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Pasteurella spp. are gram-negative, facultative anaerobic bacteria. They are part of the oral flora of domestic animals, including cats and dogs. In cases of animal bites, Pasteurella spp. bacteria can [...]

For users of hydrological models, the suitability of models can depend on how well their simulated outputs align with observed discharge. This study emphasizes the crucial role of factoring in discharge observation uncertainty when assessing the performance of hydrological models. We introduce an ad hoc approach, implemented through the eWaterCycle platform, to evaluate the significance of differences in model performance while considering the uncertainty associated with discharge observations. The analysis of the results encompasses 299 catchments from the Catchment Attributes and MEteorology for Large-sample Studies Great Britain (CAMELS-GB) large-sample catchment dataset, addressing three practical use cases for model users. These use cases involve assessing the impact of additional calibration on model performance using discharge observations, conducting conventional model comparisons, and examining how the variations in discharge simulations resulting from model structural differences compare with the uncertainties inherent in discharge observations. Based on the 5th to 95th percentile range of observed flow, our results highlight the substantial influence of discharge observation uncertainty on interpreting model performance differences. Specifically, when comparing model performance before and after additional calibration, we find that, in 98 out of 299 instances, the simulation differences fall within the bounds of discharge observation uncertainty. This underscores the inadequacy of neglecting discharge observation uncertainty during calibration and subsequent evaluation processes. Furthermore, in the model comparison use case, we identify numerous instances where observation uncertainty masks discernible differences in model performance, underscoring the necessity of accounting for this uncertainty in model selection procedures. While our assessment of model structural uncertainty generally indicates that structural differences often exceed observation uncertainty estimates, a few exceptions exist. The comparison of individual conceptual hydrological models suggests no clear trends between model complexity and subsequent model simulations falling within the uncertainty bounds of discharge observations. Based on these findings, we advocate integrating discharge observation uncertainty into the calibration process and the reporting of hydrological model performance, as has been done in this study. This integration ensures more accurate, robust, and insightful assessments of model performance, thereby improving the reliability and applicability of hydrological modelling outcomes for model users.

Abstract Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

The androgen receptor signaling inhibitor apalutamide is used successfully for the treatment of prostate cancer. An increased risk of hypothyroidism, mostly subclinical, has been reported in the SPARTAN and TITAN trials. We present three cases of subacute deterioration of previously known but well-controlled hypothyroidism treated with levothyroxine, occurring shortly after the initiation of treatment with apalutamide, resulting in severe hypothyroidism. These cases highlight the importance of awareness of thyroid dysfunction during treatment with apalutamide, particularly in patients with pre-existing thyroid disease, common in the general population. We provide practice recommendations for thyroid management prior to and during apalutamide treatment as well as after the interruption of this therapy.

An 81-year-old male patient in Germany had prosthetic valve endocarditis caused by Pasteurella dagmatis after a domestic cat bite. We surgically treated a paravalvular abscess and administered definitive antibiotic therapy consisting of penicillin G and levofloxacin. The patient was discharged from the intensive care unit in good condition 21 days after the surgery.

Abstract Background Chronic diseases such as type 2 diabetes mellitus and coronary heart disease cause medical, social, and economic burdens worldwide. Disease management programs in Germany mostly lack components to improve patients’ self-management and health-promoting lifestyles despite clear guideline recommendations. Therefore, a Personalized Self-Management Support Program (P-SUP) was developed, which includes: (1) peer support groups; (2) telephone coaching; (3) feedback reports and, (4) a web portal. This study aims to explore patients’ and implementing stakeholders’ experiences in the implementation of P-SUP to identify barriers and facilitators to the implementation of the intervention. Methods A qualitative study was conducted using face-to-face focus group interviews with participating patients and telephone-based one-to-one expert interviews with implementing stakeholders, involved in the delivery of the intervention. The transcribed interview reports were analyzed using qualitative content analysis, and the contents were categorized according to Donabedian’s Structure-Process-Outcome framework. Results A total of six themes among patients (N = 35) and five themes among implementing stakeholders (N = 32) represent the experiences. The patient themes were: (1) technical conditions, (2) indoor facilities, (3) group composition, (4) acceptance of digital components, (5) supervision and feedback and (6) impact on lifestyle behavior. The themes among the implementing stakeholders were: (1) multiprofessional approach, (2) human resources, (3) patient acceptance, (4) supervision and feedback and (5) impact on lifestyle behavior. Conclusions Multiprofessional interventions such as P-SUP appear to be valuable for patients and implementing stakeholders. Although infrastructural barriers made the implementation of peer support and digital patient education difficult, patients rated the exchange with peers and experts on health-related topics positively. The lack of supervision and feedback during the course of the intervention might be compensated by regular telephone coaching. The findings from this study can be used in future studies to guide researchers and implementing stakeholders and to improve the feasibility and effectiveness of complex interventions in different contexts. Trial registration The P-SUP study was registered in the German Clinical Trials Register (DRKS) on 16/07/2020 under the registration number DRKS00020592.

The miombo woodland is the largest dry woodland formation in sub-Saharan Africa, covering an estimated area of 2.7–3.6 million km2. Compared to other global ecosystems, the miombo woodland demonstrates unique interactions between plant phenology and climate. For instance, it experiences an increase in the leaf area index (LAI) during the dry season. However, due to limited surface exchange observations in the miombo region, there is a lack of information regarding the effect of these properties on miombo woodland evaporation. It is crucial to have a better understanding of miombo evaporation for accurate hydrological and climate modelling in this region. Currently, the only available regional evaporation estimates are based on satellite data. However, the accuracy of these estimates is questionable due to the scarcity of field estimates with which to compare. Therefore, this study aims to compare the temporal dynamics and magnitudes of six satellite-based evaporation estimates – the Topography-driven Flux Exchange (FLEX-Topo) model, Global Land Evaporation Amsterdam Model (GLEAM), Moderate-Resolution Imaging Spectrometer (MODIS) MOD16 product, operational Simplified Surface Energy Balance (SSEBop) model, Thornthwaite–Mather climatic Water Balance (TerraClimate) dataset, and Water Productivity through Open access of Remotely sensed derived data (WaPOR) – during different phenophases in the miombo woodland of the Luangwa Basin, a representative river basin in southern Africa. The goal of this comparison is to determine if the temporal dynamics and magnitudes of the satellite-based evaporation estimates align with the documented feedback between miombo woodland and climate. In the absence of basin-scale field observations, actual evaporation estimates based on the multi-annual water balance (Ewb) are used for comparison. The results show significant discrepancies among the satellite-based evaporation estimates during the dormant and green-up and mid-green-up phenophases. These phenophases involve substantial changes in miombo species' canopy phenology, including the co-occurrence of leaf fall and leaf flush, as well as access to deeper moisture stocks to support leaf flush in preparation for the rainy season. The satellite-based evaporation estimates show the highest agreement during the senescence phenophase, which corresponds to the period of high temperature, high soil moisture, high leaf chlorophyll content, and highest LAI (i.e. late rainy season into the cool-dry season). In comparison to basin-scale actual evaporation, all six satellite-based evaporation estimates appear to underestimate evaporation. Satellite-based evaporation estimates do not accurately represent evaporation in this data-sparse region, which has a phenology and seasonality that significantly differ from the typical case in data-rich ground-truth locations. This may also be true for other locations with limited data coverage. Based on this study, it is crucial to conduct field-based observations of evaporation during different miombo species phenophases to improve satellite-based evaporation estimates in miombo woodlands.

International Society of Urological Pathology grade group 1 (GG 1) prostate cancer (PCa) is generally considered insignificant, with recent suggestions that it should even be considered as “noncancerous”. We evaluated outcomes for patients with GG 1 PCa on biopsy (bGG 1) and high-risk features (prostate-specific antigen [PSA] >20 ng/ml and/or cT3–4 stage) to challenge the hypothesis that every case of bGG 1 PCa has a benign disease course. We used the multi-institutional EMPaCT database, which includes data for 9508 patients with high-risk PCa undergoing surgery. We included patients with bGG 1 PCa (n = 848) in our analysis and divided them into three groups according to PSA >20 ng/ml, cT3–4 stage, or both. The estimated 10-yr cancer-specific survival (CSS) rate was 96% in the overall population, 88% in the group with both PSA >20 ng/ml and cT3–4 stage, 97% in the group with PSA >20 ng/ml alone, and 98% in the group with cT3–4 stage alone. Similar CSS outcomes were found in subgroups with GG 1 PCa on pathology (n = 502) and with GG 1 on biopsy diagnosed after 2005 (n = 253). Study limitations include the lack of magnetic resonance imaging (MRI) staging and MRI-targeted biopsies. In conclusion, patients with GG 1 and either PSA >20 ng/ml or cT3–4 stage have a low risk of dying from their cancer after surgery. However, patients with GG 1 PCa and both PSA >20 ng/ml and cT3–4 stage are at higher risk of cancer-specific mortality and active treatment should be discussed for this subgroup. Patient summary: We assessed outcomes for patients diagnosed with low-grade prostate cancer on biopsy who also had one or two factors associated with high risk disease. Men with both of those risk factors had a higher risk of dying from their prostate cancer. Active treatment should be discussed for this subgroup of patients.

Environmental monitoring (EM) is the cornerstone for the assurance of sterility during aseptic manufacturing. In this study, the EM quality aspects in the radiopharmaceutical cleanrooms of the University Medical Center Groningen (UMCG), The Netherlands, were evaluated. Hereto, data obtained from EM over the period 2010–2022 were analyzed. The data were sorted according to the Good Manufacturing Practice (GMP) classification of the respective premises with their corresponding limits, and frequencies of excursions were determined per location. The frequency of conducted measurements gradually increased between the start and end of the assessed period. There was a trend of increased action limit excursions observed between 2010–2022. We found that EM in grade A areas appeared to be significantly less compliant with GMP specifications than the combined data from all sampled premises at the facility (p < 0.00001; two-sided Fisher’s exact test). A trend was found for reduced action limit excursions for passive air sampling and particle counting, suggesting improved GMP compliance over time for this specific type of EM. The contamination recovery rate (CRR) found for cleanroom conditions, around 10%, was considered sufficient. From this comprehensive data analysis, we learn that, in order to be fully compliant with the requirements set in the recent revision of EU (European Union)-GMP Annex 1 ‘Manufacture of sterile medicinal products’ (in force as of 25 August 2023), strategies to further improve product protection are justified. For example, improved cleaning and disinfection procedures, more efficient working methods as well as optimization of the conditions under which aseptic manufacturing is performed are to be considered.

The evolution of new traits enables expansion into new ecological and behavioural niches. Nonetheless, demonstrated connections between divergence in protein structure, function and lineage-specific behaviours remain rare. Here we show that both octopus and squid use cephalopod-specific chemotactile receptors (CRs) to sense their respective marine environments, but structural adaptations in these receptors support the sensation of specific molecules suited to distinct physiological roles. We find that squid express ancient CRs that more closely resemble related nicotinic acetylcholine receptors, whereas octopuses exhibit a more recent expansion in CRs consistent with their elaborated taste by touch sensory system. Using a combination of genetic profiling, physiology and behavioural analyses, we identify the founding member of squid CRs that detects soluble bitter molecules that are relevant in ambush predation. We present the cryo-electron microscopy structure of a squid CR and compare this with octopus CRs1 and nicotinic receptors2. These analyses demonstrate an evolutionary transition from an ancestral aromatic cage that coordinates soluble neurotransmitters or tastants to a more recent octopus CR hydrophobic binding pocket that traps insoluble molecules to mediate contact-dependent chemosensation. Thus, our study provides a foundation for understanding how adaptation of protein structure drives the diversification of organismal traits and behaviour.

Gaussian mixture models are classical but still popular machine learning models. An appealing feature of Gaussian mixture models is their tractability, that is, they can be learned efficiently and exactly from data, and also support efficient exact inference queries like soft clustering data points. Only seemingly simple, Gaussian mixture models can be hard to understand. There are at least four aspects to understanding Gaussian mixture models, namely, understanding the whole distribution, its individual parts (mixture components), the relationships between the parts, and the interplay of the whole and its parts. In a structured literature review of applications of Gaussian mixture models, we found the need for supporting all four aspects. To identify candidate visualizations that effectively aid the user needs, we structure the available design space along three different representations of Gaussian mixture models, namely as functions, sets of parameters, and sampling processes. From the design space, we implemented three design concepts that visualize the overall distribution together with its components. Finally, we assessed the practical usefulness of the design concepts with respect to the different user needs in expert interviews and an insight-based user study.