Search

Abstract Here we apply the two-high threshold eyewitness identification model to identify the effects of lineup size on the detection-based and non-detection-based processes underlying eyewitness decisions. In Experiment 1, lineup size was manipulated by showing participants simultaneous or sequential lineups that contained either three or six persons. In Experiment 2, the lineups contained either two or five persons. In both experiments, the culprit was better detected in smaller than in larger lineups. Furthermore, participants made fewer guessing-based selections in smaller than in larger lineups. However, guessing-based selection in larger lineups was not increased to a level sufficient to offset the effect of increased protection of suspects in larger lineups due to the fact that the guessing-based selections that occur are distributed across more persons. The results show that increasing the lineup size causes several changes in the detection-based and non-detection-based processes underlying eyewitness decisions.

Abstract Macrophages (MΦ) play a role in neonatal etiologies of obstructive cholestasis, however, the role for precise MΦ subsets remains poorly defined. We developed a neonatal murine model of bile duct ligation (BDL) to characterize etiology-specific differences in neonatal cholestatic MΦ polarization. Neonatal BDL surgery was performed on female BALB/c mice at 10 days of life (DOL) with sham laparotomy as controls. Comparison was made to the Rhesus Rotavirus (RRV)-induced murine model of biliary atresia (BA). Evaluation of changes at day 7 after surgery (BDL and sham groups) and murine BA (DOL14) included laboratory data, histology (H&E, anti-CD45 and anti-CK19 staining), flow cytometry of MΦ subsets by MHCII and Ly6c expression, and single cell RNA-sequencing (scRNA-seq) analysis. Neonatal BDL achieved a 90% survival rate; mice had elevated bile acids, bilirubin, and alanine aminotransferase (ALT) versus controls (p

Abstract GDF15 has recently emerged as a key driver of the development of various disease conditions including cancer cachexia. Not only the tumor itself but also adverse effects of chemotherapy have been reported to contribute to increased GDF15. Although regulation of GDF15 transcription by BET domain has recently been reported, the molecular mechanisms of GDF15 gene regulation by drugs are still unknown, leaving uncertainty about the safe and effective therapeutic strategies targeting GDF15. We screened various cardiotoxic drugs and BET inhibitors for their effects on GDF15 regulation in human cardiomyocytes and cancer cell lines and analyzed in-house and public gene signature databases. We found that DNA damaging drugs induce GDF15 in cardiomyocytes more strongly than drugs with other modes of action. In cancer cells, GDF15 induction varied depending on drug- and cell type-specific gene signatures including mutations in PI3KCA, TP53, BRAF and MUC16. GDF15 suppression by BET inhibition is particularly effective in cancer cells with low activity of the PI3K/Akt axis and high extracellular concentrations of pantothenate. Our findings provide insights that the risk for GDF15 overexpression and concomitant cachexia can be reduced by a personalized selection of anticancer drugs and patients for precision medicine.

Abstract Organic radical batteries (ORBs) represent a viable pathway to a more sustainable energy storage technology compared to conventional Li-ion batteries. For further materials and cell development towards competitive energy and power densities, a deeper understanding of electron transport and conductivity in organic radical polymer cathodes is required. Such electron transport is characterised by electron hopping processes, which depend on the presence of closely spaced hopping sites. Using a combination of electrochemical, electron paramagnetic resonance (EPR) spectroscopic, and theoretical molecular dynamics as well as density functional theory modelling techniques, we explored how compositional characteristics of cross-linked poly(2,2,6,6-tetramethyl-1-piperidinyloxy-4-yl methacrylate) (PTMA) polymers govern electron hopping and rationalise their impact on ORB performance. Electrochemistry and EPR spectroscopy not only show a correlation between capacity and the total number of radicals in an ORB using a PTMA cathode, but also indicates that the state-of-health degrades about twice as fast if the amount of radical is reduced by 15%. The presence of up to 3% free monomer radicals did not improve fast charging capabilities. Pulsed EPR indicated that these radicals readily dissolve into the electrolyte but a direct effect on battery degradation could not be shown. However, a qualitative impact cannot be excluded either. The work further illustrates that nitroxide units have a high affinity to the carbon black conductive additive, indicating the possibility of its participation in electron hopping. At the same time, the polymers attempt to adopt a compact conformation to increase radical–radical contact. Hence, a kinetic competition exists, which might gradually be altered towards a thermodynamically more stable configuration by repeated cycling, yet further investigations are required for its characterisation.

Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work, we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during the development of disease and following treatment. Samples from healthy blood donors, newly diagnosed RA patients, and established RA patients that had an inadequate response to MTX and were about to start tumor necrosis factor inhibitors (TNFi) treatment were collected before and after 3 months of treatment. We used in parallel a computational deconvolution approach based on RNA expression and flow cytometry to determine the relative cell-type frequencies. Cell-type frequencies from deconvolution of gene expression indicate that monocytes (both classical and non-classical) and CD4+ cells (Th1 and Th2) were increased in RA patients compared to controls, while NK cells and B cells (naïve and mature) were significantly decreased in RA patients. Treatment with MTX caused a decrease in B cells (memory and plasma cell), and a decrease in CD4 Th cells (Th1 and Th17), while treatment with TNFi resulted in a significant increase in the population of B cells. Characterization of the RNA expression patterns found that most of the differentially expressed genes in RA subjects after treatment can be explained by changes in cell frequencies (98% and 74% respectively for MTX and TNFi).

Abstract In eyewitness research, multiple identification decisions in sequential lineups are typically prevented by telling participants that only their first identification decision counts. These first-yes-counts instructions are incompatible with standard police protocols prescribing that witnesses shall see the entire lineup. Horry et al. were the first to experimentally test how this discrepancy between eyewitness research and standard police protocols affects eyewitness identification decisions. Here, the two-high threshold eyewitness identification model was used to disentangle the effect of the first-yes-counts instructions on the detection and guessing processes underlying eyewitness identification decisions. We report both a reanalysis of Horry et al.’s data and a conceptual replication. Both the reanalysis and the results of the conceptual replication confirm that first-yes-counts instructions do not affect the detection of the culprit but decrease the probability of guessing-based selections. To improve the ecological validity, research on sequential lineups should avoid first-yes-counts instructions.

Abstract The mock-witness task is typically used to evaluate the fairness of lineups. However, the validity of this task has been questioned because there are substantial differences between the tasks for mock witnesses and eyewitnesses. Unlike eyewitnesses, mock witnesses must select a person from the lineup and are alerted to the fact that one lineup member might stand out from the others. It therefore seems desirable to base conclusions about lineup fairness directly on eyewitness data rather than on mock-witness data. To test the importance of direct measurements of biased suspect selection in eyewitness identification decisions, we assessed the fairness of lineups containing either morphed or non-morphed fillers using both mock witnesses and eyewitnesses. We used Tredoux’s E and the proportion of suspect selections to measure lineup fairness from mock-witness choices and the two-high threshold eyewitness identification model to measure the biased selection of the suspects directly from eyewitness identification decisions. Results obtained in the mock-witness task and the model-based analysis of data obtained in the eyewitness task converged in showing that simultaneous lineups with morphed fillers were significantly more unfair than simultaneous lineups with non-morphed fillers. However, mock-witness and eyewitness data converged only when the eyewitness task mimicked the mock-witness task by including pre-lineup instructions that (1) discouraged eyewitnesses to reject the lineups and (2) alerted eyewitnesses that a photograph might stand out from the other photographs in the lineup. When a typical eyewitness task was created by removing these two features from the pre-lineup instructions, the morphed fillers no longer lead to unfair lineups. These findings highlight the differences in the cognitive processes of mock witnesses and eyewitnesses and they demonstrate the importance of measuring lineup fairness directly from eyewitness identification decisions rather than indirectly using the mock-witness task.

Abstract The misuse of antibiotics has led to the emergence of drug-resistant pathogens. Antimicrobial peptides (AMPs) may represent valuable alternative to antibiotics; nevertheless, the easy degradation due to environmental stress and proteolytic enzyme action, limits their use. So far, different strategies have been developed to overcome this drawback. Among them, glycosylation of AMPs represents a promising approach. In this work, we synthesized and characterized the N-glycosilated form of the antimicrobial peptide LL-III (g-LL-III). The N-acetylglucosamine (NAG) was covalently linked to the Asn residue and the interaction of g-LL-III with bacterial model membranes, together with its resistance to proteases, were investigated. Glycosylation did not affect the peptide mechanism of action and its biological activity against both bacteria and eukaryotic cells. Interestingly, a higher resistance to the activity of proteolytic enzymes was achieved. The reported results pave the way for the successful application of AMPs in medicine and biotechnological fields.

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

Abstract Entirely biological human tissue-engineered blood vessels (TEBV) were previously developed for clinical use. Tissue-engineered models have also proven to be valuable tools in disease modelling. Moreover, there is a need for complex geometry TEBV for study of multifactorial vascular pathologies, such as intracranial aneurysms. The main goal of the work reported in this article was to produce an entirely human branched small-caliber TEBV. The use of a novel spherical rotary cell seeding system allows effective and uniform dynamic cell seeding for a viable in vitro tissue-engineered model. In this report, the design and fabrication of an innovative seeding system with random spherical 360° rotation is described. Custom made seeding chambers are placed inside the system and hold Y-shaped polyethylene terephthalate glycol (PETG) scaffolds. The seeding conditions, such as cell concentration, seeding speed and incubation time were optimized via count of cells adhered on the PETG scaffolds. This spheric seeding method was compared to other approaches, such as dynamic and static seeding, and clearly shows uniform cell distribution on PETG scaffolds. With this simple to use spherical system, fully biological branched TEBV constructs were also produced by seeding human fibroblasts directly on custom-made complex geometry PETG mandrels. The production of patient-derived small-caliber TEBVs with complex geometry and optimized cellular distribution all along the vascular reconstructed may be an innovative way to model various vascular diseases such as intracranial aneurysms.

Abstract The COVID-19 pandemic has exposed the vulnerability of ethnic minorities again. Health inequity within ethnic minorities has been explained by factors such as higher prevalence of underlying disease, restricted access to care, and lower vaccination rates. In this study, we investigated the effect of cultural tailoring of communicators and media outlets, respectively, on vaccine willingness in an influenza vaccination campaign in the Netherlands. A total of 1226 participants were recruited from two culturally non-tailored media outlets (Dutch newspaper and Facebook), and one media outlet tailored to a large community in the Netherlands with Indian ancestry. The participants from all three media outlets were randomly exposed to a vaccination awareness video delivered by a physician with an Indian or Dutch background, followed by an online survey. Cultural tailoring compared to cultural non-tailoring of communicators showed no difference in improvement of vaccine willingness (13.9% vs. 20.7% increment, respectively, p = 0.083). However, the media outlet tailored to the community with Indian ancestry, resulted in a higher improvement of vaccine willingness compared to non-tailored media outlets (46.7% vs. 14.7% increment, respectively, p

Abstract Computational fluid dynamics (CFD) simulations are increasingly utilised to evaluate intracranial aneurysm (IA) haemodynamics to aid in the prediction of morphological changes and rupture risk. However, these models vary and differences in published results warrant the investigation of IA-CFD reproducibility. This study aims to explore sources of intra-team variability and determine its impact on the aneurysm morphology and CFD parameters. A team of four operators were given six sets of magnetic resonance angiography data spanning a decade from one patient with a middle cerebral aneurysm. All operators were given the same protocol and software for model reconstruction and numerical analysis. The morphology and haemodynamics of the operator models were then compared. The segmentation, smoothing factor, inlet and outflow branch lengths were found to cause intra-team variability. There was 80% reproducibility in the time-averaged wall shear stress distribution among operators with the major difference attributed to the level of smoothing. Based on these findings, it was concluded that the clinical applicability of CFD simulations may be feasible if a standardised segmentation protocol is developed. Moreover, when analysing the aneurysm shape change over a decade, it was noted that the co-existence of positive and negative values of the wall shear stress divergence (WSSD) contributed to the growth of a daughter sac.

Abstract Intensive care units (ICU) are often overflooded with alarms from monitoring devices which constitutes a hazard to both staff and patients. To date, the suggested solutions to excessive monitoring alarms have remained on a research level. We aimed to identify patient characteristics that affect the ICU alarm rate with the goal of proposing a straightforward solution that can easily be implemented in ICUs. Alarm logs from eight adult ICUs of a tertiary care university-hospital in Berlin, Germany were retrospectively collected between September 2019 and March 2021. Adult patients admitted to the ICU with at least 24 h of continuous alarm logs were included in the study. The sum of alarms per patient per day was calculated. The median was 119. A total of 26,890 observations from 3205 patients were included. 23 variables were extracted from patients' electronic health records (EHR) and a multivariable logistic regression was performed to evaluate the association of patient characteristics and alarm rates. Invasive blood pressure monitoring (adjusted odds ratio (aOR) 4.68, 95%CI 4.15–5.29, p

Abstract To examine the challenges faced by free-ranging Rousettus aegyptiacus living at the northern edge of their distribution, we performed a retrospective analysis of 2196 clinical cases reported by a bat rescue NGO over a period of 36 months, from throughout Israel. All cases of injured bats were evaluated and categorized according to date, place, sex, age, and etiology of the morbidity. The data analysis revealed an increase in all types of morbidity during the wintertime, with more than two-fold the number of cases per week compared to in the summer, over three consecutive years. Moreover, we found that the number of abandoned pups peaked during spring and summer, when adult morbidity is minimal. We characterized two prominent types of previously undescribed morbidities in R. aegyptiacus. We also employed GPS tracking to monitor the movement and foraging of dozens of bats, and to examine the potential correlates of elevated winter morbidity. Our results suggest that it is mainly harsh weather that drives the observed winter morbidity, with food limitations playing a minor-role. We hypothesize that R. aegyptiacus, of tropical origin, is facing major seasonal survival difficulties near the northern edge of its distribution, probably limiting its spread further northwards still.

Abstract Subclinical pulmonary tuberculosis (PTB) is a recently described intermediate state of great interest, but about which little is known. This study sought to describe and compare the frequency of key radiologic features of subclinical PTB on chest radiograph (CXR) versus computed tomographic scan (CT), and to interpret the clinical and public health relevance of the differences. Diagnostic CXRs and CT scans of the thorax and neck in a 16-year cohort of subclinical PTB patients in Canada were re-acquired and read by two independent readers and arbitrated by a third reader. Logistic regression models were fit to determine how likely CXR features can be detected by CT scan versus CXR after adjustment for age and sex. Among 296 subclinical patients, CXRs were available in 286 (96.6%) and CT scans in 94 (32.9%). CXR features in patients with and without CT scans were comparable. Lung cavitation was 4.77 times (95% CI 1.95–11.66), endobronchial spread 19.36 times (95% CI 8.05–46.52), and moderate/far-advanced parenchymal disease 3.23 times (95% CI 1.66–6.30), more common on CT scan than CXR. We conclude that the extent to which CXRs under-detect key radiologic features in subclinical PTB is substantial. This may have public health and treatment implications.

Abstract To improve police protocols for lineup procedures, it is helpful to understand the processes underlying eyewitness identification performance. The two-high threshold (2-HT) eyewitness identification model is a multinomial processing tree model that measures four latent cognitive processes on which eyewitness identification decisions are based: two detection-based processes (the detection of culprit presence and absence) and two non-detection-based processes (biased and guessing-based selection). The model takes into account the full 2 × 3 data structure of lineup procedures, that is, suspect identifications, filler identifications and rejections in both culprit-present and culprit-absent lineups. Here the model is introduced and the results of four large validation experiments are reported, one for each of the processes specified by the model. The validation experiments served to test whether the model’s parameters sensitively reflect manipulations of the processes they were designed to measure. The results show that manipulations of exposure duration of the culprit’s face at encoding, lineup fairness, pre-lineup instructions and ease of rejection of culprit-absent lineups were sensitively reflected in the parameters representing culprit-presence detection, biased suspect selection, guessing-based selection and culprit-absence detection, respectively. The results of the experiments thus validate the interpretations of the parameters of the 2-HT eyewitness identification model.

Abstract The two-high threshold (2-HT) eyewitness identification model serves as a new measurement tool to measure the latent cognitive processes underlying eyewitness identification performance. By simultaneously taking into account correct culprit identifications, false innocent-suspect identifications, false filler identifications in culprit-present and culprit-absent lineups as well as correct and false lineup rejections, the model capitalizes on the full range of data categories that are observed when measuring eyewitness identification performance. Thereby, the model is able to shed light on detection-based and non-detection-based processes underlying eyewitness identification performance. Specifically, the model incorporates parameters for the detection of culprit presence and absence, biased selection of the suspect and guessing-based selection among the lineup members. Here, we provide evidence of the validity of each of the four model parameters by applying the model to eight published data sets. The data sets come from studies with experimental manipulations that target one of the underlying processes specified by the model. Manipulations of encoding difficulty, lineup fairness and pre-lineup instructions were sensitively reflected in the parameters reflecting culprit-presence detection, biased selection and guessing-based selection, respectively. Manipulations designed to facilitate the rejection of culprit-absent lineups affected the parameter for culprit-absence detection. The reanalyses of published results thus suggest that the parameters sensitively reflect the manipulations of the processes they were designed to measure, providing support of the validity of the 2-HT eyewitness identification model.

Abstract Molecular pathology services for colorectal cancer (CRC) in Sudan represent a significant unmet clinical need. In a retrospective cohort study involving 50 patients diagnosed with CRC at three major medical settings in Sudan, we aimed to outline the introduction of a molecular genetic service for CRC in Sudan, and to explore the CRC molecular features and their relationship to patient survival and clinicopathological characteristics. Mismatch repair (MMR) and BRAF (V600E) mutation status were determined by immunohistochemistry. A mismatch repair deficient (dMMR) subtype was demonstrated in 16% of cases, and a presumptive Lynch Syndrome (LS) diagnosis was made in up to 14% of patients. dMMR CRC in Sudan is characterized by younger age at diagnosis and a higher incidence of right-sided tumours. We report a high mortality in Sudanese CRC patients, which correlates with advanced disease stage, and MMR status. Routine MMR immunohistochemistry (with sequential BRAF mutation analysis) is a feasible CRC prognostic and predictive molecular biomarker, as well as a screening tool for LS in low-middle-income countries (LMICs).