to the quality of life survey 42/55 (76%) reported total or some improvement. 42/53 (79%) had total or some improvement in pelvic pain, 9/13 (69%) in mental health and 10/12 (83%) in bleeding. CONCLUSION: Surgical removal of Essure® devices appears to improve symptoms thought to be attributable to the presence of these uterine implants in most women. However, patients should be counselled that one in five women may experience persistent or even worsening symptoms.