Targeted protein degradation via intramolecular bivalent glues.

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)-bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1-4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change 'glues' BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target-ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4-IBG1-DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.

Associations of preoperative anemia and postoperative hemoglobin values with hospital costs in total knee arthroplasty (TKA).

BACKGROUND: Total knee arthroplasty are among the most frequently conducted surgeries, due to an aging society. Since hospital costs are subsequently rising, adequate preparation of patients and reimbursement becomes more and more important. Recent literature revealed anemia as a risk factor for enhanced length of stay (LOS) and complications. This study analyzed whether preoperative hemoglobin (Hb) and postoperative Hb were associated with total hospital costs and general ward costs. METHODS: The study comprised 367 patients from a single high-volume hospital in Germany. Hospital costs were calculated with standardized cost accounting methods. Generalized linear models were applied to account for confounders, such as age, comorbidities, body mass index, insurance status, health-related quality of life, implant types, incision-suture-time and tranexamic acid. RESULTS: Preoperative anemic women had 426 Euros higher general ward costs (p < 0.01), due to increased LOS. For men, 1 g/dl less Hb loss between the preoperative value and the value before discharge reduced total costs by 292 Euros (p < 0.001) and 161 Euros fewer general ward costs (p < 0.001). Total hospital costs were reduced by 144 Euros with 1 g/dl higher Hb on day 2 postoperatively for women (p < 0.01). CONCLUSION: Preoperative anemia was associated with increased general ward costs for women and Hb loss with decreasing total hospital costs for men and women. Cost containment, especially reduced utilization of the general ward, may be feasible with the correction of anemia for women. Postoperative Hb values may be a factor for adjustments of reimbursement systems. LEVEL OF EVIDENCE: Retrospective cohort study, III.

The impact of primary patella resurfacing on health-related quality of life outcomes and return to sport in total knee arthroplasty (TKA).

INTRODUCTION: Primary patella resurfacing (PPR) in primary total knee arthroplasty (TKA) is a topic without clear clinical evidence. Using Patient Reported Outcome Measurements (PROM), previous work found TKA patients without PPR to have more pain postoperatively, but little is known whether this may impede patients from returning to their usual leisure sport. This observational study aimed at evaluating the treatment effect of PPR, with PROMs and return to sport (RTS). MATERIALS AND METHODS: 156 primary TKA patients were retrospectively included from August 2019 to November 2020, from a single hospital in Germany. PROMs were measured with the Western Ontario McMaster University Osteoarthritis Index (WOMAC) and the EuroQoL Visual Analog Scale (EQ-VAS), preoperatively and 1 year postoperatively. Leisure sport with three levels of intensity (never, sometimes, regular) were requested. The treatment effect of PPR was evaluated with a difference-in-difference (DiD) approach, with several confounders. RESULTS: Descriptively, the mean WOMAC total score and the mean WOMAC pain score were postoperatively better with PPR, ( - 4.8 points, - 1.1 points), then without PPR. The mean improvements of the WOMAC total score were better with PPR ( - 7.8 points). Mean improvements for the WOMAC pain score were also better with PPR ( - 1.2 points). Mean EQ-VAS were postoperatively similar, and the mean improvements were better with PPR (3.4 points). Rate of RTS was 93% for patients with PPR and 95% for patients without PPR. The DiD revealed minor differences in PROMs and RTS, not to result in statistically significant treatment effects. CONCLUSIONS: There was no treatment effect for TKA with PPR, regarding PROMs and RTS, and descriptive differences were below published thresholds for clinical relevance. Rate of RTS was high for all patients, regardless of PPR. For the two endpoint categories, there was no measurable advantage of TKA with PPR over TKA without PPR.

The impact of the COVID-19 pandemic on processes, resource use and cost in palliative care.

BACKGROUND: The COVID-19 pandemic impacts on working routines and workload of palliative care (PC) teams but information is lacking how resource use and associated hospital costs for PC changed at patient-level during the pandemic. We aim to describe differences in patient characteristics, care processes and resource use in specialist PC (PC unit and PC advisory team) in a university hospital before and during the first pandemic year. METHODS: Retrospective, cross-sectional study using routine data of all patients cared for in a PC unit and a PC advisory team during 10-12/2019 and 10-12/2020. Data included patient characteristics (age, sex, cancer/non-cancer, symptom/problem burden using Integrated Palliative Care Outcome Scale (IPOS)), information on care episode, and labour time calculated in care minutes. Cost calculation with combined top-down bottom-up approach with hospital's cost data from 2019. Descriptive statistics and comparisons between groups using parametric and non-parametric tests. RESULTS: Inclusion of 55/76 patient episodes in 2019/2020 from the PC unit and 135/120 episodes from the PC advisory team, respectively. IPOS scores were lower in 2020 (PCU: 2.0 points; PC advisory team: 3.0 points). The number of completed assessments differed considerably between years (PCU: episode beginning 30.9%/54.0% in 2019/2020; PC advisory team: 47.4%/40.0%). Care episodes were by one day shorter in 2020 in the PC advisory team. Only slight non-significant differences were observed regarding total minutes/day and patient (PCU: 150.0/141.1 min., PC advisory team: 54.2/66.9 min.). Staff minutes showed a significant decrease in minutes spent in direct contact with relatives (PCU: 13.9/7.3 min/day in 2019/2020, PC advisory team: 5.0/3.5 min/day). Costs per patient/day decreased significantly in 2020 compared to 2019 on the PCU (1075 Euro/944 Euro for 2019/2020) and increased significantly for the PC advisory team (161 Euro/200 Euro for 2019/2020). Overhead costs accounted for more than two thirds of total costs. Direct patient cost differed only slightly (PCU: 134.7 Euro/131.1 Euro in 2019/2020, PC advisory team: 54.4 Euro/57.3 Euro). CONCLUSIONS: The pandemic partially impacted on daily work routines, especially on time spent with relatives and palliative care problem assessments. Care processes and quality of care might vary and have different outcomes during a crisis such as the COVID-19 pandemic. Direct costs per patient/day were comparable, regardless of the pandemic.

Preoperative patients' health decrease moderately, while hospital costs increase for hip and knee replacement due to the first COVID-19 lockdown in Germany.

PURPOSE: The purpose of this study was a comparison between osteoarthritis patients with primary hip and knee replacements before, during and after the first COVID-19 lockdown in Germany. Patients' preoperative health status is assumed to decrease, owing to delayed surgeries. Costs for patients with osteoarthritis were assumed to increase, for example, due to higher prices for protective equipment. Hence, a comparison of patients treated before, during and after the first lockdown is conducted. METHODS: In total, 852 patients with primary hip or knee replacement were included from one hospital in Germany. Preoperative health status was measured with the WOMAC Score and the EQ-5D-5L. Hospital unit costs were calculated using a standardised cost calculation. Kruskal-Wallis tests and Chi-squared tests were applied for the statistical analyses. RESULTS: The mean of the preoperative WOMAC Score was slightly higher (p < 0.01) for patients before the first lockdown, compared with patients afterwards. Means of the EQ-5D-5L were not significantly different regarding the lockdown status (NS). Length of stay was significantly reduced by approximately 1 day (p < 0.001). Total inpatient hospital unit costs per patient and per day were significantly higher for patients during and after the first lockdown (p < 0.001). CONCLUSION: Preoperative health, measured with the WOMAC Score, worsened slightly for patients after the first lockdown compared with patients undergoing surgery before COVID-19. Preoperative health, measured using the EQ-5D-5L, was unaffected. Inpatient hospital unit costs increased significantly with the COVID-19 pandemic. LEVEL OF EVIDENCE: Retrospective cohort study, III.

COMPANION: development of a patient-centred complexity and casemix classification for adult palliative care patients based on needs and resource use - a protocol for a cross-sectional multi-centre study.

BACKGROUND: A casemix classification based on patients' needs can serve to better describe the patient group in palliative care and thus help to develop adequate future care structures and enable national benchmarking and quality control. However, in Germany, there is no such an evidence-based system to differentiate the complexity of patients' needs in palliative care. Therefore, the study aims to develop a patient-oriented, nationally applicable complexity and casemix classification for adult palliative care patients in Germany. METHODS: COMPANION is a mixed-methods study with data derived from three subprojects. Subproject 1: Prospective, cross-sectional multi-centre study collecting data on patients' needs which reflect the complexity of the respective patient situation, as well as data on resources that are required to meet these needs in specialist palliative care units, palliative care advisory teams, and specialist palliative home care. Subproject 2: Qualitative study including the development of a literature-based preliminary list of characteristics, expert interviews, and a focus group to develop a taxonomy for specialist palliative care models. Subproject 3: Multi-centre costing study based on resource data from subproject 1 and data of study centres. Data and results from the three subprojects will inform each other and form the basis for the development of the casemix classification. Ultimately, the casemix classification will be developed by applying Classification and Regression Tree (CART) analyses using patient and complexity data from subproject 1 and patient-related cost data from subproject 3. DISCUSSION: This is the first multi-centre costing study that integrates the structure and process characteristics of different palliative care settings in Germany with individual patient care. The mixed methods design and variety of included data allow for the development of a casemix classification that reflect on the complexity of the research subject. The consecutive inclusion of all patients cared for in participating study centres within the time of data collection allows for a comprehensive description of palliative care patients and their needs. A limiting factor is that data will be collected at least partly during the COVID-19 pandemic and potential impact of the pandemic on health care and the research topic cannot be excluded. TRIAL REGISTRATION: German Register for Clinical Studies trial registration number: DRKS00020517 .

Preoperative predictors of health-related quality of life changes (EQ-5D and EQ VAS) after total hip and knee replacement: a systematic review.

BACKGROUND: Patient-reported outcomes are of ever-increasing importance in medical decision-making. The EQ-5D is one of the generic instruments measuring health-related quality of life (HRQoL) in arthroplasty. This review aimed to identify possible predictors of HRQoL changes for patients undergoing total knee replacements (TKR) or total hip replacements (THR). METHODS: A systematic literature review according to the PRISMA guidelines was conducted, searching several databases. Preoperative to postoperative HRQoL changes were evaluated in patients undergoing THR or TKR, using the EQ-5D visual analog scale (VAS) or the preference-based EQ-5D Index were evaluated. Articles were considered with prospectively or retrospectively collected data, as well as registry data, each with statistical analyses of patient-related factors. RESULTS: Eight hundred eighty-two articles were found, of which 21 studies met the inclusion criteria. Predictors were distinguished in alterable and non-alterable ones. The EQ-5D Index indicated a tendency towards beneficial improvements for patients with a high body mass index (BMI) (> 40) and no significant results for the VAS. Additionally, one study found that patient education and preoperative physiotherapy appeared to enhance HRQoL. Some evidence indicated that male gender was negatively associated with changes in the VAS and the EQ-5D Index, but one study reported the opposite. Changes in VAS and EQ-5D Index were lower for older patients, whereas a higher educational level seemed to be advantageous. A high Charnley class led to deteriorating changes in VAS, although a high Kellgren Lawrence classification was positively associated with the EQ-5D Index, in a limited number of studies. For all results, clinical relevance was calculated differently and mainly reported as uncertain or small. CONCLUSIONS: The literature on this topic was weak and offers only limited guidance. Results for alterable predictors, such as the BMI, indicated valuable improvements for highly obese patients. Further, high-quality research is required to support medical decision-making. LEVEL OF EVIDENCE: Level IV, according to the OCEBM Levels of Evidence Working Group.