The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

1-Year pullout strength and degradation of ultrasound welded vs tapped craniomaxillofacial fixation screws

A knowledge on the pullout forces of degradable craniomaxillofacial screws is essential in designing pediatric cranial implants. Herein, four non-identical commercially available screws composed of different aliphatic polyesters were fixated to 3D-printed poly(L-lactide) screw hole test rig and onto a bone substitute material using manual tapping and ultrasonic welding fixation techniques. A method for mechanical testing was developed to determine and compare their quasi-static pullout strength. The degradation of the screws was followed for up to one year in three different degrading environments. While the screw size influences the initial pullout force, the degrading environment, size, and screw composition determine the degradation rate which in turn influences the pullout force over time. Given the limited availability of standard methods, the method developed herein can be used in determining the pullout forces of degradable craniomaxillofacial screws and comparing the effectiveness of various screw insertion techniques

High rates of implant fracture of a generic polished tapered femoral stem

OBJECTIVES: Cemented polished tapered stems have demonstrated excellent long-term outcomes. Based on this concept, many generic tapered stems have been released into the market. The aim of this study was to evaluate implant-related complications of 1 specific stem design. METHODS: Between 2010 and 2017, 315 total hip replacements were performed using a Fortress stem (Biotechni, La Ciotat, France). Patient records and radiology were retrospectively reviewed for implant-related complications. A failure analysis was performed on the failed Fortress stems in order to determine the cause of premature failure. RESULTS: 7 (2.2%) patients sustained a fracture of the neck of the implant after a mean of 5 years (range 50-81 months). All fractures were atraumatic, originating at the introducer inlet of the stem. All fractured occurred in obese patients (BMI >33 kg/m2) with a small sized prosthesis. Of these, there were 5 135° and 2 125° stems. Fracture risk was 23% (7/30) for patients with a small sized stem and a BMI >30 kg/m2. All cases were revised using a cement-in-cement technique or a cementless modular revision stem. Failure analysis on the retrieved stems revealed a stress riser at the bottom of the introducer inlet. CONCLUSIONS: An alarmingly high rate of early implant fractures was seen using this specific type of cemented stem, particularly when using smaller implant sizes in obese patients. Although based on a proven design, a specific modification led to a stress riser in the neck area, which resulted in a high incidence of implant failure. This series underlines the importance of a stepwise introduction into the market of new orthopaedic devices even when based on established concepts. Generic stems may not behave as the original stem upon which it was designed.status: publishe

A decade of commitment to hospital quality of care : overview of and perceptions on multicomponent quality improvement policies involving accreditation, public reporting, inspection and pay-for-performance

Background Quality improvement (QI) initiatives such as accreditation, public reporting, inspection and pay-for-performance are increasingly being implemented globally. In Flanders, Belgium, a government policy for acute-care hospitals incorporates aforementioned initiatives. Currently, questions are raised on the sustainability of the present policy. Objective First, to summarise the various initiatives hospitals have adopted under government encouragement between 2008 and 2019. Second, to study the perspectives of healthcare stakeholders on current government policy. Methods In this multi-method study, we collected data on QI initiative implementation from governmental and institutional sources and through an online survey among hospital quality managers. We compiled an overview of QI initiative implementation for all Flemish acute-care hospitals between 2008 (n = 62) and 2019 (n = 53 after hospital mergers). Stakeholder perspectives were assessed via a second survey available to all healthcare employees and a focus group with healthcare policy experts was consulted. Variation between professions was assessed. Results QI initiatives have been increasingly implemented, especially from 2016 onwards, with the majority (87%) of hospitals having obtained a first accreditation label and all hospitals publicly reporting performance indicators, receiving regular inspections and having entered the pay-for-performance initiative. On the topic of external international accreditation, overall attitudes within the survey were predominantly neutral (36.2%), while 34.5% expressed positive and 29.3% negative views towards accreditation. In examining specific professional groups in-depth, we learned 58% of doctors regarded accreditation negatively, while doctors were judged to be the largest contributors to quality according to the majority of respondents. Conclusions Hospitals have demonstrated increased efforts into QI, especially since 2016, while perceptions on currently implemented QI initiatives among healthcare stakeholders are heterogeneous. To assure quality of care remains a top-priority for acute-care hospitals, we recommend a revision of the current multicomponent quality policy where the adoption of all initiatives is streamlined and co-created bottom-up

The History of Quality: From an Eye for an Eye, Through Love, and Towards a Multidimensional Concept for Patients, Kin, and Professionals

In ancient civilizations, poor quality was dealt with according to the principle of "an eye for an eye." In the modern era we have learned from industry what quality really is. Quality includes standards, protocols, system thinking, and an understanding of variation to ensure good outcomes. In the post-COVID era, quality is not all about predefined specifications but rather about relationships and even love. Quality can now be defined as multidimensional, including person-centered care for patients, kin, and providers. Care should be safe, efficient, effective, timely, equitable, and eco-friendly. High quality is only possible if we include core values of dignity and respect, holistic care, partnership, and kindness with compassion in our daily practice for every stakeholder at every managerial and policy level.Patient summary: Quality of care is a multidimensional concept in which personcentered care is central. The care a patient receives should be safe, efficient, effective, timely, equitable, and eco-friendly. Attention should be given to dignity, respect, kindness, and compassion. There should be a holistic approach that includes partnership with all stakeholders. The only acceptable level of quality a professional should provide is the level they would accept if their loved one were to be the next patient. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved

The cost of a first and second hospital-wide accreditation in Flanders, Belgium

Background Hospital accreditation is a popular and widely used quality control and improvement instrument. Despite potential benefits, ques-tions are raised whether it constitutes appropriate use of hospitals' limited financial resources. Objective This study aims to calculate the cost of preparing for and undergoing a first and second accreditation by the Joint Commission International or Qualicor Europe in acute-care hospitals. Method All (n = 53) acute-care hospitals in Flanders (Belgium) were invited to participate and report on the costs in preparing for and undergoing a first and/or second accreditation cycle. To measure costs, a questionnaire with six domains and 90 questions was developed based on literature review, policy documents and a multidisciplinary expert group. All costs were recalculated to 2020 euro to correct for inflation and reported as medians with interquartile range. Results A total of 25 hospitals (47%) participated in the study. Additional investments and direct operational costs for a first accreditation cycle amounted to 879.45 euro (interquartile range: 794.81) per bed and 3.8 full-time equivalent (FTE) per hospital additional new staff members were recruited for coordination and implementation of the trajectory. A second accreditation survey costed remarkably less with a total cost of extra investments and direct operational cost of 222.88 euro (interquartile range: 244.04) per bed and less investment in additional staff (1.50 FTE). Most of the costs were situated in consulting costs and investments in infrastructure. The median total extra cost (direct operational cost and additional investments) amounted to 0.2% of the hospital's operating income for a first accreditation cycle and 0.05% for a second cycle. Conclusion A first accreditation cycle requires a strong financial commitment of hospitals, as many costs result from the preparation in the years prior to an accreditation survey. A second survey is less expensive for hospitals, but still requires a considerable effort in terms of budget and staff. Policy makers should be aware of these significant costs as hospitals are operating with public resources and budget is scarce. The identification of these costs is a necessary building block to evaluate cost-effectiveness of accreditation versus other quality improvement systems and the continuation of these accreditation systems and their costs needs further study and a thorough debate

Continuous Shoulder Activity Tracking after Open Reduction and Internal Fixation of Proximal Humerus Fractures

Postoperative shoulder activity after proximal humerus fracture treatment could influence the outcomes of osteosynthesis and may depend on the rehabilitation protocol. This multi-centric prospective study aimed at evaluating the feasibility of continuous shoulder activity monitoring over the first six postoperative weeks, investigating potential differences between two different rehabilitation protocols. Shoulder activity was assessed with pairs of accelerometer-based trackers during the first six postoperative weeks in thirteen elderly patients having a complex proximal humerus fracture treated with a locking plate. Shoulder angles and elevation events were evaluated over time and compared between the two centers utilizing different standard rehabilitation protocols. The overall mean shoulder angle ranged from 11° to 23°, and the number of daily elevation events was between 547 and 5756. Average angles showed longitudinal change <5° over 31 ± 10 days. The number of events increased by 300% on average. Results of the two clinics exhibited no characteristic differences for shoulder angle, but the number of events increased only for the site utilizing immediate mobilization. In addition to considerable inter-patient variation, not the mean shoulder angle but the number of elevations events increased markedly over time. Differences between the two sites in number of daily events may be associated with the different rehabilitation protocols