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Conjugated polymer nanoparticles have been applied for biological fluorescence imaging in cell culture and in small animals, but cannot readily be excreted through the renal system. Here the authors show fully conjugated polymer nanoparticles based on imidazole units that can be bio-degraded by activated macrophages.

Abstract Background Plasmodium falciparum, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-based combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs, such as lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite's growing resistance to existing therapies. In this study, a common characteristic of the P. falciparum proteome—stretches of poly-lysine residues, such as those found in proteins related to adhesion and pathogenicity—is investigated for its potential to treat infected erythrocytes. Methods This study utilizes in vitro culturing of intra-erythrocytic P. falciparum to assess the ability of poly-lysine peptides to inhibit the parasite’s growth, measured via flow cytometry of acridine orange-stained infected erythrocytes. The inhibitory effect of many poly-lysine lengths and modifications were tested this way. Affinity pull-downs and mass spectrometry were performed to identify the proteins interacting with these poly-lysines. Results A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytes in vitro with minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 h. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers retains or increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, affinity pull-downs and mass-spectrometry identify P. falciparum’s outer membrane proteins as likely targets for polybasic peptide medications. Conclusion Since poly-lysine dendrimers are already FDA-approved for drug delivery and this study displays their potency against intraerythrocytic P. falciparum, their adaptation as anti-malarial drugs presents a promising new therapeutic strategy for malaria.

Abstract Knowledge of thrombus behavior and visualization on MRI in acute ischemic stroke is less than optimal. However, MRI sequences could be enhanced based on the typical T1 and T2 relaxation times of the target tissues, which mainly determine their signal intensities on imaging. We studied the relaxation times of a broad spectrum of clot analogs along with their image characteristics of three sequences analyzed: a T1-weighted turbo inversion-recovery sequence (T1w Turbo IR), a T1-weighted turbo spin echo with fat suppression (T1w TSE SPIR), and a T2-weighted 3D TSE with magnetization refocusing to remove T1 dependence (T2w TSE DRIVE). We compared their imaging behavior with the intensity values of normal brain tissue using the same imaging protocols as for clots. Each histological and biochemical clot component contributed to each of the relaxation times. Overall, histological composition correlated strongly with T1 times, and iron content, specifically, with T2 relaxation time. Using decision trees, fibrin content was selected as the primary biomarker for T1 relaxation times, inducing an increase. Up to four clot subgroups could be defined based on its distinctive T1 relaxation time. Clot signal intensity in the T1 and T2-weighted images varied significantly according to T1 and T2 relaxation times. Moreover, in comparison with normal brain tissue intensity values, T2w DRIVE images depict thrombi according to the principle of the more fibrin, the higher the intensity, and in T1w TSE, the more erythrocytes, the higher the intensity. These findings could facilitate improvements in MRI sequences for clot visualization and indicate that T2w DRIVE and T1w TSE sequences should depict the vast majority of acute ischemic stroke thrombi as more hyperintense than surrounding tissues.

Abstract Carbohydrate markers of immature cells during prenatal human development can be aberrantly expressed in cancers and deserve evaluation as immune targets. A candidate target in Ewing sarcoma is the globo-series ganglioside stage-specific embryonic antigen-4 (SSEA-4). We detected SSEA-4 expression on the cell surface of all of 14 EwS cell lines and in 21 of 31 (68%) primary EwS tumor biopsies. Among paired subpopulations of tumor cells with low versus high SSEA-4 expression, SSEA-4high expression was significantly and consistently associated with functional characteristics of tumor aggressiveness, including higher cell proliferation, colony formation, chemoresistance and propensity to migrate. SSEA-4low versus SSEA-4high expression was not related to expression levels of the EWSR1-FLI1 fusion transcript or markers of epithelial/mesenchymal plasticity. SSEA-4low cells selected from bulk populations regained higher SSEA-4 expression in vitro and during in vivo tumor growth in a murine xenograft model. T cells engineered to express SSEA-4-specific chimeric antigen receptors (CARs) specifically interacted with SSEA-4 positive EwS cells and exerted effective antigen-specific tumor cell lysis in vitro. In conclusion, with its stable expression and functional significance in EwS, SSEA-4 is an attractive therapeutic immune target in this cancer that deserves further evaluation for clinical translation.

Abstract Background Resuscitation is a team effort, and it is increasingly acknowledged that team cooperation requires training. Staff shortages in many healthcare systems worldwide, as well as recent pandemic restrictions, limit opportunities for collaborative team training. To address this challenge, a learner-centred approach known as flipped learning has been successfully implemented. This model comprises self-directed, asynchronous pre-course learning, followed by knowledge application and skill training during in-class sessions. The existing evidence supports the effectiveness of this approach for the acquisition of cognitive skills, but it is uncertain whether the flipped classroom model is suitable for the acquisition of team skills. The objective of this study was to determine if a flipped classroom approach, with an online workshop prior to an instructor-led course could improve team performance and key resuscitation variables during classroom training. Methods A single-centre, cluster-randomised, rater-blinded study was conducted on 114 final year medical students at a University Hospital in Germany. The study randomly assigned students to either the intervention or control group using a computer script. Each team, regardless of group, performed two advanced life support (ALS) scenarios on a simulator. The two groups differed in the order in which they completed the flipped e-learning curriculum. The intervention group started with the e-learning component, and the control group started with an ALS scenario. Simulators were used for recording and analysing resuscitation performance indicators, while professionals assessed team performance as a primary outcome. Results The analysis was conducted on the data of 96 participants in 21 teams, comprising of 11 intervention groups and 10 control groups. The intervention teams achieved higher team performance ratings during the first scenario compared to the control teams (Estimated marginal mean of global rating: 7.5 vs 5.6, p

Abstract Treacle ribosome biogenesis factor 1 (TCOF1) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1 and CNBP (CCHC-type zinc finger nucleic acid binding protein) expression in human mesenchymal cells. Given the established role of CNBP in gene regulation during rostral development, we explored the potential for CNBP to modulate TCOF1 transcription. Computational analysis for CNBP binding sites (CNBP-BSs) in the TCOF1 promoter revealed several putative binding sites, two of which (Hs791 and Hs2160) overlap with putative G-quadruplex (G4) sequences (PQSs). We validated the folding of these PQSs measuring circular dichroism and fluorescence of appropriate synthetic oligonucleotides. In vitro studies confirmed binding of purified CNBP to the target PQSs (both folded as G4 and unfolded) with K d values in the nM range. ChIP assays conducted in HeLa cells chromatin detected the CNBP binding to TCOF1 promoter. Transient transfections of HEK293 cells revealed that Hs2160 cloned upstream SV40 promoter increased transcription of downstream firefly luciferase reporter gene. We also detected a CNBP-BS and PQS (Dr2393) in the zebrafish TCOF1 orthologue promoter (nolc1). Disrupting this G4 in zebrafish embryos by microinjecting DNA antisense oligonucleotides complementary to Dr2393 reduced the transcription of nolc1 and recapitulated the craniofacial anomalies characteristic of Treacher Collins Syndrome. Both cnbp overexpression and Morpholino-mediated knockdown in zebrafish induced nolc1 transcription. These results suggest that CNBP modulates the transcriptional expression of TCOF1 through a mechanism involving G-quadruplex folding/unfolding, and that this regulation is active in vertebrates as distantly related as bony fish and humans. These findings may have implications for understanding and treating MD.

Given the broad and intense use of plastic, society is being increasingly affected by its degradation and by-products, particularly by microplastics (MPs), fragments smaller than 5 mm in size, and nanoplastics (NPs), with sizes less than 1 µm. MPs and NPs may enter the body primarily through inhalation, consumption, and skin contact. Once ingested, MPs can penetrate tissues, deviating to other parts of the body and potentially affecting important cellular pathways such as nonconforming chemokine receptors that control the communication between the fetus and the mother. Consequently, the potential health harm induced via MP internalization is a major issue, evidenced by multiple studies demonstrating harmful consequences in diverse animal models and human cells. Here, an overview of the various modes of exposure to MPs and NPs is presented, including inhalation, placental transfer, ingestion, breastmilk consumption, and skin absorption, as well as placental and fetal toxicity due to plastic particles based on animal and in vitro studies. Though MPs in our environment are becoming more recognized, their developmental toxicity is still scarcely known. Besides negatively affecting pregnancy, MPs and NPs have been shown to potentially harm the developing fetus, given their ability to cross the placental barrier. Still, considerable gaps remain in our understanding of the dispersion and toxicity of these particles in the environment and the precise types of NPs and MPs bearing the greatest dangers. As a result, we advocate for larger-scale epidemiological investigations, the development of novel approaches for measuring NP and MP exposures, and the necessity of understanding the toxicity of various kinds of NPs to guide future research efforts.

Cigarette smoking is a common risk factor associated with negative long-term outcomes in kidney transplant recipients. However, whether donor smoking decreases graft longevity or negatively impacts recipient survival after kidney transplantation remains unknown. Therefore, this study aims to investigate the long-term outcome in patients who received a kidney graft from a deceased smoking or non-smoking donor. A total of 580 patients were divided into two groups: patients who received a graft from a smoking donor (n = 276) and those who received a graft from a non-smoking donor (n = 304). Analysis of demographic factors showed that the non-smoking cohort was older, had more extended criteria donors and longer warm ischemia times. The primary composite endpoint of patient and graft survival was better in the smoking donor cohort when analyzed using Kaplan-Meier method but not when controlled for covariates in multivariate analyses. These findings do not support a previously reported negative impact of deceased donor smoking on kidney transplant recipients. Thus, the underlying results should not be interpreted in favor of a positive donor smoking history, but rather remind the transplant community that donor smoking should not be considered as a deciding factor in refusing an otherwise acceptable kidney graft.

El síndrome de contractura del hombro congelado es una condición patológica que involucra a la contractura de la cápsula articular de la articulación glenohumeral, generando dolor, restricción del rango de movimiento tanto activo como pasivo y alteración de la función. Diversos tratamientos se han propuesto e investigado para dar solución a esta condición. Por una parte, se encuentran los tratamientos quirúrgicos, y por otra, los no quirúrgicos. En relación a los quirúrgicos, destacan la liberación capsular artroscópica y la manipulación bajo anestesia. Esta última consiste en movilizar el hombro en distintas direcciones para lograr romper las adherencias de la cápsula articular, todo esto bajo anestesia. En relación a los tratamientos no quirúrgicos más utilizados, se encuentra la prescripción de medicamentos, inyecciones de corticoides, la hidrodilatación artrográfica y la terapia física. Las modalidades de terapia física resultan una opción de fácil acceso, de bajo costo y con variadas opciones. A pesar de que se presentan múltiples alternativas, no existe consenso sobre cuál es la mejor opción de tratamiento, y específicamente sigue sin estar claro si la manipulación bajo anestesia es una mejor opción que el tratamiento de fisioterapia.

Background Although effective treatments for bulimic-spectrum eating disorders exist, access is often delayed because of limited therapist availability and lengthy waiting lists. Web-based self-help interventions have the potential to bridge waiting times for face-to-face treatment and overcome existing treatment gaps. Aims This study aims to assess the effectiveness of a web-based guided self-help intervention (everyBody Plus) for patients with bulimia nervosa, binge eating disorder and other specified feeding and eating disorders who are waiting for out-patient treatment. Method A randomised controlled trial was conducted in Germany and the UK. A total of 343 patients were randomly assigned to the intervention ‘everyBody Plus’ or a waitlist control condition. The primary outcome was the number of weeks after randomisation until a patient achieved a clinically relevant improvement in core symptoms for the first time. Secondary outcomes included eating disorder attitudes and behaviours, and general psychopathology. Results At 6- and 12-month follow-up, the probability of being abstinent from core symptoms was significantly larger for the intervention group compared with the control group (hazard ratio: 1.997, 95% CI 1.09–3.65; P = 0.0249). The intervention group also showed larger improvements in eating disorder attitudes and behaviours, general psychopathology, anxiety, depression and quality of life, compared with the control group at most assessment points. Working alliance ratings with the online therapist were high. Conclusions The self-help intervention everyBody Plus, delivered with relatively standardised online guidance, can help bridge treatment gaps for patients with bulimic-spectrum eating disorders, and achieve faster and greater reductions in core symptoms.

The issue of used rubber tires is becoming an ever-greater problem for the environment. Often these are disposed of in an illegal manner. Whether on forest paths, fields, or other unsuitable areas—illegal disposal of used tires is a punishable offense and a risk to people and the environment. Nevertheless, the number of cases increases from year to year. This is partly caused by the lack of suitable recycling options for waste tires. Reuse does take place but mainly in the form of downcycling, with the majority currently either being incinerated for energy recovery or, as shredded tires, used as substrate or filler material in roads and sporting grounds. Several reclamation technologies have been developed in the past, using for example mechanical, thermal energy and/or chemicals, aiming to provide a better solution to the waste tire problem, however, most processes cause some form of rubber degradation that limits reuse to low value applications. Only devulcanisation using a biotechnological approach with microorganisms and/or enzymes shows currently promise to reuse waste rubber for high value applications such as new tires. This review provides an overview of the technological development of different recycling options and their potential benefit to the circular economy.

Abstract Odorant binding proteins (OBPs) are extra-cellular proteins that solubilize and transport volatile organic compounds (VOCs). Thousands of OBPs have been identified through genome sequencing, and hundreds have been characterized by fluorescence ligand binding assays in individual studies. There is a limited understanding of the comparative structure-function relations of OBPs, primarily due to a lack of a centralized database that relates OBP binding affinity and structure. Combining 181 functional studies containing 382 unique OBPs from 91 insect species, we present a database, iOBPdb, of OBP binding affinities for 622 individual VOC targets. This initial database provides powerful search and associative capabilities for retrieving and analyzing OBP-VOC binding interaction data. We have validated this dataset using phylogenetic mapping to determine the authenticity of the collected sequences and whether they cluster according to their assigned subfamilies. Potential applications include developing molecular probes for biosensors, novel bioassays and drugs, targeted pesticides that inhibit VOC/OBP interactions, and understanding odor sensing and perception in the brain.

Abstract Background Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. Methods While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. Results Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. Conclusions Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

Donor proteinuria (DP) is a common but rarely evaluated aspect of today’s kidney transplant allocation process. While proteinuria after kidney transplantation is a risk factor for impaired graft function and survival, the long-term effects of DP in kidney transplantation have not yet been evaluated. Therefore, this study aims to investigate the impact of DP on the long-term outcome after kidney transplantation. A total of 587 patients were found to be eligible and were stratified into two groups: (1) those receiving a graft from a donor without proteinuria (DP−) and (2) those receiving a graft from a donor with proteinuria (DP+). At 36 months, there was no difference in the primary composite endpoint including graft loss and patient survival (log-rank test, p = 0.377). However, the analysis of DP+ subgroups showed a significant decrease in overall patient survival in the group with high DP (p = 0.017). DP did not adversely affect patient or graft survival over 36 months. Nevertheless, this work revealed a trend towards decreased overall survival of patients with severe proteinuria in the subgroup analysis. Therefore, the underlying results suggest caution in allocating kidneys from donors with high levels of proteinuria.

Monitoring groundwater quality in economically important and other aquifers is carried out regularly as part of regulatory processes for water and other resource development. Many water quality parameters are measured as part of baseline monitoring around mining and onshore gas resource development regions to develop improved understanding of the hydrogeological system as well as to inform managerial decisions to assess and manage contamination risks and health hazards. Water quality distribution in an aquifer is most often inferred from point measurements from limited number of bores drilled at arbitrary locations. Estimating the distribution of water quality parameters in the aquifer based on these point measurements is often a challenging task and results in high uncertainty in the estimates due to limited data availability. Minimizing uncertainty can be achieved by drilling more bores to collect water quality data and several approaches are available to identify optimal bore hole locations to minimize estimation uncertainty. However, optimization of borehole locations is difficult when multiple water quality parameters are of interest and have different spatial distributions in the aquifer. In this study we use geostatistical kriging to interpolate a large number of groundwater quality parameters. Then we integrate these predicted values and use the Differential Evolution algorithm to determine optimal locations for bores that would simultaneously reduce spatial prediction uncertainty of all parameters. The method is applied for designing a groundwater monitoring network in the Namoi region of Australia for monitoring groundwater quality in an economically important aquifer of the Great Artesian Basin. Optimal locations for 10 new monitoring bores are identified using this approach.

Background Long-distance rafting on anthropogenic marine debris (AMD) is thought to have a significant impact on global marine biogeography and the dispersal of non-indigenous species. Therefore, early identification of arrival sites of AMD and its epibionts is crucial for the prioritization of preventive measures. As accumulation patterns along global coastlines are largely unstudied, we tested if existing oceanographic models and knowledge about upstream sources of litter and epibionts can be used as a simple and cost-efficient approach for predicting probable arrival sites of AMD-rafting biota in coastal zones. Methods Using the Southeast Pacific as a model system, we studied daily accumulation rates, composition, and minimum floating times of AMD with and without epibionts on seven sandy beaches, covering the oceanic environment (Rapa Nui/Easter Island) and three regions (south, centre, north) along the Chilean continental coast, over a minimum of 10 consecutive days, and we contrast our results with predictions from published models. Results Total AMD accumulation rates varied from 56 ± 36 (mean ± standard deviation) to 388 ± 433 items km−1 d−1 and differed strongly between regions, in accordance with local geomorphology and socioeconomic conditions (presence of larger cities and rivers upstream, main economic activities, etc.). Daily accumulation of items with pelagic epibionts (indicators of a pelagic trajectory) ranged from 46 ± 29 (Rapa Nui) to 0.0 items km−1 d−1 (northern continental region). Minimum floating times of rafts, as estimated from the size of pelagic epibionts, were longest in the South Pacific Subtropical Gyre’s (SPSG) centre region, followed by the high-latitude continental region under the influence of the onshore West Wind Drift, and decreased along the continental alongshore upwelling current, towards lower latitudes. Apart from pelagic rafters, a wide range of benthic epibionts, including invasive and cryptogenic species, was found on rafts at the continental beaches. Similarly, we present another record of local benthic corals Pocillopora sp., on Rapa Nui rafts. Discussion Our results agree with the predictions made by recent models based on the prevailing wind and surface current regimes, with high frequencies of long-distance rafting in the oceanic SPSG centre and very low frequencies along the continental coast. These findings confirm the suitability of such models in predicting arrival hotspots of AMD and rafting species. Moreover, storm surges as well as site-related factors seem to influence AMD arrival patterns along the Chilean continental coast and might cause the observed high variability between sampling sites and days. Our results highlight the possible importance of rafting as a vector of along-shore dispersal and range expansions along the SE Pacific continental coast and add to the discussion about its role in benthic species dispersal between South Pacific oceanic islands.

Abstract Background Effective symptom control is a stated goal of palliative care (PC) to improve quality of life for terminally ill patients. Virtual reality (VR) provides temporary escapes from pharmacologically resistant pain and allows for experiences and journeys patients may not access in any other way. Enabling wishes through virtual worlds may also offer additional benefits such as controlling psychological and physical symptoms. Aims We investigated the feasibility of a single VR experience as a viable, satisfying, and effective tool for end-of-life pain relief for inpatients presenting palliative needs. Design This is an observational, single-arm and national single-center feasibility trial. Methods A one-time VR experience with a selection of several videos and games was offered to 45 inpatients receiving PC at Muenster University Hospital. Patients with brain tumors, brain metastases, seizures, motion sickness, claustrophobia, vertigo, hearing or visual impairment, or unable to consent were excluded. Primary outcome measured patient reported pain on a visual analogue scale (VAS). We also measured Karnofsky performance status, health-related quality of life (HRQOL) using the EQ-5D-5 L questionnaire, and the Pain Out Questionnaire for postoperative pain. Results We analyzed data from 21 women (52.5%) and 19 men (47.5%) at an average age of 51.9 (SD: 15.81) years. The mean Karnofsky score among the sample was 45.5 (SD: 14.97) and the HRQOL was 41.9 (SD: 23.08). While no serious side effects were reported during the intervention, three patients experienced nausea (7%), two headaches (5%), and three reported dry eyes (7%) afterwards. Significant pain reduction (baseline VAS 2.25 (SD: 0.4399)) was demonstrated during (VAS 0.7 (SD: 0.2983, p

Abstract Background Chronic heart failure (HF) is known to increase the risk of developing Alzheimer’s dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. Methods Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). Results Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = − 0.21; p = 0.013) and pTau (ρ = − 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = − 2.4 for pTau; T = − 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = − 3.1). Conclusions pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.

Abstract Background The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

Study region: Main alluvial aquifers of the Murray-Darling Basin (MDB), Australia Study focus: Around 75% of total metered groundwater use within Australia’s Murray-Darling Basin (MDB), arguably the nation’s most important food and fibre production region, is extracted from eight main alluvial aquifer systems. To date, regional-scale analyses of groundwater resilience, stress and sustainability for the region have not been completed. This study provides a systemic overview of the main alluvial systems anchored in these concepts. To achieve this, we combined three lines of evidence encompassing: a) long-term trend analysis of groundwater levels; (b) calculation of groundwater footprint indices considering volume and quality; and (c) an explicit comparison of groundwater management areas in terms of groundwater usage, sustainable use, storage volumes, presence and diversity of groundwater-dependent ecosystems (GDEs), and buffering capacity to absorb changes in recharge rates. New hydrological insights for the region: The novelty of our work rests upon an integrated assessment of these three lines of evidence incorporating twelve different metrics to prioritise future groundwater management efforts. Results indicate that eleven out of twenty-two groundwater management areas show resilience, stress and/or sustainability issues, and a further two with emergent issues. Efforts to improve our understanding and management of these key groundwater resources would be most effective if focussed on these areas.

BackgroundCognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits.MethodsThe prospective cohort study “Cognition.Matters-HF” recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing.ResultsDendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the “global deficits” cluster and the “no deficits” group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048).ConclusionApart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.

Background: Smart devices that are able to measure blood pressure (BP) are valuable for hypertension or heart failure management using digital technology. Data regarding their diagnostic accuracy in comparison to standard noninvasive measurement in accordance to Riva-Rocci are sparse. This study compared a wearable watch-type oscillometric BP monitor (Omron HeartGuide), a wearable watch-type infrared BP monitor (Smart Wear), a conventional ambulatory BP monitor, and auscultatory sphygmomanometry. Methods: Therefore, 159 consecutive patients (84 male, 75 female, mean age 64.33 ± 16.14 years) performed observed single measurements with the smart device compared to auscultatory sphygmomanometry (n = 109) or multiple measurements during 24 h compared to a conventional ambulatory BP monitor on the upper arm (n = 50). The two BP monitoring devices were simultaneously worn on the same arm throughout the monitoring period. In a subgroup of 50 patients, single measurements were also performed with an additional infrared smart device. Results: The intraclass correlation coefficient (ICC) between the difference and the mean of the oscillometric Omron HeartGuide and the conventional method for the single measurement was calculated for both systole (0.765) and diastole (0.732). This is exactly how the ICC was calculated for the individual mean values calculated over the 24 h long-term measurement of the individual patients for both systole (0.880) and diastole (0.829). The ICC between the infrared device and the conventional method was “bad” for SBP (0.329) and DBP (0.025). Therefore, no further long-term measurements were performed with the infrared device. Conclusion: The Omron HeartGuide device provided comparable BP values to the standard devices for single and long-term measurements. The infrared smart device failed to acquire valid measurement data.

Abstract Background Central airway obstruction (CAO) is one of the most challenging, potentially lethal complications in malignant and benign respiratory diseases. Worsening dyspnea is also a relevant cause for reduced quality of life in such patients. Here, we present our data on the application of covered, self‐expanding Y‐carina nitinol stents due to benign and malignant diseases. Methods We retrospectively identified 27 patients who had undergone 31 rigid bronchoscopies with implantation of covered Y‐carina nitinol stents over a period of 10 years in order to evaluate indication, clinical course, and outcome. Results Short‐term survival of successfully stented patients with palliative and curative treatment goal did not differ, allowing for diagnosis independent indication. With respect to overall survival, patients with endoluminal obstruction benefited most compared to patients with fistula and/or external compression. Granulation tissue formation (61.3%) and mucus plugging (80.6%) were the most frequent complications. Material defect (6.5%) and migration (3.2%) were rare complications that could be handled by revisional rigid bronchoscopy and stent exchange in some cases. Conclusions Implantation of self‐expanding covered Y‐carina nitinol stents via rigid bronchoscopy is a feasible and safe treatment option for benign and malignant central airway obstruction. Especially in palliative, malignant airway stenosis, stenting might facilitate additional treatment options and optimize dyspnea and eventually quality of life.

Study region: Beetaloo Sub-basin (Northern Territory) and Cooper Basin (Queensland and South Australia), Australia. Study focus: A chemical screening approach was upscaled to regional scale to assess impacts of chemical spills on unconfined aquifers. Chemical dilution factors (DFs) were developed from hydrogeochemical modelling to predict the impact of hypothetical chemical spills as part of a hazard identification process from the potential development of shale, tight and deep gas in the Beetaloo Sub-basin and Cooper Basin. Advection and dispersion modelling (non-reactive HYDRUS 1-D) was used as a conservative screening approach to estimate DFs vertically through the unsaturated zone and laterally through the unconfined aquifers. The results were upscaled to basin scale, based on spatially distributed soil, groundwater and aquifer information, including the presence of karsts. The spatial approach successfully defined areas that required additional assessment prior to any future development. New hydrological insights for the region: For chemical concentrations from surface spills to not exceed ecotoxicological thresholds at the water table, a DF of > 1000 was required. Screening areas with a DF of > 1000 constrained the area of concern for aquifer contamination from spills to 0.3 % and 14 % of the Beetaloo and Cooper regions respectively. The likelihood for long term impacts from potential undetected chemical leaks on groundwater dependent ecosystems was assessed to

BackgroundPeer victimisation is common and predicts increased internalizing symptoms. Low self-esteem, which is associated with both greater peer victimisation and higher internalizing problems, may help explain why victimised adolescents experience greater internalizing symptoms. Objectives of the present research were to establish the relationships between peer victimisation, internalizing problems, and self-esteem, and to test whether self-esteem mediates the effect of victimisation on internalizing symptoms.MethodsWe conducted a systematic literature search in Psychinfo, ERIC, Web of science, and Pubmed, following PRISMA guidelines. Inclusion criteria were: age 10-18 years; empirical studies that measured a) internalizing symptoms, b) self-esteem, and c) peer victimisation or bullying; design was either longitudinal or cross-sectional with a comparison group. Quality assessment were conducted using the Newcastle-Ottawa Quality Assessment Scale. We conducted random effects models and a meta-mediation analysis, with self-esteem acting as a mediator between peer victimization and internalizing symptoms.ResultsSixteen papers with a total of N = 35,032 (53% female) participants met the criteria for inclusion in the meta-analysis. The meta-analysis demonstrated an association between peer victimisation and both high internalizing problems (r = .31, CI 95 = .26 to.36) and low self-esteem (r = -.25, CI 95 = -.29; to -.22), and between low self-esteem and high internalizing problems ((r = -.38, CI 95 = -.42 to -.33), as well as an indirect effect of peer victimization on internalizing symptoms via self-esteem (ß = .10, CI lower = .07, CI upper = .13).ConclusionsPeer victimization, high internalizing symptoms and low self-esteem are all mutually related. Peer victimization partially mediates internalizing symptoms via self-esteem. Anti-bullying programmes may consider incorporating self-esteem building exercises in bully-victims. Limitations include high heterogeneity of results.

Triclosan (TCS), an antimicrobial agent commonly found in consumer products, has been reported to exacerbates colitis in animal models. Here, using in vitro and in vivo approaches, the authors show that gut bacterial enzymes can drive the metabolic activation and gut toxicity of TCS, highlighting an important role of intestinal microbial factors in the complex etiology of colitis.

The apparent diffusion coefficient (ADC) is a candidate marker of treatment response in osteoblastic metastases that are not evaluable by morphologic imaging. However, it is unclear whether the ADC meets the basic requirement for reliable treatment response evaluation, namely a low variance of repeated measurements in relation to the differences found between viable and nonviable metastases. The present study addresses this question by analyzing repeated in vivo ADCmedian measurements of 65 osteoblastic metastases in nine patients, as well as phantom measurements. PSMA-PET served as a surrogate for bone metastasis viability. Measures quantifying repeatability were calculated and differences in mean ADC values according to PSMA-PET status were examined. The relative repeatability coefficient %RC of ADCmedian measurements was 5.8% and 12.9% for phantom and in vivo measurements, respectively. ADCmedian values of bone metastases ranged from 595×10−6mm2/s to 2090×10−6mm2/s with an average of 63% higher values in nonviable metastases compared with viable metastases (p < 0.001). ADC shows a small repeatability coefficient in relation to the difference in ADC values between viable and nonviable metastases. Therefore, ADC measurements fulfill the technical prerequisite for reliable treatment response evaluation in osteoblastic metastases.

The growing interest in mineral resources of the deep sea, such as seafloor massive sulphide deposits, has led to an increasing number of exploration licences issued by the International Seabed Authority. In the Indian Ocean, four licence areas exist, resulting in an increasing number of new hydrothermal vent fields and the discovery of new species. Most studies focus on active venting areas including their ecology, but the non-vent megafauna of the Central Indian Ridge and South East Indian Ridge remains poorly known.In the framework of the Indian Ocean Exploration project in the German license area for seafloor massive sulphides, baseline imagery and sampling surveys were conducted yearly during research expeditions from 2013 to 2018, using video sledges and Remotely Operated Vehicles.This is the first report of an imagery collection of megafauna from the southern Central Indian- and South East Indian Ridge, reporting the taxonomic richness and their distribution. A total of 218 taxa were recorded and identified, based on imagery, with additional morphological and molecular confirmed identifications of 20 taxa from 89 sampled specimens. The compiled fauna catalogue is a synthesis of megafauna occurrences aiming at a consistent morphological identification of taxa and showing their regional distribution. The imagery data were collected during multiple research cruises in different exploration clusters of the German licence area, located 500 km north of the Rodriguez Triple Junction along the Central Indian Ridge and 500 km southeast of it along the Southeast Indian Ridge.

Sedation techniques in interventional flexible bronchoscopy and endobronchial ultrasound-guided transbronchial-needle aspiration (EBUS-TBNA) are inconsistent and the evidence for required general anesthesia under full anesthesiologic involvement is scarce. Moreover, we faced the challenge of providing bronchoscopic care with limited personnel. Hence, we retrospectively identified 513 patients that underwent flexible interventional bronchoscopy and/or EBUS-TBNA out of our institution between January 2020 and August 2022 to evaluate our deep analgosedation approach based on pethidine/meperidine bolus plus continuous flow adjusted propofol, the bronchoscopist-directed continuous flow propofol based analgosedation (BDcfP) in a two-personnel setting. Consequently, 502 out of 513 patients received BDcfP for analgosedation. We identified cardiovascular comorbidities, chronic obstructive pulmonary disease, and arterial hypertension as risk factors for periprocedural hypotension. Propofol flow rate did not correlate with hypotension. Theodrenaline and cafedrine might be used to treat periprocedural hypotension. Moreover, midazolam might be used to support the sedative effect. In conclusion, BDcfP is a safe and feasible sedative approach during interventional flexible bronchoscopy and EBUS-TBNA. In general, after the implementation of safety measures, EBUS-TBNA and interventional flexible bronchoscopy via BDcfP might safely be performed even with limited personnel.

We aimed to evaluate the predictive and prognostic value of baseline 18F-FDG-PET-CT (PET-CT) radiomic features (RFs) for immune checkpoint-inhibitor (CKI)-based first-line therapy in advanced non-small-cell lung cancer (NSCLC) patients. In this retrospective study 44 patients were included. Patients were treated with either CKI-monotherapy or combined CKI-based immunotherapy–chemotherapy as first-line treatment. Treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). After a median follow-up of 6.4 months patients were stratified into “responder” (n = 33) and “non-responder” (n = 11). RFs were extracted from baseline PET and CT data after segmenting PET-positive tumor volume of all lesions. A Radiomics-based model was developed based on a Radiomics signature consisting of reliable RFs that allow classification of response and overall progression using multivariate logistic regression. These RF were additionally tested for their prognostic value in all patients by applying a model-derived threshold. Two independent PET-based RFs differentiated well between responders and non-responders. For predicting response, the area under the curve (AUC) was 0.69 for “PET-Skewness” and 0.75 predicting overall progression for “PET-Median”. In terms of progression-free survival analysis, patients with a lower value of PET-Skewness (threshold < 0.2014; hazard ratio (HR) 0.17, 95% CI 0.06–0.46; p < 0.001) and higher value of PET-Median (threshold > 0.5233; HR 0.23, 95% CI 0.11–0.49; p < 0.001) had a significantly lower probability of disease progression or death. Our Radiomics-based model might be able to predict response in advanced NSCLC patients treated with CKI-based first-line therapy.

Achievement of complete remission signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. We used nine machine learning (ML) models to predict complete remission and 2-year overall survival in a large multicenter cohort of 1,383 AML patients who received intensive induction therapy. Clinical, laboratory, cytogenetic and molecular genetic data were incorporated and our results were validated on an external multicenter cohort. Our ML models autonomously selected predictive features including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, and U2AF1, t(8;21), inv(16)/t(16;16), del(5)/del(5q), del(17)/del(17p), normal or complex karyotypes, age and hemoglobin concentration at initial diagnosis were statistically significant markers predictive of complete remission, while t(8;21), del(5)/del(5q), inv(16)/t(16;16), del(17)/del(17p), double-mutated CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD, DNMT3A, SF3B1, U2AF1, and TP53 mutations, age, white blood cell count, peripheral blast count, serum lactate dehydrogenase level and hemoglobin concentration at initial diagnosis as well as extramedullary manifestations were predictive for 2-year overall survival. For prediction of complete remission and 2-year overall survival areas under the receiver operating characteristic curves ranged between 0.77–0.86 and between 0.63–0.74, respectively in our test set, and between 0.71–0.80 and 0.65–0.75 in the external validation cohort. We demonstrated the feasibility of ML for risk stratification in AML as a model disease for hematologic neoplasms, using a scalable and reusable ML framework. Our study illustrates the clinical applicability of ML as a decision support system in hematology.

BackgroundAlthough preventive interventions for eating disorders in general have shown promise, interventions specifically targeting individuals at risk for anorexia nervosa (AN) are lacking. ObjectiveThe aim of this study was to determine the efficacy of a guided, indicated web-based prevention program for women at risk for AN. MethodsWe conducted a randomized controlled efficacy trial for women at risk for AN. Assessments were carried out at baseline (before the intervention), after the intervention (10 weeks after baseline), and at 6- and 12-month follow-ups (FUs). A total of 168 women with low body weight (17.5 kg/m2≤BMI≤19 kg/m2) and high weight concerns or with normal body weight (19 kg/m2

Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. The use of rodent models is the most common approach to uncovering the mechanisms underlying CIBP; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative of relevant pain in patients. To improve the accuracy and strength of the preclinical, experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a home-cage monitoring assay (HCM). Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of the CIBP-phenotype, including evoked and non-evoked based assays and HCM. Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and differently) in males. Additionally, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex. This multimodal battery allows for an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalizability of results and provide information for targeted drug development in the future.

Regulators require the gas industry to assess the risks of unintentional release of chemicals to the environment and implement measures to mitigate it. Industry standard models for contaminant transport in aquifers do not explicitly model processes in the unsaturated zone and groundwater models often require long run times to complete simulation of complex processes. We propose a stochastic numerical-analytical hybrid model to overcome these two shortcomings and demonstrate its application to assess the risks associated with onshore gas drilling in the Otway Basin, South Australia. The novel approach couples HYDRUS-1D to an analytical solution to model contaminant transport in the aquifer. Groundwater velocities and chemical trajectories were derived from a particle tracking analysis. The most influential parameters controlling solute delivery to the aquifer were the soil chemical degradation constant and the hydraulic conductivity of a throttle soil horizon. Only 18% of the flow paths intercepted environmental receptors within a 1-km radius from the source, 87% of which had concentrations of