Search

Background: Distinguishing postoperative fibrosis from isolated local recurrence (ILR) after resection of pancreatic ductal adenocarcinoma (PDAC) is challenging. A prognostic model that helps to identify patients at risk of ILR can assist clinicians when evaluating patients' postoperative imaging. This nationwide study aimed to develop a clinically applicable prognostic model for ILR after PDAC resection. Patients and Methods: An observational cohort study was performed, including all patients who underwent PDAC resection in the Netherlands (2014–2019; NCT04605237). On the basis of recurrence location (ILR, systemic, or both), multivariable cause-specific Cox-proportional hazard analysis was conducted to identify predictors for ILR and presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A predictive model was developed using Akaike's Information Criterion, and bootstrapped discrimination and calibration indices were assessed. Results: Among 1194/1693 patients (71%) with recurrence, 252 patients (21%) developed ILR. Independent predictors for ILR were resectability status (borderline versus resectable, HR 1.42; 95% CI 1.03–1.96; P = 0.03, and locally advanced versus resectable, HR 1.11; 95% CI 0.68–1.82; P = 0.66), tumor location (head versus body/tail, HR 1.50; 95% CI 1.00–2.25; P = 0.05), vascular resection (HR 1.86; 95% CI 1.41–2.45; P < 0.001), perineural invasion (HR 1.47; 95% CI 1.01–2.13; P = 0.02), number of positive lymph nodes (HR 1.04; 95% CI 1.01–1.08; P = 0.02), and resection margin status (R1 < 1 mm versus R0 ≥ 1 mm, HR 1.64; 95% CI 1.25–2.14; P < 0.001). Moderate performance (concordance index 0.66) with adequate calibration (slope 0.99) was achieved. Conclusions: This nationwide study identified factors predictive of ILR after PDAC resection. Our prognostic model, available through www.pancreascalculator.com, can be utilized to identify patients with a higher a priori risk of developing ILR, providing important information in patient evaluation and prognostication. [ABSTRACT FROM AUTHOR]

Purpose: Low cardiorespiratory fitness (CRF) increases the risk of postoperative morbidity and mortality following major surgery. Assessing CRF preoperatively, by measuring peak oxygen uptake (VO2peak) during cardiopulmonary exercise testing (CPET), is valuable yet not widely available. This study aimed to assess whether questionnaires could be used preoperatively to identify high-risk surgical patients. Methods: Healthy participants and patients who underwent CPET completed the FitMáx, Duke Activity Status Index (DASI), the modified 4-questions DASI (M-DASI-4Q), Veterans-Specific Activity Questionnaire (VSAQ), and Metabolic Equivalents of Task (MET) questionnaire. Questionnaire-VO2peak was compared with CPET-VO2peak. Overall performance of the questionnaires was assessed by the area under the curve (AUC) of receiver operating characteristic (ROC) curves. Furthermore, corresponding to the Youden index or pre-specified levels, sensitivity, specificity, and predictive values were determined. Results: In total, 361 participants were included. All questionnaires showed high AUC values to identify high-risk patients, defined on the basis of CPET-VO2peak thresholds. FitMáx and VSAQ demonstrated superior results compared to the other questionnaires. Based on the Youden index, the optimal questionnaire-VO2peak cut-off values were 20.6, 21.3, and 26.1 ml·kg−1·min−1 for the FitMáx and 16.3, 18.2, and 20.4 ml·kg−1·min−1 for the VSAQ corresponding to the VO2peak thresholds 16.0, 18.2 and 24.5 ml·kg−1·min−1 respectively. Conclusion: The ability to identify high-risk surgical patients preoperatively (defined by the CPET-VO2peak thresholds) by the FitMáx and the VSAQ indicates that they could be used to identify high-risk surgical patients. Patients with a poor predicted VO2peak ≤ 21.3 and ≤ 18.2 ml·kg−1·min−1, respectively for FitMáx and VSAQ, should be referred to formal preoperative (cardiopulmonary) exercise testing. Trial registration: The study was registered as NL-OMON23304 in the Overview of Medical Research in the Netherlands, retrospectively at 28–04-2020. [ABSTRACT FROM AUTHOR]

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method. [ABSTRACT FROM AUTHOR]

Copyright of TSG: Tijdschrift Voor Gezondheidswetenschappen is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The development of gene therapy has always come with the expectation that it will offer a cure for various disorders, of which hemophilia is a paradigm example. However, although the term is used regularly, it is unclear what exactly is meant with "cure". Therefore, the aim of this paper is to analyse how the concept of cure is used in practice and evaluate which of the interpretations is most suitable in discussions surrounding gene therapy. We analysed how cure is used in four different medical fields where the concept raises discussion. We show that cure can be used in three different ways: cure as normalization of the body, cure as obtaining a normal life, or cure as a change in identity. We argue that since cure is a practical term, its interpretation should be context-specific and the various uses can exist simultaneously, as long as their use is suitable to the function the notion of cure plays in each of the settings. We end by highlighting three different settings in the domain of hemophilia gene therapy in which the term cure is used and explore the function(s) it serves in each setting. We conclude that in the clinical application of gene therapy, it could be better to abandon the term cure, whereas more modest and specified definitions of cure are required in the context of health resource allocation decisions and decisions on research funding. [ABSTRACT FROM AUTHOR]

Background: It is difficult to distinguish between tumor progression (TP) and treatment-related abnormalities (TRA) in treated glioblastoma patients via conventional MRI, but this distinction is crucial for treatment decision making. Glioblastoma is known to exhibit an invasive growth pattern along white matter architecture and vasculature. This study quantified lesion development patterns in treated glioblastoma lesions and their relation to white matter microstructure to distinguish TP from TRA. Materials and methods: Glioblastoma patients with confirmed TP or TRA with T1-weighted contrast-enhanced and DTI MR scans from two posttreatment follow-up timepoints were reviewed. The contrast-enhancing regions were segmented, and the regions were coregistered to the DTI data. Lesion increase vectors were categorized into two groups: parallel (0–20 degrees) and perpendicular (70–90 degrees) to white matter. FA-values were also extracted. To test for a statistically significant difference between the TP and TRA groups, a Mann‒Whitney U test was performed. Results: Of 73 glioblastoma patients, fifteen were diagnosed with TRA, whereas 58 patients suffered TP. TP had a 25.8% (95% CI 24.1%-27.6%) increase in parallel lesions, and TRA had a 25.4% (95% CI 20.9%-29.9%) increase in parallel lesions. The perpendicular increase was 14.7% for TP (95% CI 13.0%-16.4%) and 18.0% (95% CI 13.5%-22.5%) for TRA. These results were not significantly different (p = 0.978). FA value for TP showed to be 0.248 (SD = 0.054) and for TRA it was 0.231 (SD = 0.075), showing no statistically significant difference (p = 0.121). Conclusions: Based on our results, quantifying posttreatment contrast-enhancing lesion development directionality with DTI in glioblastoma patients does not appear to effectively distinguish between TP and TRA. [ABSTRACT FROM AUTHOR]

Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic 'fetal' and WNT-high 'embryonal', displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes. Gene regulatory network analysis reveals enrichment of regulons related to hepatic functions such as bile acid, lipid and xenobiotic metabolism in the fetal subtype but not in the embryonal subtype. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allows for a clear distinction between the fetal and embryonal tumor cells. We also perform high-throughput drug screening using patient-derived tumor organoids and identify sensitivity to HDAC inhibitors. Intriguingly, embryonal and fetal tumor organoids are sensitive to FGFR and EGFR inhibitors, respectively, indicating a dependency on EGF/FGF signaling in hepatoblastoma tumorigenesis. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies. WNT-activating mutations in CTNNB1 are common in hepatoblastoma, but downstream molecular phenotypes are heterogenous. Using multiomic approaches, the authors identify distinct subgroups of hepatoblastoma cells based on WNT-signaling patterns and create a biobank of patient-derived hepatoblastoma organoids representing these subtypes. [ABSTRACT FROM AUTHOR]

Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors. Dihydroxyacetone-supplemented slices from the fed mice yielded the highest rate, further stimulated by forskolin and dibutyryl-cAMP. Moreover, using 13C isotope tracing, we assessed the contribution of glycogenolysis and gluconeogenesis to net glucose production over time. Pharmacological inhibition of the glucose 6-phosphate transporter SLC37A4 markedly reduced net glucose production and increased lactate secretion and glycogen storage, while glucose production was completely abolished in PCLS from glycogen storage disease type Ia and Ib patients. In conclusion, this study identifies PCLS as an effective ex vivo model to study hepatic glucose production and opens opportunities for its future application in IEM research and beyond. Ex vivo precision-cut liver slices allow glucose production quantification to model glycogen storage disease and inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Background: End-stage liver diseases (ESLDs) are a significant global health challenge due to their high prevalence and severe health impacts. Despite the severe outcomes associated with ESLDs, therapeutic options remain limited. Targeting the activation of hepatic stellate cells (HSCs), key drivers of extracellular matrix accumulation during liver injury presents a novel therapeutic approach. In ESLDs patients, branched-chain amino acids (BCAAs, leucine, isoleucine and valine) levels are decreased, and supplementation has been proposed to attenuate liver fibrosis and improve regeneration. However, their effects on HSCs require further investigation. Objective: To evaluate the efficacy of BCAAs and their metabolites, branched-chain α-keto acids (BCKAs), in modulating HSCs activation in human and rat models. Methods: Primary HSCs from rats and cirrhotic and non-cirrhotic human livers, were cultured and treated with BCAAs or BCKAs to assess their effects on both preventing (from day 1 of isolation) and reversing (from day 7 of isolation) HSCs activation. Results: In rat HSCs, leucine and BCKAs significantly reduced fibrotic markers and cell proliferation. In human HSCs, the metabolite of isoleucine decreased cell proliferation around 85% and increased the expression of branched-chain ketoacid dehydrogenase. The other metabolites also showed antifibrotic effects in HSCs from non-cirrhotic human livers. Conclusion: BCAAs and their respective metabolites inhibit HSC activation with species-specific responses. Further research is needed to understand how BCAAs influence liver fibrogenesis. BCKAs supplementation could be a strategic approach for managing ESLDs, considering the nutritional status and amino acid profiles of patients. The antifibrotic effects of BCAAs and BCKAs in various conditions are depicted for human HSCs (left) and rat HSCs (right) The symbol ‘↓’ indicates a downregulation or a decrease. α-SMA alpha-smooth muscle actin, BCAAs branched-chain amino acids, BCKAs branched-chain keto acids, HSCs hepatic stellate cells, KMV α-keto-β-methylvalerate. Figure created with Biorender.com [ABSTRACT FROM AUTHOR]

Background: Assessment of the pattern of the RV outflow tract Doppler provides insights into the hemodynamics of chronic thromboembolic pulmonary hypertension (CTEPH). We studied whether pre-operative assessment of timing of the pulmonary flow systolic notch by Doppler echocardiography is associated with long-term survival after pulmonary endarterectomy (PEA) for CTEPH. Methods: Fifty-nine out of 61 consecutive CETPH patients (mean age 53 ± 14 years, 34% male) whom underwent PEA between June 2002 and June 2005 were studied. Clinical, echocardiographic and hemodynamic variables were assessed pre-operatively and repeat echocardiography was performed 3 months after PEA. Notch ratio (NR) was assessed with pulsed Doppler and calculated as the time from onset of pulmonary flow until notch divided by the time from notch until end of pulmonary flow. Long-term follow-up was obtained between May 2021 and February 2022. Results: Pre-operative mean pulmonary artery pressure (mPAP) was 45 ± 15 mmHg and pulmonary vascular resistance (PVR) was 646 ± 454 dynes.s.cm-5. Echocardiography before PEA showed that 7 patients had no notch, 33 had a NR < 1.0 and 19 had a NR > 1.0. Three months after PEA, echocardiography revealed a significant decrease in sPAP in long-term survivors with a NR < 1.0 and a NR > 1.0, while a significant increase in TAPSE/sPAP was only observed in the NR < 1.0 group. Mean long-term clinical follow-up was 14 ± 6 years. NR was significantly different between survivors and non-survivors (0.73 ± 0.25 vs. 1.1 ± 0.44, p < 0.001) but no significant differences were observed in mPAP or PVR. Long-term survival at 14 years was significantly better in patients with a NR < 1.0 compared to patients with a NR > 1.0 (83% vs. 37%, p = < 0.001). Conclusion: Pre-operative assessment of NR is a predictor of long-term survival in CTEPH patients undergoing PEA, with low mortality risk in patients with NR < 1.0. Long-term survivors with a NR < 1.0 and NR > 1.0 had a significant decrease in sPAP after PEA. However, the TAPSE/sPAP only significantly increased in the NR < 1.0 group. In the NR < 1.0 group, the 6-min walk test increased significantly between pre-operative and at 1-year post-operative follow-up. NR is a simple echocardiographic parameter that can be used in clinical decision-making for PEA. [ABSTRACT FROM AUTHOR]

Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically rely on prior identification of tumor-specific mutations. Here, we develop a tumor-independent and mutation-independent approach (DELFI-tumor fraction, DELFI-TF) using low-coverage whole genome sequencing to determine the cfDNA tumor fraction and validate the method in two independent cohorts of patients with colorectal or lung cancer. DELFI-TF scores strongly correlate with circulating tumor DNA levels (ctDNA) (r = 0.90, p < 0.0001, Pearson correlation) even in cases where mutations are undetectable. DELFI-TF scores prior to therapy initiation are associated with clinical response and are independent predictors of overall survival (HR = 9.84, 95% CI = 1.72-56.10, p < 0.0001). Patients with lower DELFI-TF scores during treatment have longer overall survival (62.8 vs 29.1 months, HR = 3.12, 95% CI 1.62-6.00, p < 0.001) and the approach predicts clinical outcomes more accurately than imaging. These results demonstrate the potential of using cfDNA fragmentomes to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction. Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically use tumor-specific mutations that may not be detected in many patients. Here, the authors develop a tumor-independent and mutation-independent approach (DELFI-TF) to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction. [ABSTRACT FROM AUTHOR]

A new species of the yeast genus Blastobotrys was discovered on ancient ship timbers in the Netherlands. The species had developed on the wood of a river barge dating to the Roman period. The growth occurred after the preservative polyethylene glycol (PEG 4000) was washed out of some of the timbers due to an undetected leak in the storage unit. Mycological analysis of various timber samples revealed the presence of Microascus melanosporus (predominant), Microascus paisii, a member of the Acremonium chrysogenum-clade, and a new Blastrobotrys species. The new species produced sporothrix-like conidiophores with clavate blastoconidia (3–7 × 1–3.5 μm) and was found to be osmotolerant, capable of growth on low water activity media like malt yeast 50% glucose agar (MY50G). In this article we formally describe and introduce Blastrobotrys nigripullensis (CBS 17879 T) based on its morphology, physiology and phylogenetic placement. [ABSTRACT FROM AUTHOR]

Projections towards 2050 of the global hydrogen (H2) demand indicate an eight-fold increase in present-day hydrogen consumption. Leakage during production, transport, and consumption therefore presents a large potential for increases in the atmospheric hydrogen burden. Although not a greenhouse gas itself, hydrogen has important indirect climate effects, and the Global Warming Potential of H2 is estimated to be 12.8 times that of CO2. Available technologies to detect hydrogen emissions have been targeted at risk mitigation of industrial facilities, while smaller climate-relevant emissions remain undetected. The latter requires measurement capacity at the parts-per-billion level (ppb). We developed and demonstrated an effective method to detect small hydrogen emissions from industrial installations that combines active AirCore sampling with ppb-precision analysis by gas chromatography. We applied our methodology at a chemical park in the province of Groningen, the Netherlands, where several hydrogen production and storage facilities are concentrated. From a car and an unmanned aerial vehicle, we detected and quantified for the first time small but persistent industrial emissions from leakage and purging across the hydrogen value chain, which include electrolysers, a hydrogen fuelling station, and chemical production plants. Our emission estimates indicate current loss rates up to 4.2% of the estimated production and storage in these facilities. This is sufficiently large to urgently flag the need for monitoring and verification of H2 emissions for the purpose of understanding our climate change trajectory in the 21st century. [ABSTRACT FROM AUTHOR]

Bidirectional communication between neurons and glial cells is crucial to establishing and maintaining normal brain function. Some of these interactions are activity-dependent, yet it remains largely unexplored how acute changes in neuronal activity affect glial-to-neuron and neuron-to-glial dynamics. Here, we use excitatory and inhibitory designer receptors exclusively activated by designer drugs (DREADD) to study the effects of acute chemogenetic manipulations of a subpopulation of layer 5 cortical projection and dentate gyrus neurons in adult (Rbp4Cre) mouse brains. We show that acute chemogenetic neuronal activation reduces synaptic density, and increases microglia and astrocyte reactivity, but does not affect parvalbumin (PV+) neurons, only perineuronal nets (PNN). Conversely, acute silencing increases synaptic density and decreases glial reactivity. We show fast glial response upon clozapine-N-oxide (CNO) administration in cortical and subcortical regions. Together, our work provides evidence of fast, activity-dependent, bidirectional interactions between neurons and glial cells. Acute manipulations of neuronal activity of cortical projection neurons using DREADDs affects synaptic connectivity and leads to rapid response and changes in glial cell dynamics in cortical and subcortical regions. [ABSTRACT FROM AUTHOR]

Fungal infections pose an increasing threat to public health. New pathogens and changing epidemiology are a pronounced risk for nosocomial outbreaks. To investigate clonal transmission between patients and trace the source, genotyping is required. In the last decades, various typing assays have been developed and applied to different medically important fungal species. While these different typing methods will be briefly discussed, this review will focus on the development and application of short tandem repeat (STR) genotyping. This method relies on the amplification and comparison of highly variable STR markers between isolates. For most common fungal pathogens, STR schemes were developed and compared to other methods, like multilocus sequence typing (MLST), amplified fragment length polymorphism (AFLP) and whole genome sequencing (WGS) single nucleotide polymorphism (SNP) analysis. The pros and cons of STR typing as compared to the other methods are discussed, as well as the requirements for the development of a solid STR typing assay. The resolution of STR typing, in general, is higher than MLST and AFLP, with WGS SNP analysis being the gold standard when it comes to resolution. Although most modern laboratories are capable to perform STR typing, little progress has been made to standardize typing schemes. Allelic ladders, as developed for Aspergillus fumigatus, facilitate the comparison of STR results between laboratories and develop global typing databases. Overall, STR genotyping is an extremely powerful tool, often complimentary to whole genome sequencing. Crucial details for STR assay development, its applications and merit are discussed in this review. [ABSTRACT FROM AUTHOR]

Purpose: Rare yeasts species are increasingly reported as causative agents of invasive human infection. Proper identification and antifungal therapy are essential to manage these infections. Candida blankii is one of these emerging pathogens and is known for its reduced susceptibility to multiple antifungals. Methods: To obtain more insight into the characteristics of this species, 26 isolates reported as C. blankii were investigated using genetic and phenotypical approaches. Results: Among the 26 isolates, seven recovered either from blood, sputum, urine, or the oral cavity, displayed substantial genetic and some phenotypical differences compared to the other isolates, which were confirmed as C. blankii. We consider these seven strains to represent a novel species, Tardiomyces depauwii. Phylogenomics assigned C. blankii, C. digboiensis, and the novel species in a distinct branch within the order Dipodascales, for which the novel genus Tardiomyces is erected. The new combinations Tardiomyces blankii and Tardiomyces digboiensis are introduced. Differences with related, strictly environmental genera Sugiyamaella, Crinitomyces, and Diddensiella are enumerated. All three Tardiomyces species share the rare ability to grow up to 42 °C, display slower growth in nutrient-poor media, and show a reduced susceptibility to azoles and echinocandins. Characteristics of T. depauwii include high MIC values with voriconazole and a unique protein pattern. Conclusion: We propose the novel yeast species Tardiomyces depauwii and the transfer of C. blankii and C. digboiensis to the novel Tardiomyces genus. [ABSTRACT FROM AUTHOR]

Disturbance factors, such as self-excited tool vibrations, limit the performance of modern machining processes and thus restrict the quality, productivity and sustainability of industrially manufactured components. The dynamic process stability is subjected to significant variances especially at the beginning of the tool life. To precisely quantify these variances, series of milling tests were conducted and analyzed using tools made of high speed steel (HSS) and cemented carbide for the machining of EN AW-7075. In all test series, a critical initial decrease of the stability limit was detected directly at the beginning of the tool life. In the following, a significant increase and subsequent almost constant stability limit was observed. In the case of the HSS cutters the achieved stability limit exceeded the initial level substantially. An increase in the process forces and flank wear was also measured over tool life but the progression cannot directly explain the extend and characteristics regarding the stability limit. The findings described have a considerable impact on the appropriate design of manufacturing processes and experiments to determine the dynamic stability of cutting operations. [ABSTRACT FROM AUTHOR]

Questionnaires are ever present in survey research. In this study, we examined whether an indirect indicator of general cognitive ability could be developed based on response patterns in questionnaires. We drew on two established phenomena characterizing connections between cognitive ability and people's performance on basic cognitive tasks, and examined whether they apply to questionnaires responses. (1) The worst performance rule (WPR) states that people's worst performance on multiple sequential tasks is more indicative of their cognitive ability than their average or best performance. (2) The task complexity hypothesis (TCH) suggests that relationships between cognitive ability and performance increase with task complexity. We conceptualized items of a questionnaire as a series of cognitively demanding tasks. A graded response model was used to estimate respondents' performance for each item based on the difference between the observed and model-predicted response ("response error" scores). Analyzing data from 102 items (21 questionnaires) collected from a large-scale nationally representative sample of people aged 50+ years, we found robust associations of cognitive ability with a person's largest but not with their smallest response error scores (supporting the WPR), and stronger associations of cognitive ability with response errors for more complex than for less complex questions (supporting the TCH). Results replicated across two independent samples and six assessment waves. A latent variable of response errors estimated for the most complex items correlated.50 with a latent cognitive ability factor, suggesting that response patterns can be utilized to extract a rough indicator of general cognitive ability in survey research. [ABSTRACT FROM AUTHOR]

Chestnut Red Stain (CRS) is a heartwood discoloration that widely affects Castanea sativa Mill. productive coppice stands in the northeast of Spain. At the early stages of infection, the structural properties of the wood are not affected, but still its economic value drops up to 70% due to the rejection of this wood. This disease is caused by the fungus Fistulina hepatica (Schaeff.) With. and causes uncertainty to forest managers since the fungal infection is virtually impossible to detect before felling. The objective of this work was to develop an efficient detection method to evaluate the presence of F. hepatica in early stages of productive periods. A total of 72 chestnuts were analyzed through molecular methods to determine the presence of F. hepatica and with an IML resistance drill to characterize their wood. Thirteen wood quality indices were calculated and their correlation with the presence of the pathogen was evaluated using linear mixed models. We found clear differences between healthy and infected trees in four indices. A new specific index (Chestnut Red Stain Danger index) was designed to estimate the probability of infection by F. hepatica. The results support the hypothesis that the early presence of F. hepatica is detectable through inexpensive and fast mechanical methods early in a rotation. The results of this work will help forest managers evaluate the incidence of CRS, as well as it establishes a novel methodology for further development of resistance drilling techniques for heartwood rot detection. [ABSTRACT FROM AUTHOR]

Background: Digital monitoring of people with multiple sclerosis (PwMS) using smartphone-based monitoring tools is a promising method to assess disease activity and progression. Objective: To study cross-sectional and longitudinal associations between active and passive digital monitoring parameters and MRI volume measures in PwMS. Methods: In this prospective study, 92 PwMS were included. Clinical tests [Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk test (T25FW), 9-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT)] and structural MRI scans were performed at baseline (M0) and 12-month follow-up (M12). Active monitoring included the smartphone-based Symbol Digit Modalities Test (sSDMT) and 2 Minute Walk Test (s2MWT), while passive monitoring was based on smartphone keystroke dynamics (KD). Linear regression analyses were used to determine cross-sectional and longitudinal relations between digital and clinical outcomes and brain volumes, with age, disease duration and sex as covariates. Results: In PwMS, both sSDMT and SDMT were associated with thalamic volumes and lesion volumes. KD were related to brain, ventricular, thalamic and lesion volumes. No relations were found between s2MWT and MRI volumes. NHPT scores were associated with lesion volumes only, while EDSS and T25FW were not related to MRI. No longitudinal associations were found for any of the outcome measures between M0 and M12. Conclusion: Our results show clear cross-sectional correlations between digital biomarkers and brain volumes in PwMS, which were not all present for conventional clinical outcomes, supporting the potential added value of digital monitoring tools. [ABSTRACT FROM AUTHOR]

Damoctocog alfa pegol (BAY 94-9027, Jivi®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate®/Adynovi®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months. Methods: CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders. Results: 125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07–8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%). Conclusion: Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between periodontitis and cardiometabolic and haemostatic parameters. Materials and methods: Between 2014 and 2019, 54 individuals needing full mouth extraction, and 50 control individuals, were recruited for a combined cross-sectional (individuals versus controls) and longitudinal (individuals before and after extraction) study. Periodontitis severity was measured using the periodontal inflamed surface area (PISA). Blood was drawn to measure the haemostatic (Factor VIII, von Willebrand factor [VWF], endogenous thrombin potential, d-dimer, clot lysis time) and cardiovascular risk (C-reactive protein [CRP], lipid profile) parameters, prior to and 12 weeks post-extraction. The results were analysed group-wise. Results: The mean VWF and CRP levels were higher and the high-density lipoprotein levels were lower in the individuals prior to extraction compared to the controls. The VWF was significantly correlated with the PISA (a 21% unit increase in VWF per 1000 mm2 increase in PISA, 95%CI: 6–36%, p = 0.01). The other analyses were comparable between the individuals and controls, and did not change in the individuals after the extraction. Conclusion: VWF levels are associated with periodontitis severity; they do not improve after full-mouth extraction. Severe periodontitis in control individuals does not induce substantial changes in their haemostatic or inflammatory systems. Clinical relevance: Treatment of periodontitis has been shown to improve the cardiometabolic blood profile of patients with established cardiometabolic disease. However, whether periodontitis treatment improves cardiometabolic and haemostatic profiles in people without cardiometabolic disease is uncertain. [ABSTRACT FROM AUTHOR]

Needs assessment is the starting point of good home care as it determines which care is necessary, based on the needs of patients, their personal situation, and social context. There are indications that practice variation in needs assessment exists among home care nurses. However, little is known about potential explanations for this variation. Therefore, we explored potential explanations for practice variation in other areas and examined whether these explanations can be applied to explain variation in needs assessment in home care nursing. We conducted a scoping review of the literature on practice variation in (1) needs assessment in home care nursing, (2) home care nursing in general, and (3) medical care in general, with searches in PubMed and CINAHL. We assessed over 6,000 references. Ultimately, 386 studies were included. Explanations for practice variation were grouped into micro, meso and macro level. This scoping review provided insight into a wide variety of variables that might play a role in explaining practice variation in (needs assessment in) home care nursing, such as availability of guidelines, organisational culture, team norms, resources, and preferences of patients. However, the small literature on needs assessment by home care nurses devoted more attention to patients and their social context, compared to the literature on practice variation in general. We discuss how and to what extent these variables could relate to practice variation in (needs assessment in) home care nursing. Future research should empirically examine the role of these variables in explaining the observed practice variation. [ABSTRACT FROM AUTHOR]

Purpose: Metastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during minimally invasive surgery. Intraoperative fluorescence imaging has the potential to overcome these challenges. The aim of this study was to assess feasibility of targeting CLM with the carcinoembryonic antigen (CEA) specific fluorescent tracer SGM-101. Methods: This was a prospective, open-label feasibility study. The primary outcome was the number of CLM that showed a true positive fluorescence signal with SGM-101. Fluorescence positive signal was defined as a signal-to-background ratio (SBR) ≥ 1.5. A secondary endpoint was the CEA expression in the colorectal lung metastases, assessed with the immunohistochemistry, and scored by the total immunostaining score. Results: Thirteen patients were included in this study. Positive fluorescence signal with in vivo, back table, and closed-field bread loaf imaging was observed in 31%, 45%, and 94% of the tumors respectively. Median SBRs for the three imaging modalities were 1.00 (IQR: 1.00–1.53), 1.45 (IQR: 1.00–1.89), and 4.81 (IQR: 2.70–7.41). All tumor lesions had a maximum total immunostaining score for CEA expression of 12/12. Conclusion: This study demonstrated the potential of fluorescence imaging of CLM with SGM-101. CEA expression was observed in all tumors, and closed-field imaging showed excellent CEA specific targeting of the tracer to the tumor nodules. The full potential of SGM-101 for in vivo detection of the tracer can be achieved with improved minimal invasive imaging systems and optimal patient selection. Trial registration: The study was registered in ClinicalTrial.gov under identifier NCT04737213 at February 2021. [ABSTRACT FROM AUTHOR]

Background: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. Patients and Methods: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014–2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB−) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC−). Overall survival (OS) was assessed using Kaplan–Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). Results: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19–23). OS was 14 months (95% CI 10 months—median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86–2.70), 13 months (95% CI 11–15) in 156 RB+C− patients (23%; HR 1.86, 95% CI 1.50–2.31), and 21 months (95% CI 12–41) in 47 RB−C+ patients (7%; HR 1.14, 95% CI 0.80–1.62) compared with 24 months (95% CI 22–27) in 465 patients with RB−C− PDAC (68%; reference). Conclusions: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC. [ABSTRACT FROM AUTHOR]

The genus Aspergillus consists of a vast number of medically and environmentally relevant species. Aspergillus species classified in series Versicolores are ubiquitous in the environment and include the opportunistic pathogen Aspergillus sydowii, which is associated with onychomycosis and superficial skin infections. Despite frequent clinical reports of A. sydowii and related series Versicolores species, antifungal susceptibility data are scarce, hampering optimal treatment choices and subsequent patient outcomes. Here, we employed antifungal susceptibility testing (AFST) based on microbroth dilution on a set of 155 series Versicolores strains using the common antifungals amphotericin B, itraconazole, voriconazole, posaconazole, isavuconazole and micafungin with the addition of luliconazole and olorofim. All strains were identified using partial calmodulin gene sequencing, with 145 being A. sydowii, seven A. creber and three A. versicolor, using the latest taxonomic insights. Overall, tested antifungals were potent against the entire strain collection. In comparison to A. fumigatus, azole and amphotericin B MICs were slightly elevated for some strains. AFST with luliconazole and olorofim, here reported for the first time, displayed the highest in vitro activity, making these antifungals interesting alternative drugs but clinical studies are warranted for future therapeutic use. [ABSTRACT FROM AUTHOR]

The automatic analysis of patent publications has potential to accelerate research across various domains, including drug discovery and material science. Within patent documents, crucial information often resides in visual depictions of molecule structures. PatCID (Patent-extracted Chemical-structure Images database for Discovery) allows to access such information at scale. It enables users to search which molecules are displayed in which documents. PatCID contains 81M chemical-structure images and 14M unique chemical structures. Here, we compare PatCID with state-of-the-art chemical patent-databases. On a random set, PatCID retrieves 56.0% of molecules, which is higher than automatically-created databases, Google Patents (41.5%) and SureChEMBL (23.5%), as well as manually-created databases, Reaxys (53.5%) and SciFinder (49.5%). Leveraging state-of-the-art methods of document understanding, PatCID high-quality data outperforms currently available automatically-generated patent-databases. PatCID even competes with proprietary manually-created patent-databases. This enables promising applications for automatic literature review and learning-based molecular generation methods. The dataset is freely accessible for download. The automatic analysis of patent documents has potential to accelerate research in chemistry. Here, the authors leverage advances in document understanding to introduce a dataset (PatCID) which allows searching for molecules displayed in documents. [ABSTRACT FROM AUTHOR]

Introduction: Dynamic susceptibility contrast (DSC) perfusion weighted (PW)-MRI can aid in differentiating treatment related abnormalities (TRA) from tumor progression (TP) in post-treatment glioma patients. Common methods, like the 'hot spot', or visual approach suffer from oversimplification and subjectivity. Using perfusion of the complete lesion potentially offers an objective and accurate alternative. This study aims to compare the diagnostic value and assess the subjectivity of these techniques. Methods: 50 Glioma patients with enhancing lesions post-surgery and chemo-radiotherapy were retrospectively included. Outcome was determined by clinical/radiological follow-up or biopsy. Imaging analysis used the 'hot spot', volume of interest (VOI) and visual approach. Diagnostic accuracy was compared using receiving operator characteristics (ROC) curves for the VOI and 'hot spot' approach, visual assessment was analysed with contingency tables. Inter-operator agreement was determined with Cohens kappa and intra-class coefficient (ICC). Results: 29 Patients suffered from TP, 21 had TRA. The visual assessment showed poor to substantial inter-operator agreement (κ = -0.72 – 0.68). Reliability of the 'hot spot' placement was excellent (ICC = 0.89), while reference placement was variable (ICC = 0.54). The area under the ROC (AUROC) of the mean- and maximum relative cerebral blood volume (rCBV) (VOI-analysis) were 0.82 and 0.72, while the rCBV-ratio ('hot spot' analysis) was 0.69. The VOI-analysis had a more balanced sensitivity and specificity compared to visual assessment. Conclusions: VOI analysis of DSC PW-MRI data holds greater diagnostic accuracy in single-moment differentiation of TP and TRA than 'hot spot' or visual analysis. This study underlines the subjectivity of visual placement and assessment. [ABSTRACT FROM AUTHOR]

The emergence of antimicrobial resistance has created an urgent need for alternative treatments against bacterial pathogens. Here, we investigated kinase inhibitors as potential host-directed therapies (HDTs) against intracellular bacteria, specifically Salmonella Typhimurium (Stm) and Mycobacterium tuberculosis (Mtb). We screened 827 ATP-competitive kinase inhibitors with known target profiles from two Published Kinase Inhibitor Sets (PKIS1 and PKIS2) using intracellular infection models for Stm and Mtb, based on human cell lines and primary macrophages. Additionally, the in vivo safety and efficacy of the compounds were assessed using zebrafish embryo infection models. Our screen identified 11 hit compounds for Stm and 17 hit compounds for Mtb that were effective against intracellular bacteria and non-toxic for host cells. Further experiments were conducted to prioritize Stm hit compounds that were able to clear the intracellular infection in primary human macrophages. From these, two structurally related Stm hit compounds, GSK1379738A and GSK1379760A, exhibited significant activity against Stm in infected zebrafish embryos. In addition, we identified compounds that were active against intracellular Mtb, including morpholino-imidazo/triazolo-pyrimidinones that target PIK3CB, as well as 2-aminobenzimidazoles targeting ABL1. Overall, this study provided insights into kinase targets acting at the host–pathogen interface and identified several kinase inhibitors as potential HDTs. [ABSTRACT FROM AUTHOR]

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990–1994) to 58 years (2015–2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990–1994) to 54 (2015–2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015–2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990–1994) to 70% (2015–2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990–1999) to 46% (2015–2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies. [ABSTRACT FROM AUTHOR]

Purpose: Quantifying the stability of individual plants or their contribution to soil reinforcement against erosion or landslides requires an understanding of the tensile properties of their roots. This work developed a new analytical model to understand the tensile stress–strain behaviour of a single root axis, which is the first to incorporating root anatomical features, in order to reduce the existing uncertainty in predictions. Methods: The root was modelled as a linear elastic stele connected to a surrounding linear elastic cortex by means of a linear elastic stele–cortex interface. By solving for force equilibrium, an analytical solution for the full tensile stress–strain behaviour — including any intermediate brittle failures of the stele, cortex and/or interface — was obtained. This model was compared to tensile tests and laser ablation tomography for maize roots. Results: The new modelling approach demonstrated that the root tensile strength is fully determined by the strength of the stele alone, which was an order of magnitude larger than that of the cortex while also 3–4 times stiffer. The reduction in root stiffness beyond the yield point was linked to continuing fracturing of the cortex and debonding along the stele–cortex interface. A larger proportion of the variation in experimentally measured biomechanical characteristics could be explained compared to root diameter power-law fitting methods typically applied in the literature. Conclusion: Stele and cortex biomechanical properties are substantially different, affecting the tensile behaviour of plant roots. Accounting for these anatomical traits increased the accuracy root biomechanical properties from tensile tests. [ABSTRACT FROM AUTHOR]

Continued climate change impose multiple stressors on crops, including pathogens, salt, and drought, severely impacting agricultural productivity. Innovative solutions are necessary to develop resilient crops. Here, using quantitative potato proteomics, we identify Parakletos, a thylakoid protein that contributes to disease susceptibility. We show that knockout or silencing of Parakletos enhances resistance to oomycete, fungi, bacteria, salt, and drought, whereas its overexpression reduces resistance. In response to biotic stimuli, Parakletos-overexpressing plants exhibit reduced amplitude of reactive oxygen species and Ca2+ signalling, and silencing Parakletos does the opposite. Parakletos homologues have been identified in all major crops. Consecutive years of field trials demonstrate that Parakletos deletion enhances resistance to Phytophthora infestans and increases yield. These findings demark a susceptibility gene, which can be exploited to enhance crop resilience towards abiotic and biotic stresses in a low-input agriculture. Crop production is threatening by multiple stressors. Here, the authors report the identification of a thylakoid protein encoding gene and show that knocking out this gene results in enhanced resistance to oomycete, fungi and bacteria, as well as increased tolerance to salt and drought mimics in potato. [ABSTRACT FROM AUTHOR]

A 50-year-old man, previously diagnosed with pulmonary tuberculosis and lung cavities, presented with symptoms including fever, shortness of breath, and cough. A pulmonary CT scan revealed multiple cavities, consolidation and tree-in-bud in the upper lungs. Further investigation through direct examination of bronchoalveolar lavage fluid showed septate hyphae with dichotomous acute branching. Subsequent isolation and morphological analysis identified the fungus as belonging to Aspergillus section Nigri. The patient was diagnosed with probable invasive pulmonary aspergillosis and successfully treated with a three-month oral voriconazole therapy. Phylogenetic analysis based on partial β-tubulin, calmodulin and RNA polymerase second largest subunit sequences revealed that the isolate represents a putative new species related to Aspergillus brasiliensis, and is named Aspergillus hubkae here. Antifungal susceptibility testing demonstrated that the isolate is resistant to itraconazole but susceptible to voriconazole. This phenotypic and genetic characterization of A. hubkae, along with the associated case report, will serve as a valuable resource for future diagnoses of infections caused by this species. It will also contribute to more precise and effective patient management strategies in similar clinical scenarios. [ABSTRACT FROM AUTHOR]

Micromilling tools face significant challenges in achieving cutting edge preparation by mechanical processes due to their small size. To address these limitations, a new approach for cutting edge preparation of micro end mills by physical vapor deposition (PVD) etching technology is presented. By adapting the etching strategy, which is conventionally used as pre-treatment process for PVD technology to clean and condition the surface of cemented carbide substrate, cutting edges of micromilling tools were successfully modified. The high-energy process variation by Advanced Arc-Enhanced Glow Discharge (AEGD) offers the possibility of achieving high material removal rates on the tool surfaces and thereby altering the cutting edge geometry. Fundamental investigations on material removal as well as on the effects on surface topography, sub-surface properties, and coating adhesion of a subsequently applied PVD coating are performed. To influence the topography and the cutting edge geometry, the preparation time tp and bias voltage UB were selected. Subsequently, the machining performance of the modified tools is evaluated in a micromilling process of the hardened powder-metallurgical high-speed steel AISI M3:2 with a hardness of 62 ± 1 HRC. For this purpose, micro end mills of cemented carbide with a diameter of D = 1 mm were conditioned, achieving asymmetric geometric properties of cutting edges with varying average cutting edges rounding of S ¯ = 5.8 ... 14.8 µm and a form-factor of K = 2.0 ... 2.7. Based on the application tests a positive influence on the process forces was found. Thus, an efficient approach to cutting edge preparation can be identified by specifically designing ion etching in the PVD coating process. [ABSTRACT FROM AUTHOR]

Effective visualization of small molecules is paramount in conveying concepts and results in cheminformatics. Scalable vector graphics (SVG) are preferred for creating such visualizations, as SVGs can be easily altered in post-production and exported to other formats. A wide spectrum of software applications already exist that can visualize molecules, and customize these visualizations, in many ways. However, software packages that can output projected 3D models onto a 2D canvas directly as SVG, while being programmatically accessible from Python, are lacking. Here, we introduce CineMol, which can draw vectorized approximations of three-dimensional small molecule models in seconds, without triangulation or ray tracing, resulting in files of around 50–300 kilobytes per molecule model for compounds with up to 45 heavy atoms. The SVGs outputted by CineMol can be readily modified in popular vector graphics editing software applications. CineMol is written in Python and can be incorporated into any existing Python cheminformatics workflow, as it only depends on native Python libraries. CineMol also provides programmatic access to all its internal states, allowing for per-atom and per-bond-based customization. CineMol’s capacity to programmatically create molecular visualizations suitable for post-production offers researchers and scientists a powerful tool for enhancing the clarity and visual impact of their scientific presentations and publications in cheminformatics, metabolomics, and related scientific disciplines. Scientific contribution We introduce CineMol, a Python-based tool that provides a valuable solution for cheminformatics researchers by enabling the direct generation of high-quality approximations of two-dimensional SVG visualizations from three-dimensional small molecule models, all within a programmable Python framework. CineMol offers a unique combination of speed, efficiency, and accessibility, making it an indispensable tool for researchers in cheminformatics, especially when working with SVG visualizations. [ABSTRACT FROM AUTHOR]

Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET/CT) is recognized as the most accurate imaging modality for detection of metastatic high-risk prostate cancer (PCa). Its role in the local staging of disease is yet unclear. We assessed the intra- and interobserver variability, as well as the diagnostic accuracy of the PSMA PET/CT based molecular imaging local tumour stage (miT-stage) for the local tumour stage assessment in a large, multicentre cohort of patients with intermediate and high-risk primary PCa, with the radical prostatectomy specimen (pT-stage) serving as the reference standard. Methods: A total of 600 patients who underwent staging PSMA PET/CT before robot-assisted radical prostatectomy was studied. In 579 PSMA positive primary prostate tumours a comparison was made between miT-stage as assessed by four nuclear physicians and the pT-stage according to ISUP protocol. Sensitivity, specificity and diagnostic accuracy were determined. In a representative subset of 100 patients, the intra-and interobserver variability were assessed using Kappa-estimates. Results: The sensitivity and specificity of the PSMA PET/CT based miT-stage were 58% and 59% for pT3a-stage, 30% and 97% for ≥ pT3b-stage, and 68% and 61% for overall ≥ pT3-stage, respectively. No statistically significant differences in diagnostic accuracy were found between tracers. We found a substantial intra-observer agreement for PSMA PET/CT assessment of ≥ T3-stage (k 0.70) and ≥ T3b-stage (k 0.75), whereas the interobserver agreement for the assessment of ≥ T3-stage (k 0.47) and ≥ T3b-stage (k 0.41) were moderate. Conclusion: In a large, multicentre study evaluating 600 patients with newly diagnosed intermediate and high-risk PCa, we showed that PSMA PET/CT may have a value in local tumour staging when pathological tumour stage in the radical prostatectomy specimen was used as the reference standard. The intra-observer and interobserver variability of assessment of tumour extent on PSMA PET/CT was moderate to substantial. [ABSTRACT FROM AUTHOR]

Emergency department overcrowding is a complex problem that persists globally. Data of visits constitute an opportunity to understand its dynamics. However, the gap between the collected information and the real-life clinical processes, and the lack of a whole-system perspective, still constitute a relevant limitation. An analytical pipeline was developed to analyse one-year of production data following the patients that came from the ED (n = 49,938) at Uppsala University Hospital (Uppsala, Sweden) by involving clinical experts in all the steps of the analysis. The key internal issues to the ED were the high volume of generic or non-specific diagnoses from non-urgent visits, and the delayed decision regarding hospital admission caused by several imaging assessments and lack of hospital beds. Furthermore, the external pressure of high frequent re-visits of geriatric, psychiatric, and patients with unspecified diagnoses dramatically contributed to the overcrowding. Our work demonstrates that through analysis of production data of the ED patient flow and participation of clinical experts in the pipeline, it was possible to identify systemic issues and directions for solutions. A critical factor was to take a whole systems perspective, as it opened the scope to the boundary effects of inflow and outflow in the whole healthcare system. [ABSTRACT FROM AUTHOR]

Neuronal network formation is facilitated by recognition between synaptic cell adhesion molecules at the cell surface. Alternative splicing of cell adhesion molecules provides additional specificity in forming neuronal connections. For the teneurin family of cell adhesion molecules, alternative splicing of the EGF-repeats and NHL domain controls synaptic protein-protein interactions. Here we present cryo-EM structures of the compact dimeric ectodomain of two teneurin-3 isoforms that harbour the splice insert in the EGF-repeats. This dimer is stabilised by an EGF8-ABD contact between subunits. Cryo-EM reconstructions of all four splice variants, together with SAXS and negative stain EM, reveal compacted dimers for each, with variant-specific dimeric arrangements. This results in specific trans-cellular interactions, as tested in cell clustering and stripe assays. The compact conformations provide a structural basis for teneurin homo- and heterophilic interactions. Altogether, our findings demonstrate how alternative splicing results in rearrangements of the dimeric subunits, influencing neuronal recognition and likely circuit wiring. [ABSTRACT FROM AUTHOR]

Plant production systems worldwide are struggling to meet the diverse and increasing needs of humankind while also facing challenges such as climate change and biodiversity loss. This, combined with the desirable transition from the use of conventional pesticides to more sustainable plant protection solutions, has led to an urgent, and increasing, need for low-risk plant protection products (PPPs) to be developed, applied, and integrated into management practices across all types of plant production systems. Despite a high demand from end users and consumers together with joint political goals at the EU level to replace conventional pesticides, the number of low-risk PPPs on the European market remains low, in comparison to synthetic agrochemicals. In this review, we summarize knowledge about the policy, technical, and administrative issues hampering the process of bringing new low-risk PPPs to the European market. We present an overview of the challenges in using the low-risk PPPs that are currently available within the EU agricultural, horticultural, and forestry sectors. We describe the variation in modes of action and the limitations associated with different application techniques and give concrete examples of problems and solutions from Swedish plant production sectors, in contrast to global perspectives as demonstrated by examples from African agriculture. Finally, we conclude that trans-sectoral, multi-actor approaches are required and provide suggestions on how to address the remaining knowledge gaps related to efficiency, application, and economics of low-risk PPP use in Integrated Pest Management (IPM) solutions for plant protection to improve future food security in Europe. [ABSTRACT FROM AUTHOR]

Background: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. Patients and Methods: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014–2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. Results: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4–8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1–7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23–28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318–0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886–5.234)], and major morbidity [HR = 2.031 (95% CI 1.272–3.244)] were associated with OS. Conclusions: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy. [ABSTRACT FROM AUTHOR]

Tomosyns are widely thought to attenuate membrane fusion by competing with synaptobrevin-2/VAMP2 for SNARE-complex assembly. Here, we present evidence against this scenario. In a novel mouse model, tomosyn-1/2 deficiency lowered the fusion barrier and enhanced the probability that synaptic vesicles fuse, resulting in stronger synapses with faster depression and slower recovery. While wild-type tomosyn-1m rescued these phenotypes, substitution of its SNARE motif with that of synaptobrevin-2/VAMP2 did not. Single-molecule force measurements indeed revealed that tomosyn's SNARE motif cannot substitute synaptobrevin-2/VAMP2 to form template complexes with Munc18-1 and syntaxin-1, an essential intermediate for SNARE assembly. Instead, tomosyns extensively bind synaptobrevin-2/VAMP2-containing template complexes and prevent SNAP-25 association. Structure-function analyses indicate that the C-terminal polybasic region contributes to tomosyn's inhibitory function. These results reveal that tomosyns regulate synaptic transmission by cooperating with synaptobrevin-2/VAMP2 to prevent SNAP-25 binding during SNARE assembly, thereby limiting initial synaptic strength and equalizing it during repetitive stimulation. SNARE-dependent membrane fusion underlies neurotransmission in the nervous system. Here, the authors demonstrate how, in mammalian neurons, the synaptic protein tomosyn controls secretion by increasing the energy barrier for fusion. [ABSTRACT FROM AUTHOR]

The electrical characterisation of classical and quantum devices is a critical step in the development cycle of heterogeneous material stacks for semiconductor spin qubits. In the case of silicon, properties such as disorder and energy separation of conduction band valleys are commonly investigated individually upon modifications in selected parameters of the material stack. However, this reductionist approach fails to consider the interdependence between different structural and electronic properties at the danger of optimising one metric at the expense of the others. Here, we achieve a significant improvement in both disorder and valley splitting by taking a co-design approach to the material stack. We demonstrate isotopically purified, strained quantum wells with high mobility of 3.14(8) × 105 cm2 V−1 s−1 and low percolation density of 6.9(1) × 1010 cm−2. These low disorder quantum wells support quantum dots with low charge noise of 0.9(3) μeV Hz−1/2 and large mean valley splitting energy of 0.24(7) meV, measured in qubit devices. By striking the delicate balance between disorder, charge noise, and valley splitting, these findings provide a benchmark for silicon as a host semiconductor for quantum dot qubits. We foresee the application of these heterostructures in larger, high-performance quantum processors. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic has emphasized the need to explore how variations in the immune system relate to the severity of the disease. This study aimed to explore inter-individual variation in response to SARS-CoV-2 infection by comparing T cell, B cell, and innate cell immune subsets among primary infected children and adults (i.e., those who had never experienced SARS-CoV-2 infection nor received vaccination previously), with varying disease severity after infection. We also examined immune subset kinetics in convalescent individuals compared to those with persistent infection to identify possible markers of immune dysfunction. Distinct immune subset differences were observed between infected adults and children, as well as among adult cases with mild, moderate, and severe disease. IgM memory B cells were absent in moderate and severe cases whereas frequencies of B cells with a lack of surface immunoglobulin expression were significantly higher in severe cases. Interestingly, these immune subsets remained stable during recovery implying that these subsets could be associated with underlying baseline immune variation. Our results offer insights into the potential immune markers associated with severe COVID-19 and provide a foundation for future research in this area. [ABSTRACT FROM AUTHOR]

Purpose : The curative strategy for patients with esophageal cancer without distant metastases consists of esophagectomy with preceding chemo(radio)therapy (CRT). In 10–40% of patients treated with CRT, no viable tumor is detectable in the resection specimen (pathological complete response (pCR)). This study aims to define the clinical outcomes of patients with a pCR and to assess the accuracy of post-CRT FDG-PET/CT in the detection of a pCR. Methods: Four hundred sixty-three patients with cancer of the esophagus or gastroesophageal junction who underwent esophageal resection after CRT between 1994 and 2013 were included. Patients were categorized as pathological complete responders or noncomplete responders. Standardized uptake value (SUV) ratios of 135 post-CRT FDG-PET/CTs were calculated and compared with the pathological findings in the corresponding resection specimens. Results: Of the 463 included patients, 85 (18.4%) patients had a pCR. During follow-up, 25 (29.4%) of these 85 patients developed recurrent disease. Both 5-year disease-free survival (5y-DFS) and 5-year overall survival (5y-OS) were significantly higher in complete responders compared to noncomplete responders (5y-DFS 69.6% vs. 44.2%; P = 0.001 and 5y-OS 66.5% vs. 43.7%; P = 0.001). Not pCR, but only pN0 was identified as an independent predictor of (disease-free) survival. Conclusion: Patients with a pCR have a higher probability of survival compared to noncomplete responders. One third of patients with a pCR do develop recurrent disease, and pCR can therefore not be equated with cure. FDG-PET/CT was inaccurate to predict pCR and therefore cannot be used as a sole diagnostic tool to predict pCR after CRT for esophageal cancer. [ABSTRACT FROM AUTHOR]