Prevalence and predictors of alternative diagnoses on whole-leg ultrasound negative for acute deep venous thrombosis

Background!#!To investigate the prevalence, spectrum, and predictors of alternative diagnoses explaining leg symptoms in patients negative for suspected acute deep venous thrombosis (DVT), which can be detected with whole-leg ultrasound.!##!Methods!#!We retrospectively analyzed a cohort of 789 patients (median age 70 years, 50.6% women) evaluated with a whole-leg ultrasound examination for suspected acute DVT within one year. All findings in the radiology report were analyzed and electronic chart review was performed to collect clinical information.!##!Results!#!Ultrasound was negative for acute DVT in 531 patients (67.3%). Among these, alternative diagnoses explaining leg symptoms were seen in 349 patients (65.7%). The most frequent alternative diagnoses were chronic venous insufficiency (147 patients, 27.7%), followed by lymphedema (48 patients, 9.0%) and chronic post-thrombotic changes (41 patients, 7.7%). Patients with alternative diagnoses were older (median 71 vs. 66 years, p = 0.0226), as well as more likely to present with leg swelling (39.5% vs. 23.1%, p = 0.0002), difference in leg circumference (25.5% vs. 14.8%, p = 0.0055) and redness (7.7% vs. 2.7%, p = 0.0213) than patients without alternative diagnosis. Independent predictors of finding alternative diagnoses on whole-leg ultrasound were older age (odds ratio 1.014 per year, p = 0.0119), leg swelling (OR 1.949, p = 0.0020) and history of previous DVT (OR 2.235, p = 0.0154).!##!Conclusions!#!Alternative diagnoses explaining leg symptoms can be detected on whole-leg ultrasound in two thirds of patients with no evidence of acute DVT. Our data supports performing a comprehensive ultrasound evaluation beyond the venous system, particularly, in older patients, who present with leg swelling and a past history of DVT

Reaction Mechanisms and Rate Constants of Auto‐Catalytic Urethane Formation and Cleavage Reactions

The chemistry of urethanes plays a key role in important industrial processes. Although catalysts are often used, the study of the reactions without added catalysts provides the basis for a deeper understanding. For the non-catalytic urethane formation and cleavage reactions, the dominating reaction mechanism has long been debated. To our knowledge, the reaction kinetics have not been predicted quantitatively so far. Therefore, we report a new computational study of urethane formation and cleavage reactions. To analyze various potential reaction mechanisms and to predict the reaction rate constants quantum chemistry and transition state theory were employed. For validation, experimental data from literature and from own experiments were used. Quantitative agreement of experiments and predictions could be demonstrated. The calculations confirm earlier assumptions that urethane formation reactions proceed via mechanisms where alcohol molecules act as auto-catalysts. Our results show that it is essential to consider several transition states corresponding to different reaction orders to enable agreement with experimental observations. Urethane cleavage seems to be catalyzed by an isourethane, leading to an observed 2nd-order dependence of the reaction rate on the urethane concentration. The results of our study support a deeper understanding of the reactions as well as a better description of reaction kinetics and will therefore help in catalyst development and process optimization

Isolated calf deep venous thrombosis: frequency on venous ultrasound and clinical characteristics

Background!#!It remains controversial whether to include calf veins in the initial ultrasound evaluation of suspected deep venous thrombosis (DVT). We sought to investigate the frequency and clinical characteristics of isolated calf DVT.!##!Materials and methods!#!In this retrospective analysis, we investigated a cohort of 596 patients (median age 69 years, 52.3% women) who had been imaged with complete lower extremity venous duplex ultrasound for suspected acute DVT. Radiology reports were analyzed for the presence and localization of DVT. Clinical information was collected from patients' electronic charts.!##!Results!#!DVT was found in 157 patients (26.3%), of which 74 patients (47.1%) had isolated calf DVT. Isolated calf DVTs were located in the posterior tibial veins (22 patients, 29.7%), peroneal veins (41 patients, 55.4%) and muscle veins (19 patients, 25.7%). There were no differences in age or sex between patients with isolated calf DVT and patients with proximal DVT. Isolated calf DVT was more commonly associated with leg pain (52.7% vs. 33.7%, p = 0.0234) and less commonly associated with subjective leg swelling (35.1% vs. 55.4%, p = 0.0158) and objectively measured difference in leg circumference (23% vs. 39.8%, p = 0.0268). D-Dimers were significantly lower in patients with isolated lower leg DVT (median 2.3 vs. 6.8 mg/L, p < 0.0001) compared to patients with proximal DVT.!##!Conclusions!#!Isolated calf DVT represents approximately half of DVT cases and has different clinical characteristics than proximal DVT

Encapsulated Cells Expressing a Chemotherapeutic Activating Enzyme Allow the Targeting of Subtoxic Chemotherapy and Are Safe and Efficacious: Data from Two Clinical Trials in Pancreatic Cancer

Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more

Global Alliance for the Promotion of Physical Activity: the Hamburg Declaration

Non-communicable diseases (NCDs), including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers, are on the rise worldwide and are often associated with a lack of physical activity (PA). Globally, the levels of PA among individuals are below WHO recommendations. A lack of PA can increase morbidity and mortality, worsen the quality of life and increase the economic burden on individuals and society. In response to this trend, numerous organisations came together under one umbrella in Hamburg, Germany, in April 2021 and signed the ‘Hamburg Declaration’. This represented an international commitment to take all necessary actions to increase PA and improve the health of individuals to entire communities. Individuals and organisations are working together as the ‘Global Alliance for the Promotion of Physical Activity’ to drive long-term individual and population-wide behaviour change by collaborating with all stakeholders in the community: active hospitals, physical activity specialists, community services and healthcare providers, all achieving sustainable health goals for their patients/clients. The ‘Hamburg Declaration’ calls on national and international policymakers to take concrete action to promote daily PA and exercise at a population level and in healthcare settings

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

Background!#!The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.!##!Methods!#!In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.!##!Results!#!Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.!##!Conclusions!#!Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity