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Extracellular vesicles (EVs) are valuable targets for liquid biopsy. However, attempts to introduce EV‐based biomarkers into clinical practice have not been successful to the extent expected. One of the reasons for this failure is the lack of reliable methods for EV baseline purification from complex biofluids, such as cell‐free plasma or serum. Because available one‐step approaches for EV isolation are insufficient to purify EVs, the majority of studies on clinical samples were performed either on a mixture of EVs and lipoproteins, whilst the real number of EVs and their individual specific biomarker content remained elusive, or on a low number of samples of sufficient volume to allow elaborate 2‐step EV separation by size and density, resulting in a high purity but utmost low recovery. Here we introduce Fast Protein Liquid Chromatography (FPLC) using Superose 6 as a matrix to obtain small EVs from biofluids that are almost free of soluble proteins and lipoproteins. Along with the estimation of a realistic number of small EVs in human samples, we show temporal resolution of the effect of the duration of postprandial phase on the proportion of lipoproteins in purified EVs, suggesting acceptable time frames additionally to the recommendation to use fasting samples for human studies. Furthermore, we assessed a potential value of pure EVs for liquid biopsy, exemplarily examining EV‐ and tumour‐biomarkers in pure FPLC‐derived fractions isolated from the serum of patients with pancreatic cancer. Consistent among different techniques, showed the presence of diseases‐associated biomarkers in pure EVs, supporting the feasibility of using single‐vesicle analysis for liquid biopsy.

Background The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur (\"Kinetic Targeting\"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity. Methods For the CARL-trial ( C ontrolled A pplication and R emoval of L iposomal chemotherapeutics), pegylated liposomal doxorubicin (PLD) was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP) was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m 2 every 3 weeks in combination with vinorelbine 2 × 25 mg/m 2 (neoadjuvant treatment of breast cancer, 12 patients), or as 40 mg/m 2 every 4 weeks (recurrent ovarian cancer, 3 patients). Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response. Results DFPP eliminated ~62% of circulating PLD, corresponding to ~45% of the total dose (n = 57 cycles). AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant) and in 1/3 patients (recurrent). Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia) and a single palmar-plantar erythrodysesthesia grade 2 were reported. Conclusion Extracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main dose-limiting side effects of PLD, and probably many different DDS alike. Trial registration DRKS00000163

Background Preeclampsia is a life-threatening disease in pregnancy, and its complex pathomechanisms are poorly understood. In preeclampsia, lipid metabolism is substantially altered. In late onset preeclampsia, remnant removal disease like lipoprotein profiles have been observed. Lipid apheresis is currently being explored as a possible therapeutic approach to prolong preeclamptic pregnancies. Here, apheresis-induced changes in serum lipid parameters are analyzed in detail and their implications for preeclamptic lipid metabolism are discussed. Methods In the Freiburg H.E.L.P.-Apheresis Study, 6 early onset preeclamptic patients underwent repeated apheresis treatments. Serum lipids pre- and post-apheresis and during lipid rebound were analyzed in depth via ultracentrifugation to yield lipoprotein subclasses. Results The net elimination of Apolipoprotein B and plasma lipids was lower than theoretically expected. Lipids returned to previous pre-apheresis levels before the next apheresis even though apheresis was repeated within 2.9 ± 1.2 days. Apparent fractional catabolic rates and synthetic rates were substantially elevated, with fractional catabolic rates for Apolipoprotein B / LDL-cholesterol being 0.7 ± 0.3 / 0.4 ± 0.2 [day − 1 ] and synthetic rates being 26 ± 8 / 17 ± 8 [mg*kg − 1 *day − 1 ]. The distribution of LDL-subclasses after apheresis shifted to larger buoyant LDL, while intermediate-density lipoprotein-levels remained unaffected, supporting the notion of an underlying remnant removal disorder in preeclampsia. Conclusion Lipid metabolism seems to be highly accelerated in preeclampsia, likely outbalancing remnant removal mechanisms. Since cholesterol-rich lipoprotein remnants are able to accumulate in the vessel wall, remnant lipoproteins may contribute to the severe endothelial dysfunction observed in preeclampsia. Trial registration ClinicalTrails.gov, NCT01967355 .

Background Omega-3 polyunsaturated fatty acids (PUFAs) have a highly anti-angiogenic effect in animal models. However, the clinical relevance of omega-3PUFAs in human retinal pathologies remains unclear. The ARED 2 study found no effect of omega-3 PUFA supplementation on progression of age related macular degeneration (AMD). The aim of this study was to compare serum levels of omega-3- and omega-6 PUFAs between patients with diabetic retinopathy (DR), AMD and retinal vein occlusion (RVO), and to identify potential confounders of serum level measurements. Methods Venous blood samples were collected from 44 patients with DR, 25 with AMD, 12 with RVO and 27 controls. The lipid phase was extracted and analyzed using mass spectrometry. Retinal disease staging was done by indirect funduscopy and FAG where appropriate. Patient demographics and medical history including current medication and fasting state were acquired. Tukey contrasts for multiple comparisons of the mean and linear regression analysis were used for statistical analysis. Results Our data revealed no significant differences in omega-6 PUFA serum levels between patients with AMD, DR, RVO and controls ( p  > 0.858). Uncorrected omega-3 PUFA levels were significantly higher in patients with AMD compared to DR but not compared to controls ( p  = 0.004). However, after correcting for possible confounders such as body mass index (BMI), age, sex, fasting and use of statins, no statistically significant difference remained for serum omega-3 PUFA levels. Fasting was identified as an independent confounder of total omega-6 PUFAs, three individual omega-6 PUFAs and one omega-3 PUFA( p  < 0.0427). Statin use was identified as an independent confounder of α-linolenic acid (an omega-3PUFA; p  = 0.0210). Conclusion In this pilot study with relatively low patient numbers, we report significant differences in serum levels of omega-3PUFAs among patients with different types of retinal diseases. However, these differences were not robust for disease specificity after correction for possible confounders in our cohort. Our results demonstrate that serum lipid profiles need to be interpreted with caution since they are significantly altered by variables like fasting and medication use independent from the underlying disease. Correcting for respective confounders is thus necessary to compare serum lipid profiles in clinical studies.

Misperceptions about the world’s grassy biomes contribute to their alarming rates of loss due to conversion for agriculture and tree plantations, as well as to forest encroachment. To illustrate the causes and consequences of these misperceptions, we show that the World Resources Institute and the International Union for Conservation of Nature misidentified 9 million square kilometers of ancient grassy biomes as providing “opportunities” for forest restoration. Establishment of forests in these grasslands, savannas, and open-canopy woodlands would devastate biodiversity and ecosystem services. Such undesired outcomes are avoidable if the distinct ecologies and conservation needs of forest and grassy biomes become better integrated into science and policy. To start with, scientists should create maps that accurately depict grassy biomes at global and landscape scales. It is also crucial that international environmental agreements (e.g., the United Nations Framework Convention on Climate Change) formally recognize grassy biomes and their environmental values.

We expand the concept of \"old growth\" to encompass the distinct ecologies and conservation values of the world's ancient grass-dominated biomes. Biologically rich grasslands, savannas, and open-canopy woodlands suffer from an image problem among scientists, policy makers, land managers, and the general public, that fosters alarming rates of ecosystem destruction and degradation. These biomes have for too long been misrepresented as the result of deforestation followed by arrested succession. We now know that grassy biomes originated millions of years ago, long before humans began deforesting. We present a consensus view from diverse geographic regions on the ecological characteristics needed to identify old-growth grasslands and to distinguish them from recently formed anthropogenic vegetation. If widely adopted, the old-growth grassland concept has the potential to improve scientific understanding, conservation policies, and ecosystem management.

Post-traumatic stress symptoms (PTSSs) are associated with an imbalanced time perspective (TP) as well as with unhealthy substance use. Although neurodevelopmental processes during adolescence may impact PTSS, most etiological models of post-traumatic stress disorder (PTSD) are derived from studies with adults and neglect possible distinctive characteristics in adolescent PTSD. This study examined possible direct and mediated relations between exposure to potentially traumatic experiences (EPTEs) and PTSS with TP as a potential mediator. In addition, the study investigated the direct and indirect effects of EPTE, TP, and PTSS on cannabis use. The aim of this study was to investigate whether findings from adult studies can be transferred to adolescent PTSD. One hundred and five patients between 14 and 20 years of age were recruited from child and adolescent psychiatric units. They answered questionnaires to assess EPTE, PTSS, TP, and cannabis use. Participants with clinically relevant PTSS showed imbalanced TP with a high orientation to negative past and a low orientation to positive past and future. Higher EPTE was associated with higher level of PTSS, but TP mediated the level of PTSS in this relation. PTSS predicted the frequency of cannabis use. It may therefore be beneficial to consider TP in PTSD therapy with the aim of reducing deviation from balanced TP and PTSS and preventing comorbid substance use.

The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only. SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50–85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017. 513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6–60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0–5·8) with CEA plus BMT, 4·4% (2·2–8·6) with CAS plus BMT, and 3·1% (1·0–9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22–3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41–5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group. CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution. German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

International air traffic has contributed to the global spread of SARS-CoV-2 and its variants. In early 2023, wastewater-based epidemiology (WBE) has been implemented at airports as a surveillance tool to detect emerging variants at short notice. This study investigates the feasibility and challenges of applying WBE at Berlin Brandenburg (BER) Airport, including a rapid implementation of wastewater sampling and analysis under unprecedented circumstances. For this purpose, aircraft and airport wastewater was sampled over 13 weeks. Established sampling and analysis protocols for municipal wastewater treatment plants (WWTPs) had to be adapted to the specific conditions of the airport environment. SARS-CoV-2 RNA was quantified and sequenced, revealing SARS-CoV-2 mutations not previously observed in clinical surveillance data in Germany. Despite the logistical and methodological challenges, the study demonstrates that WBE can serve as an early warning system for pathogen introduction. However, our study also underscores the need for realistic timelines for the establishment and validation of WBE monitoring strategies in new contexts. Investments in the establishment of WBE systems, e.g., infrastructure, protocols, trained personnel, and a network of stakeholders at strategic nodes including airports, can act as an effective tool for pandemic preparedness and global health security.