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Despite the importance of organic chemistry to human health and quality of life, very few outreach programs have been successful in communicating this message. This contributes to negative public perceptions of organic chemistry and obscures the enormous advances in quality of life engendered by organic synthesis. New chemical outreach programs that provide insight and hands-on experience of small molecule chemistry are vital to improving public engagement with the science. Make a Molecule is an organic chemistry workshop program that provides high school students with the opportunity to synthesize and biologically assess short peptides in a safe and easy manner, allowing them to experience the thrill of making and testing new bioactive molecules in a classroom environment. This manuscript details the development of the Make a Molecule project from its origins in our "synthetic fermentation" chemistry to its initial application in high schools. Scientific protocols were optimized to suit a classroom setting with the help of high school students. An accompanying website was constructed to serve as an experimental guide, aid with the workshop execution, and provide an educational resource for students and teachers. With everything in hand, the first Make a Molecule workshops were conducted in a local high school in Zurich, Switzerland, during which students were able to successfully synthesize and test novel bioactive molecules.

Abstract Very low carbohydrate high fat (VLCHF) diet and high-intensity interval training (HIIT) are widely utilized for weight reduction and cardiorespiratory fitness improvement, respectively. To assess the acceptability of these approaches, it is essential to examine mental health-related indicators. This secondary analysis of a randomized controlled trial investigated the isolated and synergistic effects of VLCHF and HIIT on mental health-related indicators in individuals with excessive weight or obesity. Sixty-eight participants (age = 42 ± 10.2; 20–60 years; BMI = 29.8 ± 3.7) were analysed across four groups: HIIT (n = 15, 4 males, 11 females), VLCHF (n = 19, 4 males, 15 females), VLCHF + HIIT (n = 19, 4 males, 15 females), and control (n = 15, 4 males, 11 females). The 12-week intervention, involved VLCHF diet or HIIT sessions, depending on group affiliation and completing online questionnaires via Qualtrics software before and after the intervention. The questionnaires included the 12-item Short Form Survey (SF-12) for mental (MHS) and physical health scores (PHS), the Satisfaction with Life Scale (SWLS), and the Perceived Stress Scale (PSS). Using the Kruskal–Wallis test, we found no significant differences in mental health-related indicators between groups after 12 weeks, except for SWLS (p = 0.031; ES = 0.133; medium), which improved significantly in the VLCHF + HIIT group compared to the HIIT group. Our findings indicate that HIIT and VLCHF, alone or combined, do not significantly affect mental health-related indicators.

Abstract Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.

Abstract Sarcopenia, defined as age-associated loss of skeletal muscle function and muscle mass, is a negative prognostic marker for survival in several tumor entities. However, data evaluating the impact of sarcopenia and fat distribution on penile cancer are rarely described. We performed a retrospective study including 38 patients who were diagnosed with squamous cell carcinoma of the penis. By measuring skeletal muscle mass and fat distribution at axial abdominal computed tomography images at the third lumbar vertebra several body composition parameters including skeletal muscle index (SMI), psoas muscle index (PMI), visceral obesity and visceral-to-subcutaneous fat ratio were determined. Among 38 patients, 26% (n = 10) of the patients with penile cancer were identified as sarcopenic. SMI, age, lymph node metastases, distant metastases and penile cancer of the shaft were identified as significant risk factors for overall survival. PMI and distant metastases were significantly associated with cancer specific survival. None of the analysed adipose tissue parameters could be identified as risk factors for survival in this study. We showed that sarcopenia occurs in a relevant part of patients with penile cancer and is a significant risk factor for overall survival (p = 0.032) and cancer specific survival (p = 0.034) for patients with penile cancer. Regarding fat distribution further studies are needed to evaluate its impact on sarcopenia and survival.

Abstract The generation of tailored supercontinua is essential for studying ultrafast light-matter interactions and for a variety of practical applications requiring broadband light. Liquid-core fibers (LCFs) have emerged as an innovative nonlinear photonic platform, demonstrating high efficiency in nonlinear frequency conversion. In this study, we showcase that LCFs provide a stable platform for ultrafast supercontinuum generation in a selected higher-order vector mode at $$1.55\;\upmu \hbox {m}$$ 1.55 μ m . Specifically, we demonstrate soliton fission and double-dispersive wave generation using a radially polarized mode in a $$\hbox {CS}_{2}$$ CS 2 -silica liquid-core fiber. The experiments were performed in a temperature-controlled laboratory, showing excellent stability with no evidence of fiber degradation, material degradation, or drift-induced changes in mode excitation over extended periods under standard environmental conditions. Our results confirm that liquid-core fibers are a reliable platform for nonlinear photonics, suitable for applications such as computationally tailored supercontinuum generation, single pulse spxectroscopy, and tailored light sources, all of which rely on consistent and stable nonlinear frequency conversion.

Abstract Smartphone applications are one of the main delivery modalities in digital health. Many of these mHealth apps use gamification to engage users, improve user experience, and achieve better health outcomes. Yet, it remains unclear whether gamified approaches help to deliver effective, safe, and clinically beneficial products to users. This study examines the compliance of 69 gamified mHealth apps with the EU Medical Device Regulation and assesses the specific risks arising from the gamified nature of these apps. Of the identified apps, 32 (46.4%) were considered non-medical devices; seven (10.1%) were already cleared/approved by the regulatory authorities, and 31 (44.9%) apps were assessed as likely non-compliant or potentially non-compliant with regulatory requirements. These applications and one approved application were assessed as on the market without the required regulatory approvals. According to our analysis, a higher proportion of these apps would be classified as medical devices in the US. The level of risk posed by gamification remains ambiguous. While most apps showed only a weak link between the degree of gamification and potential risks, this link was stronger for those apps with a high degree of gamification or an immersive game experience.

Abstract Bio-based carbon dioxide removal encompasses a range of (1) natural sink enhancement concepts in agriculture and on organic soils including peatlands, and in forestry, (2) bio-based building materials, and (3) bioenergy production with CO2 capture and storage (BECCS). A common database on these concepts is crucial for their consideration in strategies and implementation. In this study, we analyse standardised factsheets on these concepts. We find different dynamics of deployment until 2045: for CO2 removal rates from the atmosphere, natural sink enhancement concepts are characterised by gradually increasing rates, followed by a saturation and potentially a decrease after few decades; forest-related measures ramp up slowly and for construction projects and bioenergy plants, annually constant removal rates are assumed during operation which drop to zero afterwards. The expenses for removing 1 t CO2 from the atmosphere were found to be between 8 and 520 € t CO2 −1, which arises from high divergence both in capital and operational expenditures among the concepts. This high variability of expenses seems to suggest the more cost-effective concepts should be implemented first. However, aspects from economics, resource base and environmental impacts to social and political implications for Germany need to be considered for developing implementation strategies. All concepts investigated could be deployed on scales to significantly contribute to the German climate neutrality target.

Abstract This study aimed to (1) replicate a deep-learning-based model for cerebral aneurysm segmentation in TOF-MRAs, (2) improve the approach by testing various fully automatic pre-processing pipelines, and (3) rigorously validate the model’s transferability on independent, external test-datasets. A convolutional neural network was trained on 235 TOF-MRAs acquired on local scanners from a single vendor to segment intracranial aneurysms. Different pre-processing pipelines including bias field correction, resampling, cropping and intensity-normalization were compared regarding their effect on model performance. The models were tested on independent, external same-vendor and other-vendor test-datasets, each comprised of 70 TOF-MRAs, including patients with and without aneurysms. The best-performing model achieved excellent results on the external same-vendor test-dataset, surpassing the results of the previous publication with an improved sensitivity (0.97 vs. ~ 0.86), a higher Dice score coefficient (DSC, 0.60 ± 0.25 vs. 0.53 ± 0.31), and an improved false-positive rate (0.87 ± 1.35 vs. ~ 2.7 FPs/case). The model further showed excellent performance in the external other-vendor test-datasets (DSC 0.65 ± 0.26; sensitivity 0.92, 0.96 ± 2.38 FPs/case). Specificity was 0.38 and 0.53, respectively. Raising the voxel-size from 0.5 × 0.5×0.5 mm to 1 × 1×1 mm reduced the false-positive rate seven-fold. This study successfully replicated core principles of a previous approach for detecting and segmenting cerebral aneurysms in TOF-MRAs with a robust, fully automatable pre-processing pipeline. The model demonstrated robust transferability on two independent external datasets using TOF-MRAs from the same scanner vendor as the training dataset and from other vendors. These findings are very encouraging regarding the clinical application of such an approach.

Abstract Keeping up to date with the latest clinical advances in prostate cancer can be challenging. We investigated the impact of guideline use on quality of treatment decisions as well as the impact of a novel, CE-certified clinical decision support tool (Siemens AIPC software) on the amount of time clinicians spend on decision-making in a multicenter setting. Ten urologists assessed ten clinical cases (screening and localized prostate cancer) in three settings: without support, using a digital version of the EAU guidelines, and with the AIPC tool, resulting in 300 clinical decisions. Comparison involved time spent, decision correct- and completeness. Using AIPC compared to digital guidelines led to a significant reduction of expenditure of time at a per case level (3.57 min and 0:14 min, p

Abstract Diagnosis of relevant organ injury after blunt abdominal injury (AI) in multiple-injury/polytraumatised patients is challenging. AI can be distinguished between injuries of parenchymatous organs (POI) of the upper abdomen (liver, spleen) and bowel and mesenteric injuries (BMI). Still, such injuries may be associated with delays in diagnosis and treatment. The present study aimed to verify laboratory parameters, imaging diagnostics, physical examination and related injuries to predict intraabdominal injuries. This retrospective, single-centre study includes data from multiple-injury/polytraumatised patients between 2005 and 2017. Two main groups were defined with relevant abdominal injury (AI+) and without abdominal injury (AI−). The AI+ group was divided into three subgroups: BMI+, BMI+/POI+, and POI+. Groups were compared in a univariate analysis for significant differences. Logistic regression analysis was used to determine predictors for AI+, BMI+ and POI+. 26.3% (271 of 1032) of the included patients had an abdominal injury. Subgroups were composed of 4.7% (49 of 1032) BMI+, 4.7% (48 of 1032) BMI+/POI+ and 16.8% (174 of 1032) POI+. Pathological abdominal signs had a sensitivity of 48.7% and a specificity of 92.4% for AI+. Transaminases were significantly higher in cases of AI+. Pathological computed tomography (CT) (free fluid, parenchymal damage, Bowel Injury Prediction Score (BIPS), CT Grade > 4) was summarised and had a sensitivity of 94.8%, a specificity of 98%, positive predictive value (PPV) of 94.5% and, negative predictive value (NPV) of 98.2% for AI+. The detected predictors for AI+ were pathological abdominal findings (odds ratio (OR) 3.93), pathological multi-slice computed tomography (MSCT) (OR 668.9), alanine (ALAT) ≥ 1.23 µmol/ls (OR 2.35) and associated long bone fractures (OR 3.82). Pathological abdominal signs, pathological MSCT and lactate (LAC) levels ≥ 1.94 mmol/l could be calculated as significant risk factors for BMI+. For POI+ pathological abdominal MSCT, ASAT ≥ 1.73 µmol/ls and concomitant thoracic injuries had significant relevance. The study presents reliable risk factors for abdominal injury and its sub-entities. The predictors can be explained by the anatomy of the trunk and existing studies. Elevated transaminases predicted abdominal injury (AI+) and, specifically, the POI+. The pathological MSCT was the most reliable predictive parameter. However, it was essential to include further relevant parameters.

Abstract Pathophysiological processes following aneurysmal subarachnoid hemorrhage (aSAH) include upregulated underlying systemic inflammation, which is reflected by changes in different peripheral blood cells and their sub-populations. As inflammation is a crucial process that contributes to post-aSAH complications and clincal outcome, blood cell numbers and ratios in systemic circulation may predict the outcome and provide rapid and easy to quantify point of care biomarkers for these critically ill patients. To identify blood-derived cellular inflammatory parameters which allow a precise prediction of patient outcome after aSAH. In this single-center retrospective study, 19 whole blood-derived cellular inflammatory markers and clinical and demographic parameters for 101 aSAH patients were recorded within 24 h after aSAH. Clinical outcome was quantified with modified Rankin scale (mRS) on discharge. Proportional odds logistic regression (POLR) was used to model the patient outcome as the function of clinical parameters and inflammatory markers. The results were validated on a separate hold-out dataset (220 patients). The on-admission platelet count, mean platelet volume (MPV) and mean platelet volume to platelet ratio (MPR) were found to be significant and predictive of patient outcome on discharge. Mean platelet volume (MPV) and mean platelet volume to platelet ratio (MPR) predicted clinical outcome and may serve as easy to quantify point of care biomarker. The findings are potentially relevant for the management of aSAH.

Abstract Background 7 T cardiac magnetic resonance imaging (MRI) studies may enable higher precision in clinical metrics like cardiac function, ventricular mass, and more. Higher precision may allow early detection of functional impairment and early evaluation of treatment responses in clinical practice and pre-clinical studies. Methods: Seven female German Landrace pigs were scanned prior to and at three time points (3–4 days, 7–10 days, and ~60 days) post myocardial infarction using a whole body 7 T system and three radiofrequency (RF) coils developed and built in-house to accompany animal growth. Results: The combination of dedicated RF hardware and 7 T MRI enables a longitudinal study in a pig model of acute and chronic infarction, providing consistent blood tissue contrast and high signal-to-noise ratio (SNR) in measurements of cardiac function, as well as low coefficients of variation (CoV) for ejection fraction (CoVintra-observer: 2%, CoVinter-observer: 3.8%) and infarct size (CoVintra-observer: 8.4%, CoVinter-observer: 3.8%), despite drastic animal growth. Conclusions: Best results are achieved via manual segmentation. We define state-of-the-art procedures for large animal studies at 7 T.

Abstract Conventional radiography is regularly used to evaluate complications after total hip arthroplasty. In various recent consensus meetings, however, plain radiographs of a potentially infected hip joint have been judged as being only relevant to exclude diagnoses other than infection. Solid data on radiographic presentations of periprosthetic joint infection (PJI) are scarce. As a result, the prognostic value of radiological features in low-grade PJI remains uncertain. The present review article aims to present an overview of the available literature and to develop ideas on future perspectives to define the diagnostic possibilities of radiography in PJIs of the hip. The primary outcome of interest of this systematic review was the radiologic presentation of periprosthetic joint infections of the hip. As secondary outcome of interest served the sensitivity and specificity of the radiologic presentation of periprosthetic joint infections. Of the included articles, 26 were reviews, essays, or case reports and only 18 were clinical studies. Typical radiologic abnormalities of PJI were a periosteal reaction, a wide band of radiolucency at the cement–bone or metal–bone interface, patchy osteolysis, implant loosening, bone resorption around the implant, and transcortical sinus tracts. The frequency of their occurrence is still inadequately defined. A deeper understanding of the underlying causes and the relation between microorganisms to radiologic abnormalities can probably help clinicians in the future to diagnose a PJI. This is why further research shall focus on the radiographic features of PJI.

Summary: Background: A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters. Methods: 50 livers subjected to NMP for up to 24 h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction. Findings: Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6 h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6 h NMP correlated with impaired graft function. Interpretation: Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation. Funding: The research was supported by “In Memoriam Dr. Gabriel Salzner Stiftung”, Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.

Proteasomes are essential molecular machines responsible for the degradation of proteins in eukaryotic cells. Altered proteasome activity has been linked to neurodegeneration, auto-immune disorders and cancer. Despite the relevance for human disease and drug development, no method currently exists to monitor proteasome composition and interactions in vivo in animal models. To fill this gap, we developed a strategy based on tagging of proteasomes with promiscuous biotin ligases and generated a new mouse model enabling the quantification of proteasome interactions by mass spectrometry. We show that biotin ligases can be incorporated in fully assembled proteasomes without negative impact on their activity. We demonstrate the utility of our method by identifying novel proteasome-interacting proteins, charting interactomes across mouse organs, and showing that proximity-labeling enables the identification of both endogenous and small-molecule-induced proteasome substrates.

Abstract Cardiac magnetic resonance (CMR) imaging allows precise non-invasive quantification of cardiac function. It requires reliable image segmentation for myocardial tissue. Clinically used software usually offers automatic approaches for this step. These are, however, designed for segmentation of human images obtained at clinical field strengths. They reach their limits when applied to preclinical data and ultrahigh field strength (such as CMR of pigs at 7 T). In our study, eleven animals (seven with myocardial infarction) underwent four CMR scans each. Short-axis cine stacks were acquired and used for functional cardiac analysis. End-systolic and end-diastolic images were labelled manually by two observers and inter- and intra-observer variability were assessed. Aiming to make the functional analysis faster and more reproducible, an established deep learning (DL) model for myocardial segmentation in humans was re-trained using our preclinical 7 T data (n = 772 images and labels). We then tested the model on n = 288 images. Excellent agreement in parameters of cardiac function was found between manual and DL segmentation: For ejection fraction (EF) we achieved a Pearson’s r of 0.95, an Intraclass correlation coefficient (ICC) of 0.97, and a Coefficient of variability (CoV) of 6.6%. Dice scores were 0.88 for the left ventricle and 0.84 for the myocardium.

Abstract The aim of this study was to investigate the associations between cardiorespiratory fitness (CRF), long-term air pollution exposure and biochemical markers of oxidative status and inflammation. This is a cross-sectional investigation focusing on biochemical markers of oxidative status and inflammation. Participants were Caucasian (N = 1188; age 18–65 years) who lived for at least 5 years in a high air-polluted (Moravian-Silesian; MS) or low air-polluted (South Bohemia; SB) region of the Czech Republic. Healthy runners and inactive individuals were recruited. A multiple regression analysis was used to explain the relationship between multiple independent variables (CRF, trunk fat mass, sex, socioeconomic status, and region (MS region vs. SB region) and dependent variables (oxidative status, inflammation). CRF, trunk fat mass, age and sex significantly predicted almost all selected markers of oxidative status and inflammation (except GSSG, GSH/GSSG and BDNF). Participants living in the MS region presented significantly higher GPx (by 3.1%) and lower BDNF values (by 4.5%). All other investigated biochemical markers were not significantly influenced by region. We did not find meaningful interactions between long-term air-pollution exposure versus markers of oxidative status and inflammation. However, we showed various significant interactions with sex, age, CRF and body composition. The significant association of living in the high air polluted MS region with the BDNF level warrants further attention.

Abstract Psychological flexibility plays a crucial role in how young adults adapt to their evolving cognitive and emotional landscapes. Our study investigated a core aspect of psychological flexibility in young adults: adaptive variability and maladaptive rigidity in the capacity for behavior change. We examined the interplay of these elements with cognitive-affective processes within a dynamic network, uncovering their manifestation in everyday life. Through an Ecological Momentary Assessment design, we collected intensive longitudinal data over 3 weeks from 114 young adults ages 19 to 32. Using a dynamic network approach, we assessed the temporal dynamics and individual variability in flexibility in relation to cognitive-affective processes in this sample. Rigidity exhibited the strongest directed association with other variables in the temporal network as well as highest strength centrality, demonstrating particularly strong associations to other variables in the contemporaneous network. In conclusion, the results of this study suggest that rigidity in young adults is associated with negative affect and cognitions at the same time point and the immediate future.

Abstract Feline leukemia virus (FeLV) infection is considered one of the most serious disease threats for the endangered Iberian lynx (Lynx pardinus) Over 14 years (2008–2021), we investigated FeLV infection using point-of-care antigen test and quantitative real-time TaqMan qPCR for provirus detection in blood and tissues in lynxes from Andalusia (Southern Spain). A total of 776 samples from 586 individuals were included in this study. The overall prevalence for FeLV antigen in blood/serum samples was 1.4% (5/360) (95% CI: 0.2–2.6), FeLV proviral DNA prevalence in blood samples was 6.2% (31/503) (95% CI: 4.1–8.6), and FeLV proviral DNA in tissues samples was 10.2% (34/333) (95% CI: 7–13.5). From a subset of 129 longitudinally sampled individuals, 9.3% (12/129) PCR-converted during the study period. Our results suggest that FeLV infection in the Andalusian population is enzootic, with circulation of the virus at low levels in almost all the sampling years. Moreover, since only one viremic individual succumbed to the infection, this study suggests that lynxes may therefore control the infection decreasing the possibility of developing a more aggressive outcome. Although our results indicate that the FeLV infection in the Iberian lynx from Andalusia tends to stay within the regressive stage, continuous FeLV surveillance is paramount to predict potential outbreaks and ensure the survival of this population.

Human leucocyte antigen class I (HLA-I) molecules play a central role for both NK and T-cell responses that prevent serious human cytomegalovirus (HCMV) disease. To create opportunities for viral spread, several HCMV-encoded immunoevasins employ diverse strategies to target HLA-I. Among these, the glycoprotein US10 is so far insufficiently studied. While it was reported that US10 interferes with HLA-G expression, its ability to manipulate classical HLA-I antigen presentation remains unknown. In this study, we demonstrate that US10 recognizes and binds to all HLA-I (HLA-A, -B, -C, -E, -G) heavy chains. Additionally, impaired recruitment of HLA-I to the peptide loading complex was observed. Notably, the associated effects varied significantly dependending on HLA-I genotype and allotype: (i) HLA-A molecules evaded downregulation by US10, (ii) tapasin-dependent HLA-B molecules showed impaired maturation and cell surface expression, and (iii) β2m-assembled HLA-C, in particular HLA-C*05:01 and -C*12:03, and HLA-G were strongly retained in complex with US10 in the endoplasmic reticulum. These genotype-specific effects on HLA-I were confirmed through unbiased HLA-I ligandome analyses. Furthermore, in HCMV-infected fibroblasts inhibition of overlapping US10 and US11 transcription had little effect on HLA-A, but induced HLA-B antigen presentation. Thus, the US10-mediated impact on HLA-I results in multiple geno- and allotypic effects in a so far unparalleled and multimodal manner.

Summary: Background: The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. Methods: We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. Findings: By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients’ subgroups. Interpretation: An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. Funding: German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.

Abstract In 70 patients with KIT D816V positive systemic mastocytosis (SM) including 36 patients with advanced SM (AdvSM), we correlated the extent of reported mucosal mast cell ([m]MC) infiltration of the upper and/or lower gastrointestinal tract (UGIT, n = 63; LGIT, n = 64; both, n = 57) with symptoms and markers of MC burden/subtype. GI symptoms were reported by all patients (mean 2.1 number of symptoms). A strong mMC infiltration was identified in 24 patients (UGIT, 17/63, 27%; LGIT, 19/64, 30%). Concurrent involvement of UGIT and LGIT (n = 12) correlated with female gender (75%) and a higher symptom burden (mean 2.7) but not with MC burden or subtype. Significant differences between non-AdvSM and AdvSM were reported regarding food intolerance (54% vs. 17%), cramping (54% vs. 22%) and weight loss (0% vs. 64%). KIT D816V was identified in 54/56 (96%) available biopsies. In 46 patients, digital PCR revealed a correlation with low albumin levels (r = − 0.270, P = 0.069) and the KIT D816V VAF in peripheral blood (r = 0.317, P = 0.036) but not with the extent of mMC infiltration or markers of MC burden/subtype. Although MC mediator triggered GI symptoms have a substantial impact on the quality of life, correlation to objective disease parameters is lacking thus making its systematic assessment challenging.

Abstract Cardiac myocyte sodium (Na+) homoeostasis is pivotal in cardiac diseases and heart failure. Intracellular Na+ ([Na+]i) is an important regulator of excitation–contraction coupling and mitochondrial energetics. In addition, extracellular Na+ ([Na+]e) and its water-free storage trigger collagen cross-linking, myocardial stiffening and impaired cardiac function. Therefore, understanding the allocation of tissue Na+ to intra- and extracellular compartments is crucial in comprehending the pathophysiological processes in cardiac diseases. We extrapolated [Na+]e using a three-compartment model, with tissue Na+ concentration (TSC) measured by in vivo 23Na-MRI, extracellular volume (ECV) data calculated from T1 maps, and [Na+]i measured by in vitro fluorescence microscopy using Na+ binding benzofuran isophthalate (SBFI). To investigate dynamic changes in Na+ compartments, we induced pressure overload (TAC) or myocardial infarction (MI) via LAD ligation in mice. Compared to SHAM mice, TSC was similar after TAC but increased after MI. Both TAC and MI showed significantly higher [Na+]i compared to SHAM (around 130% compared to SHAM). Calculated [Na+]e increased after MI, but not after TAC. Increased TSC after TAC was primarily driven by increased [Na+]i, but the increase after MI by elevations in both [Na+]i and [Na+]e.

Abstract When treating ankle fractures, the question of syndesmosis complex involvement often arises. So far, there is no standardized method to reliably detect syndesmosis injuries in the surgical treatment of ankle fractures. For this reason, an intraoperative syndesmosis-test-tool (STT) was developed and compared to the recommended and established hook-test (HT). Tests were performed on cadaveric lower legs (n = 20) and the diastasis was visualized by 3D camera. Tests were performed at 50, 80, and 100 N in native conditions and four instability levels. Instability was induced from anterior to posterior and the reverse on the opposite side. The impact on diastasis regarding the direction, the force level, the instability level, and the device used was checked using a general linear model for repeated measurement. The direction of the induced instability showed no influence on the diastasis during the stability tests. The diastasis measured with the STT increased from 0.5 to 3.0 mm depending on the instability, while the range was lower with the HT (1.1 to 2.3 mm). The results showed that the differentiation between the instability levels was statistically significantly better for the developed STT. The last level of maximum instability was significantly better differentiable with the STT compared to the HT. An average visualizable diastasis of more than 2 mm could only be achieved at maximum instability. In conclusion, the newly developed STT was superior to the commonly used HT to detect instability.

Abstract In this work, the quasi-analog to discrete transition occurring in the current–voltage characteristic of oxygen engineered yttrium oxide-based resistive random-access memory (RRAM) devices is investigated in detail. In particular, the focus of our research is not on the absolute conductance values of this characteristic but on the magnitude of its conductance changes occurring during the reset process of the device. It is found that the detected changes correspond to conductance values predominantly of the order of the quantum unit of conductance G 0 = 2e 2/h, where e is the electron charge and h the Planck constant. This feature is observed even at conductance levels far above G 0 , i.e. where electron transport is seemingly diffusive. It is also observed that such behavior is reproducible across devices comprising yttrium oxide layers with different oxygen concentrations and measured under different voltage sweep rates. While the oxygen deficiency affects the total number of quantized conductance states, the magnitude of the changes in conductance, close to 1 G 0 , is invariant to the oxygen content of the functional layer.

Abstract Serological assays measuring antibodies against SARS-CoV-2 are key to describe the epidemiology, pathobiology or induction of immunity after infection or vaccination. Of those, multiplex assays targeting multiple antigens are especially helpful as closely related coronaviruses or other antigens can be analysed simultaneously from small sample volumes, hereby shedding light on patterns in the immune response that would otherwise remain undetected. We established a bead-based 17-plex assay detecting antibodies targeting antigens from all coronaviruses pathogenic for humans: SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV strains 229E, OC43, HKU1, and NL63. The assay was validated against five commercial serological immunoassays, a commercial surrogate virus neutralisation test, and a virus neutralisation assay, all targeting SARS-CoV-2. It was found to be highly versatile as shown by antibody detection from both serum and dried blot spots and as shown in three case studies. First, we followed seroconversion for all four endemic HCoV strains and SARS-CoV-2 in an outbreak study in day-care centres for children. Second, we were able to link a more severe clinical course to a stronger IgG response with this 17-plex-assay, which was IgG1 and IgG3 dominated. Finally, our assay was able to discriminate recent from previous SARS-CoV-2 infections by calculating the IgG/IgM ratio on the N antigen targeting antibodies. In conclusion, due to the comprehensive method comparison, thorough validation, and the proven versatility, our multiplex assay is a valuable tool for studies on coronavirus serology.

Summary: Background: Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored. Methods: Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca2+ dynamics and decoders to elucidate the pathway from receptor to phenotype. Findings: CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state. This shifts the Ca2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca2+ dynamic changes. Ca2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation. Interpretation: CHRFAM7A introduces an additional, human specific, layer to Ca2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis. Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae).

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Objectives The objective of this study is to investigate the proportion of potentially low-value knee MRI in Norway and to provide an estimate of the related costs.Design Register study based on conditional data extraction and analysis of data from Control and Reimbursement of Healthcare Claims registry in Norway.Setting MRI in public specialist healthcare with universal health coverage (Norway).Participants 48 212 MRIs for 41 456 unique patients and 45 946 reimbursement claims.Outcome measures Proportion of MRIs of the knee that (1) did not have a relevant tentative diagnosis prior to the knee MRI, (2) did not have a relevant alternative image of the knee before the MRI or (3) did not have a relevant code from the specialist care within 6 months after the MRI, and those that had combinations of 1, 2 and 3. Estimated costs for those that had combinations of 1, 2 and 3.Results Very few patients (6.4%) had a relevant diagnosis code or prior imaging examination when having the MRI and only 14.6% got a knee-related diagnosis code from the specialist care within 6 months after the MRI. 21.8% of the patients had knee X-ray, CT or ultrasound within 6 months before the MRI. Between 58% and 85% of patients having knee MRIs in Norway have no relevant examinations or diagnoses six months prior to or after the MRI examination. These examinations are unlikely to benefit patients and they correspond to between 24 108 and 35 416 MRIs at a cost of €6.7–€9.8 million per year.Conclusion A substantial proportion of MRIs of the knee in Norway have no relevant examinations or diagnoses before or after the MRI and are potentially of low value. Reducing low-value MRIs could free resources for high-value imaging, reduce waiting times, improve the quality of care and increase patient safety and professional integrity.

A cluster of 3 persons in Germany experienced hantavirus disease with renal insufficiency. Reverse transcription PCR–based genotyping revealed infection by Seoul hantavirus transmitted from pet rats. Seoul virus could be responsible for disease clusters in Europe, and infected pet rats should be considered a health threat.

Abstract Background Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p

Abstract Is disease demotion more important than health promotion? The question is crucial for the ethos of medicine and for priority setting in healthcare. When things get tough, where should our attention and resources go: to health or disease? This study investigates two general perspectives on health and disease to address whether there is a stronger moral appeal from people’s disease than from their health. While naturalist conceptions of health and disease are mute on moral appeal, normativist conceptions give diverse answers. Classical utilitarianism provides a symmetrical view of health and disease, according to which we have an equally strong moral appeal to further health as we have to reduce disease. Other normativist positions argue that there is an asymmetry between health and disease providing substantial support for a stronger moral appeal from disease than from health. This has a wide range of radical implications, especially within priority setting. In particular, treatment, palliation, and prevention of disease should have priority to the promotion and enhancement of health.

Abstract Total hip arthroplasty (THA) is a common procedure for patients suffering from hip pain e.g. from osteoarthritis, osteonecrosis, or hip fractures. The satisfaction of patients undergoing THA is influenced by the choice of implant type and material, with one key factor being the selection of the appropriate material combination for the bearing surface. In this Bayesian network meta-analysis, we investigated the impact of material combinations for the bearing surface on the longevity of hip implants. The wear penetration rate per year and the total wear penetration in the liner resulting from different material combinations, as well as the survival rate at last follow-up, were examined. We analyzed a total of 663,038 THAs, with 55% of patients being women. Mean patient age was 59.0 ± 8.1 years and mean BMI 27.6 ± 2.6 kg/m2. The combination of an aluminium oxide (Al2O3) head and an Al2O3 liner demonstrated the lowest wear penetration at last follow-up and the lowest rate of wear penetration per year. Additionally, the combination of a crosslinked polyethylene (XLPE) liner and a zircon oxide (ZrO2) head demonstrated the lowest rate of revision at last follow-up. These findings underscore the importance of careful material selection for hip implant bearing surfaces to optimize their longevity and patient satisfaction after THA.

Abstract Computer tomography-derived skeletal muscle index normalized for height in conjunction with muscle density enables single modality-based sarcopenia assessment that accounts for all diagnostic criteria and cutoff recommendations as per the widely accepted European consensus. Yet, the standard approach to quantify skeletal musculature at the third lumbar vertebra is limited for certain patient groups, such as lung cancer patients who receive chest CT for tumor staging that does not encompass this lumbar level. As an alternative, this retrospective study assessed sarcopenia in lung cancer patients treated with curative intent at the tenth thoracic vertebral level using appropriate cutoffs. We showed that skeletal muscle index and radiation attenuation at level T10 correlate well with those at level L3 (Pearson’s R = 0.82 and 0.66, p

Abstract Purpose Dental implant abutments are defined as medical devices by their intended use. Surfaces of custom-made CAD/CAM two-piece abutments may become contaminated during the manufacturing process in the dental lab. Inadequate reprocessing prior to patient care may contribute to implant-associated complications. Risk-adapted hygiene management is required to meet the requirements for medical devices. Methods A total of 49 CAD/CAM-manufactured zirconia copings were bonded to prefabricated titanium bases. One group was bonded, polished, and cleaned separately in dental laboratories throughout Germany (LA). Another group was left untreated (NC). Five groups received the following hygiene regimen: three-stage ultrasonic cleaning (CP and FP), steam (SC), argon–oxygen plasma (PL), and simple ultrasonic cleaning (UD). Contaminants were detected using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) and segmented and quantified using interactive machine learning (ML) and thresholding (SW). The data were statistically analysed using non-parametric tests (Kruskal–Wallis test, Dunn’s test). Results Significant differences in contamination levels with the different cleaning procedures were found (p ≤ 0.01). The FP–NC/LA groups showed the most significant difference in contamination levels for both measurement methods (ML, SW), followed by CP–LA/NC and UD–LA/NC for SW and CP–LA/NC and PL–LA/NC for ML (p ≤ 0.05). EDS revealed organic contamination in all specimens; traces of aluminum, silicon, and calcium were detected. Conclusions Chemothermal cleaning methods based on ultrasound and argon–oxygen plasma effectively removed process-related contamination from zirconia surfaces. Machine learning is a promising assessment tool for quantifying and monitoring external contamination on zirconia abutments. Graphical Abstract

Peracetic acid (PAA) shows potential for use in drinking water treatment as an alternative to prechlorination, such as for mussel control and disinfection by-product precursor destruction, though its impact as a preoxidant during cyanobacterial blooms remains underexplored. Here, Microcystis aeruginosa inactivation and microcystin-LR and -RR release and degradation using PAA were explored. The toxin degradation rates were found to be higher in alkaline conditions than in neutral and acidic conditions. However, all rates were significantly smaller than comparable rates when using free chlorine. The inactivation of M. aeruginosa cells using PAA was faster at acidic pH, showing immediate cell damage and subsequent cell death after 15–60 min of exposure to 10 mg/L PAA. In neutral and alkaline conditions, cell death occurred after a longer lag phase (3–6 h). During cell inactivation, microcystin-LR was released slowly, with M. aeruginosa cell inactivation or microcystin-LR and -RR destruction in drinking water treatment, but this slow reactivity may also allow it to continue to be applied as a preoxidant for other purposes during cyanobacterial blooms without the risk of toxin release.

Abstract Despite the growing deployment of network representation to comprehend psychological phenomena, the question of whether and how networks can effectively describe the effects of psychological interventions remains elusive. Network control theory, the engineering study of networked interventions, has recently emerged as a viable methodology to characterize and guide interventions. However, there is a scarcity of empirical studies testing the extent to which it can be useful within a psychological context. In this paper, we investigate a representative psychological intervention experiment, use network control theory to model the intervention and predict its effect. Using this data, we showed that: (1) the observed psychological effect, in terms of sensitivity and specificity, relates to the regional network control theoretic metrics (average and modal controllability), (2) the size of change following intervention negatively correlates with a whole-network topology that quantifies the “ease” of change as described by control theory (control energy), and (3) responses after intervention can be predicted based on formal results from control theory. These insights assert that network control theory has significant potential as a tool for investigating psychological interventions. Drawing on this specific example and the overarching framework of network control theory, we further elaborate on the conceptualization of psychological interventions, methodological considerations, and future directions in this burgeoning field.

Abstract The timing, sequence, and scale of uplift of the Himalayan–Tibetan Orogen (HTO) are controversially debated. Many geoscientific studies assume paleoelevations close to present-day elevations and the existence of alpine environments across the HTO already in the late Paleogene, contradicting fossil data. Using molecular genetic data of ground beetles, we aim to reconstruct the paleoenvironmental history of the HTO, focusing on its southern margin (Himalayas, South Tibet). Based on a comprehensive sampling of extratropical Carabus, and ~ 10,000 bp of mitochondrial and nuclear DNA we applied Bayesian and Maximum likelihood methods to infer the phylogenetic relationships. We show that Carabus arrived in the HTO at the Oligocene–Miocene boundary. During the early Miocene, five lineages diversified in different parts of the HTO, initially in its southern center and on its eastern margin. Evolution of alpine taxa occurred during the late Miocene. There were apparently no habitats for Carabus before the late Oligocene. Until the Late Oligocene elevations must have been low throughout the HTO. Temperate forests emerged in South Tibet in the late Oligocene at the earliest. Alpine environments developed in the HTO from the late Miocene and, in large scale, during the Pliocene–Quaternary. Findings are consistent with fossil records but contrast with uplift models recovered from stable isotope paleoaltimetry.

Abstract Here we analyze the trends of rainfall and the frequency of rainy days over the Brazilian Cerrado between 1960 and 2021 in four distinct periods according to the seasonal patterns over the region. We also evaluated trends in evapotranspiration, atmospheric pressure, winds, and atmospheric humidity over the Cerrado to elucidate the possible reasons for the detected trends. We recorded a significant reduction in rainfall and frequency of rainy days in the northern and central Cerrado regions for all periods except at the beginning of the dry season. The most pronounced negative trends were recorded during the dry season and the beginning of the wet season, where we recorded reductions of up to 50% in total rainfall and the number of rainy days. These findings are associated with the intensification of the South Atlantic Subtropical Anticyclone, which has been shifting atmospheric circulation and raising regional subsidence. Moreover, during the dry season and the beginning of the wet season, there was a reduction in regional evapotranspiration, which also potentially contributed to the rainfall reduction. Our results suggest an expansion and intensification of the dry season in the region, potentially bringing broad environmental and social impacts that transcend the Cerrado boundaries.

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is associated with significant postoperative complications. Early detection of at-risk patients may lead to improved outcomes. The role of C-reactive protein (CRP) in predicting postoperative complications has only been recently investigated.

Abstract Background Although mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8+ T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness. Methods Comparison groups included persons with lung transplantation and no history of COVID-19 (21 and 19 persons after initial mRNA vaccination and a third booster vaccination respectively), 8 lung transplantation participants recovered from COVID-19, and 22 non-immunocompromised healthy control individuals after initial mRNA vaccination (without history of COVID-19). Anti-spike T cell responses were assayed by stimulating peripheral blood mononuclear cells (PBMCs) with pooled small overlapping peptides spanning the SARS-CoV-2 spike protein, followed by intracellular cytokine staining (ICS) and flow cytometry for release of cytokines in response to stimulation, including negative controls (no peptide stimulation) and positive controls (phorbol myristate acetate [PMA] and ionomycin stimulation). To evaluate for low frequency memory responses, PBMCs were cultured in the presence of the mRNA-1273 vaccine for 14 days before this evaluation. Results Ionophore stimulation of PBMCs revealed a less inflammatory milieu in terms of interleukin (IL)-2, IL-4, and IL-10 profiling in lung transplantation individuals, reflecting the effect of immunosuppressive treatments. Similar to what we previously reported in healthy vaccinees, spike-specific responses in lung transplantation recipients were undetectable (

Objectives Healthcare workers (HCWs) are on the frontline of combating COVID-19, hence are at elevated risk of contracting an infection with SARS-CoV-2. The present study aims to measure the impact of SARS-CoV-2 on HCWs in central sub-Saharan Africa.Setting A cross-sectional serological study was conducted at six urban and five rural hospitals during the first pandemic wave in the South Kivu province, Democratic Republic of the Congo (DRC).Participants Serum specimens from 1029 HCWs employed during the first pandemic wave were collected between August and October 2020, and data on demographics and work-related factors were recorded during structured interviews.Primary and secondary outcome measures The presence of IgG antibodies against SARS-CoV-2 was examined by ELISA. Positive specimens were further tested using a micro-neutralisation assay. Factors driving SARS-CoV-2 seropositivity were assessed by multivariable analysis.Results Overall SARS-CoV-2 seroprevalence was high among HCWs (33.1%), and significantly higher in urban (41.5%) compared with rural (19.8%) hospitals. Having had presented with COVID-19-like symptoms before was a strong predictor of seropositivity (31.5%). Personal protective equipment (PPE, 88.1% and 11.9%) and alcohol-based hand sanitizer (71.1% and 28.9%) were more often available, and hand hygiene was more often reported after patient contact (63.0% and 37.0%) in urban compared with rural hospitals, respectively. This may suggest that higher exposure during non-work times in high incidence urban areas counteracts higher work protection levels of HCWs.Conclusions High SARS-CoV-2 seropositivity indicates widespread transmission of the virus in this region of DRC. Given the absence of publicly reported cases during the same time period at the rural sites, serological studies are very relevant in revealing infection dynamics especially in regions with low diagnostic capacities. This, and discrepancies in the application of PPE between urban and rural sites, should be considered in future pandemic response programmes.

The COVID-19 pandemic disrupted scientific research, teaching, and learning in higher education and forced many institutions to explore new modalities in response to the abrupt shift to remote learning. Accordingly, many colleges and universities struggled to provide the training, technology, and best practices to support faculty and students, especially those at historically disadvantaged and underrepresented institutions. In this study we investigate different remote learning modalities to improve and enhance research education training for faculty and students. We specifically focus on Responsible and Ethical Conduct of Research (RECR) and research mentoring content to help address the newly established requirements of the National Science Foundation for investigators. To address this need we conducted a workshop to determine the effectiveness of three common research education modalities: Live Lecture, Podcast, and Reading. The Live Lecture sessions provided the most evidence of learning based on the comparison between pre- and post-test results, whereas the Podcast format was well received but produced a slight (and non-significant) decline in scores between the pre- and post-tests. The Reading format showed no significant improvement in learning. The results of our workshop illuminate the effectiveness and obstacles associated with various remote learning modalities, enabling us to pinpoint areas that require additional refinement and effort, including the addition of interactive media in Reading materials.

Abstract Introduction The management of periprosthetic joint infections (PJI) of the lower limb is challenging, and evidence-based recommendations are lacking. The present clinical investigation characterized the pathogens diagnosed in patients who underwent revision surgery for PJI of total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods The present study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The institutional databases of the RWTH University Medical Centre of Aachen, Germany, were accessed. The OPS (operation and procedure codes) 5–823 and 5–821 and the ICD (International Statistical Classification of Diseases and Related Health Problems) codes T84.5, T84.7 or T84.8 were used. All patients with PJI of a previous THA and TKA who underwent revision surgery were retrieved and included for analysis. Results Data from 346 patients were collected (181 THAs and 165 TKAs). 44% (152 of 346 patients) were women. Overall, the mean age at operation was 67.8 years, and the mean BMI was 29.2 kg/m2. The mean hospitalization length was 23.5 days. 38% (132 of 346) of patients presented a recurrent infection. Conclusion PJI remain a frequent cause for revisions after total hip and knee arthroplasty. Preoperative synovial fluid aspiration was positive in 37%, intraoperative microbiology was positive in 85%, and bacteraemia was present in 17% of patients. Septic shock was the major cause of in-hospital mortality. The most common cultured pathogens were Staph. epidermidis, Staph. aureus, Enterococcus faecalis, and Methicillin-resistant Staph aureus (MRSA). An improved understanding of PJI pathogens is important to plan treatment strategies and guide the choice of empirical antibiotic regimens in patients presenting with septic THAs and TKAs. Level of Evidence: Level III, retrospective cohort study.

Abstract Octreotide, a somatostatin analogue, has shown its efficacy for the diagnostics and treatment of various types of cancer, i.e., in octreotide scan, as radio-marker after labelling with a radiopharmaceutical. To avoid toxicity of radio-labeling, octreotide-based assays can be implemented into magnetic resonance techniques, such as MRI and NMR. Here we used a Parahydrogen-Induced Polarization (PHIP) approach as a cheap, fast and straightforward method. Introduction of l-propargyl tyrosine as a PHIP marker at different positions of octreotide by manual Solid-Phase Peptide Synthesis (SPPS) led to up to 2000-fold proton signal enhancement (SE). Cell binding studies confirmed that all octreotide variants retained strong binding affinity to the surface of human-derived cancer cells expressing somatostatin receptor 2. The hydrogenation reactions were successfully performed in methanol and under physiologically compatible mixtures of water with methanol or ethanol. The presented results open up new application areas of biochemical and pharmacological studies with octreotide.