Virtual Reality for Emergency Medicine Training in Medical School: Prospective, Large-Cohort Implementation Study.

BACKGROUND: Virtual reality (VR)-based simulation is being increasingly used to train medical students in emergency medicine. However, because the usefulness of VR may depend on various factors, the best practices for implementing this technology in the medical school curriculum are yet to be determined. OBJECTIVE: The overall objective of our study was to assess the perceptions of a large cohort of students toward VR-based training and to identify the associations between these attitudes and individual factors, such as gender and age. METHODS: The authors implemented a voluntary, VR-based teaching session in the emergency medicine course at the Medical Faculty in Tübingen, Germany. Fourth-year medical students were invited to participate on a voluntary basis. Afterward, we asked the students about their perceptions, collected data on individual factors, and assessed the test scores achieved by them in the VR-based assessment scenarios. We used ordinal regression analysis and linear mixed-effects analysis to detect the impact of individual factors on the questionnaire answers. RESULTS: A total of 129 students participated in our study (mean age 24.7, SD 2.9 years; n=51, 39.8% male; n=77, 60.2% female). No student had previously used VR for learning, and only 4.7% (n=6) of the students had prior experience with VR. Most of the students agreed that VR can convey complex issues quickly (n=117, 91%), that VR is a useful addition to mannequin-based courses (n=114, 88%) or could even replace them (n=93, 72%), and that VR simulations should also be used for examinations (n=103, 80%). However, female students showed significantly less agreement with these statements. Most students perceived the VR scenario as realistic (n=69, 53%) and intuitive (n=62, 48%), with a relatively lower agreement for the latter among female respondents. We found high agreement among all participants (n=88, 69%) for immersion but strong disagreement (n=69, 54%) for empathy with the virtual patient. Only 3% (n=4) of the students felt confident regarding the medical content. Responses for the linguistic aspects of the scenario were largely mixed; however, most of the students were confident with the English language (not native) scenarios and disagreed that the scenario should be offered in their native language (female students agreed more strongly than male students). Most of the students would not have felt confident with the scenarios in a real-world context (n=69, 53%). Although physical symptoms during VR sessions were reported by 16% (n=21) of the respondents, this did not lead to the termination of the simulation. The regression analysis revealed that the final test scores were not influenced by gender, age, or prior experience in emergency medicine or with virtual reality. CONCLUSIONS: In this study, we observed a strong positive attitude in medical students toward VR-based teaching and assessment. However, this positivity was comparatively lower among female students, potentially indicating that gender differences need to be addressed when VR is implemented in the curriculum. Interestingly, gender, age, or prior experience did not influence the final test scores. Furthermore, confidence regarding the medical content was low, which suggests that the students may need further training in emergency medicine.

Atrial fibrillation and anticoagulation are associated with hospitalisations in patients with end-stage kidney disease on haemodialysis: a prospective population-based cohort study.

BACKGROUND: Patients with end-stage kidney disease on haemodialysis suffer from frequent complications requiring hospitalisation. Atrial fibrillation is a burdensome comorbidity amongst patients on haemodialysis. We aimed to assess frequency, reasons, and duration of hospitalisations in haemodialysis patients and their association with atrial fibrillation and anticoagulation. METHODS: Prevalent patients with end-stage kidney disease on haemodialysis were recruited into a prospective cohort study and observed for a median observation time of 3.4 years. Hospitalisations were recorded from discharge letters, medical records, and patient interviews. The association of atrial fibrillation, anticoagulation, and time-in-therapeutic range of vitamin K antagonist treatment with hospitalisations was analysed using negative binomial regression. RESULTS: Out of 625 patients, 238 (38.1%) had atrial fibrillation. Median number of hospitalisations per patient was 3.0 (1.0-5.0). Incidence rate of hospitalisation was 1.7 per patient-year in all and 1.9 in atrial fibrillation patients, median duration per hospitalisation was 7.9 (4.8-12.9) and 8.8 (5.7-13.3) days, respectively. Most frequent reasons for hospitalisation were vascular access complication/intervention (11.7%) and infection/fever (11.4%), while bleeding events comprised 6.0% of all hospitalisations. Atrial fibrillation patients had 27% higher risk of hospitalisation than patients without atrial fibrillation (incidence rate ratio [IRR] 1.27, 95% confidence interval [CI] 1.10-1.47). In atrial fibrillation patients, anticoagulation (enoxaparin or phenprocoumon, 41.6% of AF patients) was associated with increased risk of all-cause (IRR 1.38, 95%CI 1.14-1.69) and bleeding-related hospitalisation (IRR 1.96, 95%CI 1.06-3.63). There was no association between anticoagulation and stroke-related hospitalisation. In atrial fibrillation patients on phenprocoumon, increasing time-in-therapeutic range was associated with decreased risk of all-cause (IRR 0.35, 95%CI 0.14-0.87), but not bleeding-related hospitalisation (IRR 0.13, 95%CI 0.01-1.38). CONCLUSION: In haemodialysis patients, presence of atrial fibrillation and, among those with atrial fibrillation, anticoagulation were associated with higher risk of all-cause hospitalisation, including bleeding-related hospitalisation in the latter. Increasing time-in-therapeutic range in patients on vitamin K antagonist treatment was associated with decreased risk of all-cause, but not bleeding-related hospitalisation.

The influence of migration of the exeter V40 stem on patient reported outcome measures: a 2-year follow-up of 112 total hip arthroplasties using radiostereometric analysis.

PURPOSE: The cemented Exeter V40 stem is known to migrate distally. Several previous studies have reported on the extent of stem migration and its influence on clinical outcome. However, no studies have investigated the influence of stem migration on Patient Reported Outcome Measures (PROM). METHODS: One hundred and twelve total hip arthroplasties (THA) were included in a 2-year follow-up using Radiostereometric Analysis (RSA). Patients were evaluated using the Oxford Hip Score (OHS) and EQ-5D-3L PROMs. The purpose of this study was to assess the influence of stem migration, measured by Maximum Total Point Motion (MTPM), on the 2-year postoperative score (OHS and EQ-5D). Furthermore, the influence of pre-operative PROM, age, gender, acetabular component and BMI was associated with the 2-year postoperative OHS and EQ-5D scores. RESULTS: MTPM was a non-significant predictor of the 2-year postoperative OHS (regression coefficient (B) = - 2.38 (CI - 5.44; .69)) and of the 2-year postoperative EQ-5D (B = - .01 (CI - .04; .02)). The only significant predictor of the 2-year postoperative OHS and 2-year postoperative EQ-5D was gender (B = 8.71 (CI 3.52; 13.90)) and (B = .13 (CI .07; .18)), respectively. CONCLUSION: Stem migration did not significantly influence PROMs at 2 years post-operatively. Using a patient-focused approach, our results seem to corroborate results reported by previous studies, showing that slow migration of the Exeter V40 stem does not seem to influence the clinical outcome.

Effects of gait adaptability training on falls and fall-related fractures in older adults: a systematic review and meta-analysis.

OBJECTIVE: falls among older adults are common and can have devastating consequences. A novel task-specific exercise modality, gait adaptability training (GAT), has shown promising preventive effects. This systematic review and meta-analysis synthesise the evidence regarding GATs effect on falls and fall-related fractures in community-dwelling older adults. METHODS: electronic databases (PubMed, EMBASE, CINAHL, CENTRAL) were systematically searched from inception to 18 June 2020. Additional sources include searches of trial registrations, manual screening of reference lists and requests to experts. We included randomised controlled trials (RCTs) evaluating the effect of GAT on falls with at least 6-month follow-up among community-dwelling people aged 60+ years. Two reviewers independently screened studies against eligibility criteria, extracted relevant information and appraised studies for bias. Random-effects meta-analytic models were employed to pool effect estimates. RESULTS: eleven studies with 1,131 participants were included. A meta-analysis in which an outlier study was excluded showed that GAT reduces fall rates by 42% (incidence rate ratio 0.58, 95% confidence interval [CI] 0.39-0.81, I2 = 0.00%; moderate certainty; seven RCTs). Moreover, proportion with fall-related fractures and proportion of fallers was reduced by 81% (risk ratio [RR] 0.19, 95% CI 0.06-0.56, I2 = 0.00%; very low certainty; two RCTs) and 43% (RR 0.57, 95% CI 0.4-to 0.8, I2 = 47.08%; low certainty; 11 RCTs), respectively. CONCLUSIONS: our results show that GAT significantly reduces the number of falls and prevents fall-related fractures in older community dwellers. GAT is a promising and feasible exercise modality; however, studies of high quality should be conducted to support a robust conclusion. PROTOCOL REGISTRATION: PROSPERO; CRD42020191051.

Importance of diagnostics and risk of secondary malignancies in primary cutaneous lymphomas.

BACKGROUND AND OBJECTIVES: Primary cutaneous lymphomas (PCL) often strongly differ in clinical behavior and prognosis from systemic lymphomas of the same histopathologic type. The aim of the study was to investigate the distribution of PCL subtypes, the average time from disease manifestation to diagnosis, the importance of diagnostic procedures, the occurrence of secondary malignancies and the different treatment modalities. PATIENTS AND METHODS: Retrospective analysis of 152 patients with PCL examined at the Department of Dermatology of the University Hospital Tübingen from 2010-2012. RESULTS: 105 patients with CTCL (69.1 %) and 47 patients with CBCL (30.9 %) were included. The average time from disease manifestation to diagnosis was four years. The most common diagnosed lymphoma was mycosis fungoides (MF) (47.4 %). First-line therapies here include phototherapy only (psoralen-UV-A [PUVA], n = 48; UVB 311 nm, n = 7) or combination therapies primarily phototherapy with systemic retinoids (n = 18). Most frequent second-line therapy was interferon (INF)-α plus PUVA (n = 15). The outcome was favorable (45.2 % remission, 28.6 % stable disease, 22.6 % progressive disease). Malignant comorbidities were observed more frequently compared to a healthy control group. CONCLUSIONS: The diagnosis of lymphoma often takes several years. The value of staging procedures is still low and the treatment modalities for MF in earlier stages are mainly based on phototherapy.

Stellenwert diagnostischer Verfahren und Risiko von Zweittumoren bei primär kutanen Lymphomen.

HINTERGRUND: Primär kutane Lymphome (PCL) unterscheiden sich oft stark im klinischen Verhalten und in der Prognose von systemischen Lymphomen des gleichen histopathologischen Typs. Ziel der Studie war es, die Verteilung der PCL-Subtypen, die Zeitspanne von der Krankheitsmanifestation bis zur Diagnosestellung, den Stellenwert diagnostischer Verfahren, das Auftreten von Zweittumoren und die verschiedenen Behandlungsmodalitäten im Rahmen des Krankheitsverlaufs zu untersuchen. PATIENTEN UND METHODIK: Retrospektive Analyse von 152 Patienten mit PCL, die von 2010-2012 an der Universitäts-Hautklinik Tübingen behandelt wurden. ERGEBNISSE: 105 Patienten mit primär kutanem T-Zell-Lymphom (CTCL) (69,1 %) und 47 Patienten mit primär kutanem B-Zell-Lymphom (CBCL) (30,9 %) wurden eingeschlossen. Die Zeitspanne von der Krankheitsmanifestation bis zur Diagnose betrug durchschnittlich vier Jahre. Mycosis fungoides (MF) (47,4 %) wurde am häufigsten diagnostiziert. Die First-Line-Therapien umfassten hier entweder eine alleinige Phototherapie (PUVA, n = 48; UVB 311 nm, n = 7) oder Kombinationstherapien (PUVA mit systemischen Retinoiden, n = 18). Häufigste Second-Line-Therapie war Interferon (INF)-α plus PUVA (n = 15). Der Behandlungsverlauf war insgesamt günstig (45,2 % Remission, 28,6 % stabile Erkrankung, 22,6 % Progress). Maligne Komorbiditäten wurden im Vergleich zu einer gesunden Vergleichsgruppe häufiger beobachtet. SCHLUSSFOLGERUNGEN: Bis zur Diagnosestellung der PCL dauert es oft mehrere Jahre. Der Wert der Staging-Verfahren ist gering. Die Behandlungsmodalitäten in früheren MF-Stadien basieren hauptsächlich auf der Phototherapie.

Retrieval of high-fidelity memory arises from distributed cortical networks.

Medial temporal lobe (MTL) function is well established as necessary for memory of facts and events. It is likely that lateral cortical regions critically guide cognitive control processes to tune in high-fidelity details that are most relevant for memory retrieval. Here, convergent results from functional and structural MRI show that retrieval of detailed episodic memory arises from lateral cortical-MTL networks, including regions of inferior frontal and angular gyrii. Results also suggest that recognition of items based on low-fidelity, generalized information, rather than memory arising from retrieval of relevant episodic details, is not associated with functional connectivity between MTL and lateral cortical regions. Additionally, individual differences in microstructural properties in white matter pathways, associated with distributed MTL-cortical networks, are positively correlated with better performance on a mnemonic discrimination task.

Anticoagulation in atrial fibrillation and end-stage kidney disease on hemodialysis: a meta-analysis of randomized trials comparing direct oral anticoagulants with vitamin K antagonists.

Background: Only small randomized trials have investigated the efficacy and safety of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) and end-stage kidney disease. Objectives: To perform a systematic review and meta-analysis comparing anticoagulation with DOACs to VKAs in patients with NVAF undergoing chronic hemodialysis. Methods: A systematic search using Medline, Web of Science, and Embase was performed. All randomized trials comparing DOACs with VKAs in patients with NVAF undergoing chronic hemodialysis were included. As primary endpoint, we analyzed all-cause mortality. As secondary endpoints, we investigated total bleeding events, life-threatening or major bleeding events, and thromboembolic events or stroke. We used the odds ratio as outcome measure and fitted a random-effects model due to the expected heterogeneity. Results: Three studies fulfilled the inclusion criteria comprising 383 patients (218 on apixaban or rivaroxaban, 165 on VKA). No significant difference between DOACs and VKAs regarding death (OR, 0.94; 95% CI, 0.55-1.63; p = .84), total bleedings (OR, 0.99; 95% CI, 0.63-1.54; p = .96) and life-threatening or major bleeding (OR, 0.65; 95% CI, 0.32-1.33, p = .24) was detected. There was a trend toward a reduction of thromboembolic events or stroke in patients receiving DOACs (OR, 0.39; 95% CI, 0.14-1.05; p = .06). Conclusion: Orally administered activated factor X inhibitors carried a similar risk of bleeding and death when compared with VKAs in patients with NVAF undergoing chronic hemodialysis. Moreover, there was a trend towards a reduction of thromboembolic events or stroke in patients receiving DOACs.

The substitute ENSO 16 has low impact on glucose metabolism in healthy humans: a randomized, double-blind, active-controlled, cross-over trial.

High sugar consumption is associated with cardiovascular diseases and diabetes. Current sugar substitutes may cause taste sensations and gastrointestinal symptoms. ENSO 16 is a combination of 16 different sugar substitutes and plant fibers and has been designed as a sugar alternative. The impact on plasma glucose metabolism as well as on gastrointestinal tolerance has not been investigated yet. 17 healthy participants were enrolled in this randomized, double-blind trial. Participants received a single oral dose of 30 g glucose or 30 g ENSO 16 and crossed over to the alternate treatment after a 7 day wash out period. The study endpoint was the effect on plasma glucose, insulin, C-peptide concentrations and gastrointestinal disorders. A questionnaire regarding gastrointestinal symptoms was used for individual subjective scoring. The mean baseline adjusted plasma glucose AUC0-180 min was significantly greater after glucose administration compared to ENSO 16 (n = 15, p = 0.0128, paired t-test). Maximum plasma glucose elevation over baseline was 117 mg*dl-1 and 20 mg*dl-1 after oral glucose or ENSO 16, respectively. Insulin and C-peptide AUC0-180 min were significantly greater after glucose compared to ENSO 16 intake (p < 0.01, Wilcoxon rank sum test). The mean maximal concentrations of plasma glucose, insulin and C-peptide after glucose intake were 1.5, 4.6 and 2.7-fold greater after glucose intake compared to ENSO 16 intake, respectively. Adverse reactions were mostly mild and not different between treatments. Conclusion. ENSO 16 has only a small impact on plasma glucose metabolism. This may be of interest in a dietary context and may help to reduce calory intake.Trail registration NCT05457400. First registration: 14/07/2022. https://clinicaltrials.gov/study/NCT05457400 .

Risk of Depression after Venous Thromboembolism in Patients with Hematological Cancer: A Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) may complicate the clinical course of cancer patients and add to their psychological burden. OBJECTIVES: We aimed to investigate the association between VTE and risk of subsequent depression in patients with hematological cancer. PATIENTS AND METHODS: We conducted a population-based cohort study using Danish national health registries. Between 1995 and 2020, we identified 1,190 patients with hematological cancer and incident VTE diagnosed within 6 months before to 1 year after cancer diagnosis. A comparison cohort of patients with hematological cancer without VTE (n = 5,325) was matched by sex, year of birth, cancer type, and year of cancer diagnosis. Patients were followed until diagnosis of depression, emigration, death, study end (2021), or for a maximum of 3 years. Depression was defined as hospital discharge diagnosis of depression or ≥1 prescription for antidepressants. Absolute risks of depression were computed with cumulative incidence functions, treating death as competing event. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using Cox proportional hazards regression models, adjusting for comorbidities. RESULTS: Depression was observed in 158 hematological cancer patients with and 585 without VTE. The 3-year absolute risks of depression were 13.3% (95% CI: 11.5-15.3%) in the VTE cancer cohort and 11.1% (95% CI: 10.3-12.0%) in the comparison cancer cohort, corresponding to a risk difference of 2.2% (95% CI: -1.8-6.5%). VTE was associated with an increased relative risk of depression (adjusted HR: 1.56, 95% CI: 1.28-1.90). CONCLUSION: VTE was associated with an elevated risk of subsequent depression in patients with hematological cancer.

Early discharge and home treatment of patients with acute pulmonary embolism in the tertiary care setting.

Acute pulmonary embolism (PE) is a potentially life-threatening disease. Current guidelines suggest risk-adapted management. Hospitalization is required for intermediate- and high-risk patients. Early discharge and home treatment are considered safe in the majority of low-risk patients. In this study, we describe characteristics, discharge, and outcome of outpatients diagnosed with acute PE at a tertiary care center. All outpatients undergoing computed tomography pulmonary angiography or ventilation/perfusion lung scan between 01.01.2016 and 31.12.2019 at the University Hospital Vienna, Austria, were screened for a PE diagnosis. Electronic patient charts were used to extract characteristics, clinical course, and outcomes. Within the 4-year period, 709 outpatients (median age: 62 years, 50% women) were diagnosed with PE. Thirty-three (5%) patients were classified as high-risk, 159 (22%) as intermediate-high, 332 (47%) as intermediate-low, and 185 (26%) as low-risk PE according to the European Society of Cardiology risk stratification. In total, 156 (22%) patients (47% with low-risk and 20% with intermediate-low-risk PE) were discharged as outpatients and received home treatment. Rates for home treatment increased 2.4-fold during the study period. Thirty-day mortality in the entire population was 4.9%. All low-risk patients and all but one patient with home treatment survived the first 30 days. Home treatment significantly increased over time and seems to be safe in routine clinical practice. Notably, one in five intermediate-low-risk patients was discharged immediately, suggesting that a subpopulation of intermediate-low-risk patients may also be eligible for home treatment.

Impact of thrombosis location on walking capacity: a cohort study of patients with acute deep vein thrombosis.

Background: Data on walking impairment during the acute phase of deep vein thrombosis (DVT) are limited. Objectives: This study aimed to assess the degree of walking impairment in patients with acute DVT, with a particular focus on the relation to the DVT's anatomical location. Methods: Patients with sonographically confirmed DVT were eligible for inclusion in this cohort study. Pain-free walking distance (PWD) and maximum walking distance (MWD) were determined using standardized treadmill ergometer tests and analyzed in relation to DVT location. The impact of previous DVT on walking capacity was evaluated in an exploratory analysis. Results: The study included 64 patients (31% women; median age, 55 years). The median (IQR) time from diagnosis to exercise test was 3 (1-5) days. Patients with suprainguinal DVT demonstrated significantly shorter median (IQR) MWD than those with infrainguinal DVT (130 (61-202) m vs 565 (128-750) m; P < .01), while PWD did not significantly differ (PWD: 20 (0-30) m vs 40 (0-222) m; P = .14). The proportion of patients who had to terminate treadmill tests prematurely was higher in patients with suprainguinal DVT (91.7% vs 57.7%; P = .04). PWD and MWD seemed to be similar in patients with and without a history of DVT. Premature test termination and suprainguinal DVT location were associated with reduced quality of life, as measured by the EuroQoL Group 5-Dimension 5-Level questionnaire and visual analog scale. Conclusion: Suprainguinal DVT was linked to a more pronounced walking impairment compared with infrainguinal DVT. Limited walking capacity was associated with a reduced quality of life.

The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).

A field facility to simulate climate warming and increased nutrient supply in shallow aquatic ecosystems.

Global warming and excess nitrogen deposition can exert strong impacts on aquatic populations, communities, and ecosystems. However, experimental data to establish clear cause-and-effect relationships in naturally complex field conditions are scarce in aquatic environments. Here, we describe the design and performance of a unique outdoor enclosure facility used to simulate warming, increased nitrogen supply, and both factors combined in a littoral freshwater wetland dominated by common reed, Phragmites australis. The experimental system effectively simulated a 2.8 °C climate warming scenario over an extended period, capturing the natural temperature variations in the wetland at diel and seasonal scales with only small deviations. Excess nitrogen supply enhanced nitrate concentrations especially in winter when it was associated with increased concentration of ammonium and dissolved organic carbon. Nitrogen also reduced dissolved oxygen concentrations, particularly in the summer. Importantly, by stimulating biological activity, warming enhanced the nitrogen uptake capacity of the wetland during the winter, emphasizing the need for multifactorial global change experiments that examine both warming and nitrogen loading in concert. Establishing similar experiments across broad environmental gradients holds great potential to provide robust assessments of the impacts of climate change on shallow aquatic ecosystems.

The post-VTE functional status scale for assessment of functional limitations in patients with venous thromboembolism: Construct validity and responsiveness in a prospective cohort study.

BACKGROUND: A large proportion of patients experience functional limitations after an acute episode of venous thromboembolism (VTE). Recently, the post-VTE functional status (PVFS) scale was proposed to capture these limitations. We performed a prospective cohort study to validate this scale. METHODS: The PVFS scale, PROMIS physical function 10a, EQ-5D-5L, and disease-specific quality of life (VEINES-QOL/Sym, PEmb-QoL) were assessed within three weeks of VTE diagnosis and after a median (IQR) follow-up of 13.4 (12.7-15.9) weeks. To evaluate construct validity of the PVFS scale, we determined correlations of PVFS scale with the other health measurements and investigated differences in patients above/below 70 years. Responsiveness was evaluated with a linear regression model, predicting change in PROMIS with change in PVFS scale. RESULTS: We included 211 patients (median (IQR) age: 55.1 (44.1-67.6) years, 40 % women). Pulmonary embolism was diagnosed in 105 (49.8 %) patients and 62.6 % of events were unprovoked. The PVFS scale correlated with PROMIS physical function (Spearman's rho (r): -0.67 and -0.63, p < 0.001) and EQ-5D-5L index (r = -0.61 and -0.61, p < 0.001) at baseline and follow-up. Furthermore, PVFS correlated moderately to strongly with disease-specific quality of life. Patients >70 years had significantly higher PVFS grades at follow-up (median (IQR): 2 (0-3) vs. 1 (0-2), p = 0.010). Changes in PVFS scale over time were significantly associated with changes in PROMIS physical function. CONCLUSIONS: The PVFS scale showed adequate construct validity and responsiveness in a prospective cohort study of patients with VTE, suggesting that it can be incorporated as additional health measurement and outcome parameter in research and clinical practice.

Lymphovascular Invasion at the Time of Radical Prostatectomy Adversely Impacts Oncological Outcomes.

Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan-Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7-23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6-2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6-3.0). The same relationship was seen across D'Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis.

Bispecific designed ankyrin repeat proteins (DARPins) targeting epidermal growth factor receptor inhibit A431 cell proliferation and receptor recycling.

The EGF receptor (EGFR) has been implicated in the development and progression of many tumors. Although monoclonal antibodies directed against EGFR have been approved for the treatment of cancer in combination with chemotherapy, there are limitations in their clinical efficacy, necessitating the search for robust targeting molecules that can be equipped with new effector functions or show a new mechanism of action. Designed ankyrin repeat proteins (DARPins) may provide the targeting component for such novel reagents. Previously, four DARPins were selected against EGFR with (sub)nanomolar affinity. As any targeting module should preferably be able to inhibit EGFR-mediated signaling, their effect on A431 cells overexpressing EGFR was examined: three of them were shown to inhibit proliferation by inducing G(1) arrest, as seen for the Food and Drug Administration-approved antibody cetuximab. To understand this inhibitory mechanism, we mapped the epitopes of the DARPins using yeast surface display. The epitopes for the biologically active DARPins overlapped with the EGF-binding site, whereas the fourth DARPin bound to a different domain, explaining the lack of a biological effect. To optimize the biological activity of the DARPins, we combined two DARPins binding to different epitopes with a flexible linker or with a leucine zipper, leading to a homodimer. The latter DARPin was able to reduce surface EGFR by inhibiting receptor recycling, leading to a dramatic decrease in cell viability. These results indicate that multispecific EGFR-specific DARPins are superior to cetuximab and may form the basis of new opportunities in tumor targeting and tumor therapy.

Risk assessment and primary prevention of VTE in patients with cancer: Advances, challenges, and evidence gaps.

Venous thromboembolism (VTE) is a common complication in cancer patients, which is associated with increased morbidity and mortality as well as high risk of VTE recurrence and bleeding. Furthermore, it impairs quality of life, interferes with anti-cancer treatment schedules, and increases costs. Therefore, identifying patients at high VTE risk and primary prevention are of clinical importance. In ambulatory patients, specific risk assessment models and clinical trials on primary thromboprophylaxis with low-molecular-weight heparins and direct oral factor Xa inhibitors are available. In hospitalized medical patients, there is lack of evidence. In surgical patients, no specific VTE risk assessment tools have been developed. However, extended thromboprophylaxis after major abdominal and pelvic cancer surgery is recommended because VTE risk persists beyond hospital discharge. In this review, we provide an overview on thromboprophylaxis strategies for patients with cancer in the ambulatory, hospitalized, and surgical setting. We also highlight recent advances and discuss evidence gaps.

Rhabdomyosarcoma and pleomorphic sarcoma in the same location : Recurrence or new entity?

Soft tissue sarcomas (STS) represent a small group of adult solid malignancies, with risk factors such as environmental factors, genetic predisposition, and prior radiotherapy. In STS patients with a novel swelling, differential diagnoses include recurrence, second primary cancer, metastasis from unknown primary cancer, and radiation-associated STS, the latter usually occurring approximately 10 years after radiotherapy. We present the case of a 64-year-old male patient with pleomorphic rhabdomyosarcoma, who underwent resection and radiotherapy. The patient presented again 5 years later with painful swelling in the area of the prior sarcoma, raising suspicion of recurrence. Resection was performed and a diagnosis of pleomorphic sarcoma (not otherwise specified [NOS]) was made. The patient was treated with radiotherapy and remained sarcoma-free for the following 7 years. A molecular analysis of both neoplasms, using RNA next-generation sequencing, did not detect any specific fusions. Due to the lack of rhabdomyoblastic differentiation in the second sarcoma and the low likelihood of a second primary in the same previously irradiated location, the diagnosis of a radiation-associated STS was suggested. This short report illustrates the difficult diagnostic work-up of a presumably radiation-associated STS, as these neoplasms lack characteristic morphological and immunohistochemical features. In our case, the suggested diagnosis may have pointed against another course of radiotherapy in an already irradiation-harmed region. Therefore, a relatively low latency period between surgery, radiotherapy, and diagnosis of another STS should not automatically point towards recurrence and may prompt further in-depth investigation.

Risk of stroke or systemic embolism in patients with degenerative mitral stenosis with or without atrial fibrillation: A cohort study.

Background: Atrial fibrillation (AF) is associated with an increased risk of stroke and the combination of AF and mitral stenosis (MS) is associated with a higher risk. In developed nations, degenerative mitral stenosis (DMS) constitutes a sizeable proportion of patients with MS. Current international guidelines do not offer recommendations regarding anticoagulation in these patients. The objective of this study was to describe the incidence of stroke or systemic embolism in patients with DMS with or without prevalent AF. Methods: A cohort study of DMS patients from 1997 to 2018, using data from the Danish health registries. The cohort was stratified based on AF prevalence and prior ischemic stroke. The primary outcome was a diagnosis of ischemic stroke or systemic embolism after 1 year of follow-up from time of DMS diagnosis. Results: The study included 1162 patients with DMS, of which 421 had prevalent AF. The incidence rate of stroke or systemic embolism after 1 year of follow-up was highest in the DMS without AF group (7.58 vs. 6.63 per 100 person-years). In both groups, DMS without AF and DMS with AF, the incidence rate was highest in patients with prior thromboembolic events (29.61 vs. 5.15 and 19.53 vs. 5.15, respectively). Conclusions: The incidence rate of stroke or systemic embolism was highest in DMS patients without AF. Current Danish guidelines recommend DMS patients should be treated with anticoagulation only with concurrent AF, yet our results call for additional research to establish if DMS patients without AF could benefit from stroke prevention therapy.