Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells.

Introduction: Total hip arthroplasty (THA) surgeries are expected to exponentially increase in the upcoming years, likely because of the overall broader indication of THAs. With these developments, an increasing number of younger (< 50 years) and active patients will receive surgical interventions, and expectations for an active lifestyle will accordingly increase. In addition, surgeons now have a growing array of techniques and implant materials to choose from. Despite these developments, evidence to provide the best standard-of-care to patients with high expectations for return to sports (RTS) is scarce and urgently needed. What recommendations do arthroplasty surgeons currently make to patients with high return to sports expectations, what factors may influence their recommendations and what surgical techniques and implant specifications are considered favorable in the treatment of patients with a more active lifestyle? This study was conducted to analyze the current recommendations, patient assessment, and patient counseling after THA to identify trends and relevant factors for surgical decision-making in patients with high-RTS expectations.Material and methods: We designed a questionnaire comprising five general items and 19 specific items that included 46 sub-items for hip arthroplasty and conducted a survey among 300 German surgeons specialized in arthroplasty at the German Arthroplasty Society (AE) to assess expert opinions, recommendations, surgical decision-making, and patient counseling for patients with high expectations for RTS after THA.Results: The majority of surgeons (81.9%) were in favor of RTS after THA. Risks associated with sports after THA were considered minimal (1%), with periprosthetic fractures ranking highest, followed by hip dislocation and polyethylene wear. Some surgical decision-making was influenced by high-RTS expectations in regard to implant fixation, stem type, femoral head diameter, and bearing-surface tribology. We observed an increasingly liberal counseling of patients for high-impact sports.Conclusion: With the improvement of implants and surgical techniques, surgeons are more willing to encourage patients to adopt a more active lifestyle. However, the true long-term limitations need further investigation in future studies.Level of evidence: 5 Expert opinions.

Purpose: Even though spinal infections are associated with high mortality and morbidity, their therapy remains challenging due to a lack of established classification systems and widely accepted guidelines for surgical treatment. This study’s aim therefore was to propose a comprehensive classification system for spinal instability based on the Spinal Instability Neoplastic Score (SINS) aiding spine surgeons in choosing optimal treatment for spontaneous spondylodiscitis. Methods: Patients who were treated for spontaneous spondylodiscitis and received computed tomography (CT) imaging were included retrospectively. The Spinal Instability Spondylodiscitis Score (SISS) was developed by expert consensus. SINS and SISS were scored in CT-images by four readers. Intraclass correlation coefficients (ICCs) and Fleiss’ Kappa were calculated to determine interrater reliabilities. Predictive validity was analyzed by cross-tabulation analysis. Results: A total of 127 patients were included, 94 (74.0%) of which were treated surgically. Mean SINS was 8.3 ± 3.2, mean SISS 8.1 ± 2.4. ICCs were 0.961 (95%-CI: 0.949–0.971) for total SINS and 0.960 (95%-CI: 0.946–0.970) for total SISS. SINS yielded false positive and negative rates of 12.5% and 67.6%, SISS of 15.2% and 40.0%, respectively. Conclusion: We show high reliability and validity of the newly developed SISS in detecting unstable spinal lesions in spontaneous spondylodiscitis. Therefore, we recommend its use in evaluating treatment choices based on spinal biomechanics. It is, however, important to note that stability is merely one of multiple components in making surgical treatment decisions.

(1) Background: Improved surgical techniques and implants in total knee arthroplasty (TKA) have led to broader indications for surgical interventions of osteoarthritis of the knee. There is a growing young and active patient subgroup with high return to sports (RTS) expectations after TKA. The current lack of evidence regarding RTS capacity in this patient cohort, requires the consolidation of experts’ opinions and experiences to address the special needs among these patients. The aim of this study was to assess current expert opinions in regard to preoperative patient assessment, surgical technique and decision-making and patient counseling for these patients. (2) Methods: We performed a survey among surgeons specialized in arthroplasty with a questionnaire designed to assess current recommendations, surgical techniques, and implant preferences as well as patient counseling in patients with high expectations for RTS after TKA. (3) Results: The majority of surgeons are in favor of return to low-impact sports after TKA within 3 to 6 months. Some even recommend return to high-impact sports. Despite improvement of surgical techniques and implants, we observed no clear preference for a single surgical technique or implant specification in active patients. (4) Conclusions: Current evidence for sports-associated complications after TKA is scarce. Despite a growing array of surgical techniques and implants, the available literature is still controversial with no single surgical technique or TKA design distinguishing itself clearly from others. Surgeons’ recommendations are mostly based on their experience and training. Nonetheless, we observed growing faith in modern implants with some surgeons even recommending high-impact sports after TKA.

Gas in the intervertebral disc is mainly associated with degenerative disc diseases and experts generally assume that it is unlikely in spinal infection. However, large-scale studies supporting this notion are lacking, which is why our study’s aim was to analyze the prevalence of and factors associated with the occurrence of gas in patients with spontaneous spondylodiscitis. Patients presenting with spontaneous spondylodiscitis from 2006 to 2020 were included retrospectively. Exclusion criteria were previous interventions in the same spinal segment and missing imaging data. Clinical data were retrieved from electronic medical reports. Computed tomography (CT) scans were evaluated for the presence of intervertebral gas. Causative pathogens were identified from CT-guided biopsy, open biopsy, intraoperative tissue samples, and/or blood cultures. 135 patients with a mean age of 66.0 ± 13.7 years were included. In 93 patients (68.9%), a causative pathogen was found. Intervertebral gas was found in 31 patients (23.0%) in total and in 19 patients (20.4%) with positive microbiology. Patients with gas presented with significantly higher body temperatures (37.2 ± 1.1 vs. 36.8 ± 0.7 °C, p = 0.044) and CRP levels (134.2 ± 127.1 vs. 89.8 ± 97.3 mg/L, p = 0.040) on admission. As a considerable number of patients with spondylodiscitis showed intervertebral gas formation, the detection of intervertebral gas is not suited to ruling out spondylodiscitis but must be interpreted in the context of other imaging and clinical findings, especially in elderly patients.