Prevalence and patterns of higher-order drug interactions in Escherichia coli.

Interactions and emergent processes are essential for research on complex systems involving many components. Most studies focus solely on pairwise interactions and ignore higher-order interactions among three or more components. To gain deeper insights into higher-order interactions and complex environments, we study antibiotic combinations applied to pathogenic Escherichia coli and obtain unprecedented amounts of detailed data (251 two-drug combinations, 1512 three-drug combinations, 5670 four-drug combinations, and 13608 five-drug combinations). Directly opposite to previous assumptions and reports, we find higher-order interactions increase in frequency with the number of drugs in the bacteria's environment. Specifically, as more drugs are added, we observe an elevated frequency of net synergy (effect greater than expected based on independent individual effects) and also increased instances of emergent antagonism (effect less than expected based on lower-order interaction effects). These findings have implications for the potential efficacy of drug combinations and are crucial for better navigating problems associated with the combinatorial complexity of multi-component systems

GP trainees’ perceptions on learning EBM using conversations in the workplace : a video-stimulated interview study

Background To be able to practice evidence-based medicine (EBM) when making decisions for individual patients, it is important to learn how to combine the best available evidence with the patient's preferences and the physician's clinical expertise. In general practice training, these skills can be learned at the workplace using learning conversations: meetings between the supervising general practitioner (GP) and GP trainee to discuss medical practice, selected topics or professional performance. This study aimed to give insight into the perceptions of GP trainees on their EBM learning processes during learning conversations. Methods We held semi-structured video-stimulated elicitation interviews (n = 22) with GP trainees affiliated to GP training institutes in the Netherlands and Belgium. GP trainees were shown fragments of their learning conversations, enabling reflection during the interview. Taking an inductive approach, interview recordings were transcribed verbatim and analysed with NVivo software. Results GP trainees perceived learning conversations as useful for learning and discussing EBM. Multiple EBM learning activities were identified, such as discussing evidence together, relating evidence to cases in daily practice and discussing the supervisor's experience and the specific local context in the light of what the evidence recommends. However, for learning to occur, trainees need and expect specific behaviour, both from their supervisors and themselves. Supervisors should supply well-substantiated answers that are applicable in practice and give the trainee confirmation. In turn, the trainee needs to prepare well in order to ask focused, in-depth questions. A safe space allowing equal and open discussion between trainee and supervisor is perceived as an essential context for optimal EBM learning. Conclusions Our findings show that trainees find learning conversations useful for EBM learning in general practice. To bring EBM learning to its full potential, attention should be paid to optimising the behavioural and contextual factors found relevant to enhancing EBM learning

Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory

Abstract Spondyloarthritides (SpA) include inflammatory joint diseases with various clinical phenotypes that may also include the axial skeleton and/or entheses. SpA include psoriatic arthritis, reactive arthritis, enteropathic arthritis and ankylosing spondylitis; the latter is frequently associated with extra-articular manifestations, such as uveitis, psoriasis, and inflammatory bowel disease. SpA are associated with the HLA-B27 allele and recognize T cells as key pathogenetic players. In contrast to other rheumatic diseases, SpA affect women and men equally and are not associated with detectable serum autoantibodies. In addition, but opposite to rheumatoid arthritis, SpA are responsive to treatment regimens including IL-23 or IL-17-targeting biologics, yet are virtually unresponsive to steroid treatment. Based on these differences with prototypical autoimmune diseases, such as rheumatoid arthritis or connective tissue diseases, SpA may be better classified among autoinflammatory diseases, with a predominant innate immunity involvement. This would rank SpA closer to gouty arthritis and periodic fevers in the spectrum of rheumatic diseases, as opposed to autoimmune-predominant diseases. We herein provide available literature on risk factors associated with SpA in support of this hypothesis with a specific focus on genetic and environmental factors

Lower-Resolution Retrieval of Scenes in Older Adults With Subjective Cognitive Decline

Objective Scenes with more perceptual detail can help detect subtle memory deficits more than scenes with less detail. Here, we investigated whether older adults with subjective cognitive decline (SCD) show less brain activation and more memory deficits to scenes with more (vs. scenes with less) perceptual detail compared to controls (CON). Method In 37 healthy older adults (SCD: 16), we measured blood oxygenation level-dependent-functional magnetic resonance imaging during encoding and behavioral performance during retrieval. Results During encoding, higher activation to scenes with more (vs. less) perceptual detail in the parahippocampal place area predicted better memory performance in SCD and CON. During retrieval, superior performance for new scenes with more (vs. less) perceptual detail was significantly more pronounced in CON than in SCD. Conclusions Together, these results suggest a present, but attenuated benefit from perceptual detail for memory retrieval in SCD. Memory complaints in SCD might, thus, refer to a decreased availability of perceptual detail of previously encoded stimuli

Subclinical myasthenia gravis in thymomas

Background: A proportion of thymoma-patients without a history of myasthenia gravis (MG) before thymectomy, appears to have positive anti-AChR-antibodies in the serum. These subclinical MG-patients could be under diagnosed because analyzation of anti-AChR-antibodies in thymomas is not always performed in patients who did not experience neurological symptoms. The prevalence and long-term outcomes of subclinical MG are never described in literature yet.Methods: We retrospectively analyzed 398 consecutive patients who underwent a robotic-assisted thoracoscopic surgery at the Maastricht University Medical Center+ (MUMC+) between April 2004 and December 2018. In the MUMC+, a robotic approach is the standard surgical approach in patients with thymic diseases. Inclusion criteria were thymomas, thymectomy performed in the MUMC + with a follow-up of at least one year and age above 18 years old. Exclusion criteria were patients with thymic carcinomas, refused participation, or those who were lost to follow-up.Results: Of the 102 included thymoma-patients, 87 patients (85 %) were tested for anti-AChR-antibodies before thymectomy, of which 57 patients were diagnosed with clinical MG and seven subclinical MG-patients were found. Of the 15 patients who were not tested for anti-AChR-antibodies, four more subclinical MG-patients were discovered in the years after thymectomy. The median follow-up time was 62 months. In total, 11 subclinical MG-patients were found, with a mean age of 54 years and predominantly females (64 %). Ten subclinical MG patients (91 %) developed clinical-MG, within six years after thymectomy. Immunosuppressive drugs were prescribed in five patients. Four patients were diagnosed with a recurrence of the thymoma. No surgical mortality was reported. Two patients died due to a myasthenic crisis.Conclusions: The prevalence of subclinical MG in thymomas was found to be 10.8 %. One in four patients who experienced no neurological symptoms before thymectomy, appeared to have anti-AChR-antibodies and 91 % of these patients developed clinical MG within six years after the thymectomy. Analyzing anti-AChR-antibodies in the serum is recommended in all suspected thymomas before a thymectomy is performed

High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis.

Mechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that β-catenin phosphorylated at Y489 (p-β-cateninY489) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/β-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/β-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-β-cateninY489. Collectively, our work elucidates a dysregulated Wnt/p-β-cateninY489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/β-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative medicine studies with implications for restoring normal airway homeostasis after injury