Search

Translation is the fundamental process of protein synthesis and is catalysed by the ribosome in all living cells1. Here we use advances in cryo-electron tomography and sub-tomogram analysis2,3 to visualize the structural dynamics of translation inside the bacterium Mycoplasma pneumoniae. To interpret the functional states in detail, we first obtain a high-resolution in-cell average map of all translating ribosomes and build an atomic model for the M. pneumoniae ribosome that reveals distinct extensions of ribosomal proteins. Classification then resolves 13 ribosome states that differ in their conformation and composition. These recapitulate major states that were previously resolved in vitro, and reflect intermediates during active translation. On the basis of these states, we animate translation elongation inside native cells and show how antibiotics reshape the cellular translation landscapes. During translation elongation, ribosomes often assemble in defined three-dimensional arrangements to form polysomes4. By mapping the intracellular organization of translating ribosomes, we show that their association into polysomes involves a local coordination mechanism that is mediated by the ribosomal protein L9. We propose that an extended conformation of L9 within polysomes mitigates collisions to facilitate translation fidelity. Our work thus demonstrates the feasibility of visualizing molecular processes at atomic detail inside cells.

With the rapid progress in metabolomics and sequencing technologies, more data on the metabolome of single microbes and their communities become available, revealing the potential of microorganisms to metabolize a broad range of chemical compounds. The analysis of microbial metabolomics datasets remains challenging since it inherits the technical challenges of metabolomics analysis, such as compound identification and annotation, while harboring challenges in data interpretation, such as distinguishing metabolite sources in mixed samples. This review outlines the recent advances in computational methods to analyze primary microbial metabolism: knowledge-based approaches that take advantage of metabolic and molecular networks and data-driven approaches that employ machine/deep learning algorithms in combination with large-scale datasets. These methods aim at improving metabolite identification and disentangling reciprocal interactions between microbes and metabolites. We also discuss the perspective of combining these approaches and further developments required to advance the investigation of primary metabolism in mixed microbial samples., This work was funded by the European Molecular Biology Laboratory. MZ-K acknowledges support from the AXA Research Fund., info:eu-repo/semantics/publishedVersion

Early deafness enhances responses of auditory cortices to non-auditory tasks, yet the nature of the reorganization is not well understood. Here, naturalistic stimuli were used to induce neural synchrony across early deaf and hearing individuals. Participants watched a silent animated film in an intact version and three versions with gradually distorted meaning. Differences between groups were observed in higher-order auditory cortices in all stimuli, with no significant effects in the primary auditory cortex. Comparison between levels of scrambling revealed a heterogeneity of function in secondary auditory areas. Both hemispheres showed greater synchrony for the intact movie than for low-level variants. However, the right hemisphere showed an increased inter-subject synchrony for the low-level movie variants, which was not present on the left. An event segmentation validated these results: the dynamics of the right secondary auditory cortex unfolded as shorter length events with more transitions than the left. It also uncovered a further left-right asymmetry: Only left-hemisphere patterns matched the patterns of the hippocampus, a brain region situated at the top of cortical hierarchy. Our results reveal how deaf subjects use their auditory cortex to process visual meaning.

Purpose To assess the accuracy of preoperative sonographic staging for prediction of limited axillary disease (LAD, one or two metastatic lymph nodes) and to identify factors associated with high prediction–pathology concordance in patients with early-stage breast cancer meeting the Z0011 criteria. Materials and Methods Patients treated between January 2015 and January 2020 were included in this retrospective, multicentric analysis of prospectively acquired service databases. The accuracy of LAD prediction was assessed separately for patients with one and two suspicious lymph nodes on preoperative sonography. Test validity outcomes for LAD prediction were calculated for both groups, and a multivariate model was used to identify factors associated with high accuracy of LAD prediction. Results Of 2059 enrolled patients, 1513 underwent sentinel node biopsy, 436 primary and 110 secondary axillary dissection. For LAD prediction in patients with one suspicious lymph node on preoperative ultrasound, sensitivity was 92% (95% CI 87–95%), negative predictive value (NPV) was 92% (95% CI 87–95%), and the false-negative rate (FNR) was 8% (95% CI 5–13%). For patients with two preoperatively suspicious nodes, the sensitivity, NPV, and FNR were 89% (95% CI 84–93%), 73% (62–83%), and 11% (95% CI 7–16%), respectively. On multivariate analysis, the number of suspicious lymph nodes was associated inversely with correct LAD prediction ([OR 0.01 (95% CI 0.01–0.93), p ≤ 0.01]. Conclusions Sonographic axillary staging in patients with one metastatic lymph node predicted by preoperative ultrasound showed high accuracy and a false-negative rate comparable to sentinel node biopsy for prediction of limited axillary disease.

O presente capítulo discute a importância do planejamento urbano para a efetivação de direitos humanos como os direitos à cidade e à moradia. Para isto, é necessário o acesso igualitário à serviços e bens produzidos na cidade. Devido à desigualdade social estes direitos não são sempre cumpridos no Brasil. O déficit habitacional também é um problema latente que pode ser combatido pela efetivação do direito à moradia. Ainda, estes direitos refletem em diversos outros como o direito à saúde e o direito ao meio ambiente saudável, que também são garantidos pela existência de um planejamento urbano de qualidade. Desta forma, um eficiente planejamento urbano pode efetivar diversos direitos humanos.

Marfan syndrome (MFS) is the most prevalent inherited connective tissue disorder, still remains uncurable, and is characterized by high mortality at early age driven by dissection and rupture of thoracic aortic aneurysms. MFS is caused by mutations in the fibrillin-1 gene and aberrant TGFß signaling.Here we addressed whether myeloperoxidase (MPO), a leukocyte derived enzyme with potent matrix modulating properties also influences the aortic phenotype in MFS.MFS patients displayed increased circulating MPO levels compared to controls as well as marked aortic MPO deposition. In an MFS mouse model, MPO induced inflammatory endothelial activation and endothelial to mesenchymal transition which triggered aortic leukocyte recruitment. Moreover, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitration of proteins within the vascular wall. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and - in the absence of any pharmacological treatment so far in this disease - a first anti-inflammatory target to modulate disease progression.

Objective:To assess the concordance and discordance between the core Alzheimer’s disease (AD) CSF biomarkers and [18F]FDG-PET patterns evaluated clinically in memory clinic patients who meet appropriate use criteria for AD biomarker investigations.Methods:We retrospectively assessed subjects with atypical and/or early-onset dementia evaluated at a tertiary care memory clinic. All individuals underwent CSF evaluations for Aβ42, P-tau181 and T-tau, and brain [18F]FDG-PET. [18F]FDG-PET data was visually interpreted by two nuclear medicine experts as being consistent with AD or non-AD. CSF biomarker results were similarly grouped into AD biomarker positive/negative. Contingency tables and Kappa coefficients were used to establish the level of agreement and disagreement between CSF and [18F]FDG-PET results in all individuals.Results:136 individuals had both [18F]FDG-PET and lumbar puncture performed as part of the early-onset and/or atypical dementia assessments. [18F]FDG-PET showed a pattern suggestive of AD in 43% of patients, while CSF biomarkers showed results consistent with AD in 57% of subjects. In patients who met criteria for AD biomarker investigations, we found that [18F]FDG-PET was discordant with CSF AD biomarkers in nearly 20% of cases; 12% of individuals with [18F]FDG-PET scans consistent with AD had AD-negative CSF results; and 7% of individuals with [18F]FDG-PET scans not consistent with AD had AD-positive CSF results, potentially suggesting atypical AD variants or less advanced neurodegeneration. [18F]FDG-PET discriminated patients with an AD-positive CSF profile from patients with an AD-negative profile with a sensitivity and specificity higher than 80% (SN: 81%, 95% CI = 71-88%, SP: 81%, 95% CI = 68-89%). Furthermore, [18F]FDG-PET had a positive predictive value of 87% (95% CI=78-93%) and a negative predictive value of 72% (95% CI = 60-82%).Discussion:CSF and [18F]FDG-PET disagreed in nearly 20% of the cases studied in this clinical series. While CSF Aβ42 and P-tau181 biomarkers are specific for AD, the topographical information from [18F]FDG-PET may providecomplementary information.

Dietary nutrients, host metabolism, and gut microbiota activity each influence the host’s metabolic phenotype; however, the interplay between these factors remains poorly understood. We employed tissue-resolved metabolomics in gnotobiotic mice carrying a synthetic human gut microbiota and germfree mice in two dietary conditions to develop an intestinal flux model that quantifies diet, host, and bacterial contributions to the levels of 2,700 intestinal metabolites. While diet was the main factor affecting metabolite profiles, we identified 1,117 potential microbial substrates and products in the gut. By integrating metagenomics and metatranscriptomics data into genome-scale enzymatic networks, we linked 202 potential substrate-product pairs by a single enzymatic reaction. We further identified bacterial species and enzymes that can explain the differential abundance of 13% of the identified microbial products between the mouse groups. This quantitative modelling approach paves the way for controlling an individual’s metabolic phenotype by modulating their gut microbiome composition and diet.

(Future) teachers should acquire skills in sourcing science-related information online, so they can use evidence appropriately in their pedagogical practice. To successfully use such evidence, it is vital that teachers critically question their selection of online information. Based on findings from collaborative learning, we hypothesized that collaboration promotes teachers' critical elaboration of their selection of online educational information. Additionally, collaboration allows for social comparison and may thus impact teachers' self-efficacy in seeking information. In a 2 × 2 mixed-design study with the between-participants factor reasoning (individual vs. collaborative) and the within-participants factor self-reported information seeking self-efficacy (pre vs. post the reasoning task), each of N = 83 future teachers individually sought online information regarding the educational use of mobile phones in classrooms. This constituted a realistic search on the Internet, in a natural setting. Based on each participant's particular search, s / he was asked to select the online sources that s / he perceived relevant for reasoning whether mobile phones should be used in class. To foster reflection on how they selected information, participants were asked either to reason individually (individual group, n = 33) or to chat collaboratively (collaboration group, n = 50 in 25 dyads) about their selections. Participants in both groups reported higher information seeking self-efficacy after the reasoning task. Yet participants who collaboratively reflected on their selections more frequently showed elaborated reasoning behavior, than did participants in the individual group. Nonetheless, participants in both groups referred to certain criteria that guided their selection (i. e., criteria related to the information, the provider of information, or media) with the same frequency. Considering the potential benefits and challenges of collaboration, we discuss the findings in terms of how to promote future teachers' ability to critically reflect on their selection of online educational information. (Zukünftige) Lehrkräfte sollten ihre pädagogische Praxis auch auf der Basis von bildungswissenschaftlichen Evidenzen begründen. Dazu müssen sie Fähigkeiten erwerben, wie sie angemessen wissenschaftsbezogene Online-Informationen recherchieren können. Um Evidenzen aus Online-Informationen sinnvoll nutzen zu können, ist es wichtig, die Auswahl von Online-Informationen kritisch zu hinterfragen. Basierend auf Forschungsarbeiten zum kollaborativen Lernen wurde angenommen, dass Kollaboration eine kritisch-reflektierte Auseinandersetzung mit der Auswahl von Online-Informationen fördern kann. Zusätzlich bietet die Kollaboration die Möglichkeit zum sozialen Vergleich mit anderen und kann daher die erlebte Selbstwirksamkeit der Lehrkräfte beim Suchen nach Informationen beeinflussen. In einem 2 × 2 Mixed-Design mit dem Zwischensubjektfaktor Erörterung (individuell vs. kollaborativ) und dem Innersubjektfaktor selbstberichtete Selbstwirksamkeit bei der Suche nach Online-Informationen (Prä- vs. Post der Erörterung) suchten N = 83 Lehramtsstudierende individuell nach Online- Informationen zum Thema Handynutzung im Unterricht. Basierend auf ihren Rechercheergebnissen wählten sie diejenigen Webinhalte aus, die sie für eine Entscheidung für ihre didaktische Vorgehensweise als relevant einschätzten. Die Lehramtsstudierenden wurden dann gebeten entweder alleine (individuelle Gruppe, n = 33) oder gemeinsam im Chat mit einer weiteren Lehramtsstudierenden (kollaborative Gruppe, n = 50 in 25 Dyaden) zu erörtern, welche Kriterien die Auswahl ihrer Webinhalte leiteten. Im Anschluss berichteten die Lehramtsstudierenden beider Bedingungen eine höhere Selbstwirksamkeit in Bezug auf die Suche nach Online-Informationen. Die Lehramtsstudierenden, die sich kollaborativ austauschten, konnten ihre Auswahl jedoch argumentativ elaborierter begründen. Des Weiteren verwiesen die Lehramtsstudierenden beider Bedingungen ähnlich häufig auf die jeweiligen Kriterien, die sie für ihre Auswahl nutzten (d. h. Kriterien in Bezug auf die Informationen, die Autoren und Autorinnen, oder die Online-Medien). Die Rolle von Kollaboration bei der Beschaffung von bildungswissenschaftlichen Online-Informationen wird hinsichtlich der Förderung einer kompetenten und kritischen Reflexion über mögliche Vorgehensweisen diskutiert.

Aufgrund der steigenden Nachfrage nach virtuellen Deutschkursen und dem Ausbruch der Covid-19-Pandemie 2019, besteht eine große Notwendigkeit, die Lehr-Lern-Prozesse in virtuellen Umgebungen besser zu verstehen. Ziel der vorliegenden Arbeit war es, die instrumentelle/integrative Motivation (GARDNER und LALONDE, 1985) brasilianischer Lernender beim Deutschlernen in virtuellen Umgebungen wie Skype, Zoom, Google Meets u.a. zu untersuchen. Hierbei lag der Fokus auf den Faktoren subjektive Theorien, Erwartungen an den Onlineunterricht, Erfahrungen, Autonomie, Selbstwahrnehmung der eigenen Leistung im Onlineunterricht sowie digitale Kompetenz, die eine solche Motivation beeinflussen können. Die Studie hat einen qualitativen-quantitativen Charakter. Die Datenerhebung erfolgte anhand eines Online-Fragebogens. Es hat sich gezeigt, dass Zeitersparnis aufgrund fehlender Fahrzeiten zur Sprachschule und Flexibilität die Hauptgründe für eine Teilnahme an OnlineDeutschkursen sind. Die Informanten zeigen sowohl integrative als auch instrumentelle Motivation zum Erlernen der deutschen Sprache, jedoch überwiegt die instrumentelle Motivation mit dem Ziel, in Deutschland zu leben. Es lässt sich schlussfolgern, dass vor allem subjektive Theorien bezüglich der Interaktion zwischen Schülern und Lehrern während des Online-Unterrichts und durch die neuen Medien, sowie das Maß an Lerner-Autonomie die Motivation beim Deutschlernen in der virtuellen Umgebung positiv steigern können, wohingegen negative Erfahrungen die Motivation verringern können. Insbesondere dann, wenn die Lernenden Online-Unterricht als einzige Option zur Auswahl haben, wie es während der Pandemie der Fall war Com a crescente busca por aulas virtuais de língua alemã e o surgimento da pandemia de Covid19 em 2019, há uma grande necessidade de entendermos melhor o processo do ensinoaprendizagem em ambientes virtuais. Neste contexto, o presente trabalho investigou a motivação instrumental/integrativa (GARDNER e LALONDE, 1985) de aprendizes brasileiros ao aprender alemão em ambientes virtuais como Skype, Zoom, Google Meet, entre outros. A investigação teve como foco os fatores crenças, expectativas face ao ensino remoto, experiências, autonomia, autopercepção sobre o desempenho nas aulas online e letramento digital, os quais podem influenciar a motivação estudada. A pesquisa tem um desenho de caráter quantitativo-qualitativo, e a coleta de dados dos informantes realizou-se por meio de um questionário online. Os dados apontaram que a redução do tempo utilizado para deslocamento até a escola e a flexibilidade de horários são os principais fatores motivacionais para frequentar aulas online da língua alemã. Observou-se ainda, que os informantes demostram tanto a motivação integrativa quanto a instrumental ao estudar a língua alemã, porém, a motivação instrumental prevalece e está relacionada ao objetivo de viver na Alemanha. Concluímos que, especialmente no que se refere às crenças na interação entre aluno e professor durante as aulas online e ou através das novas mídias, bem como a autonomia dos aprendizes, são aspectos que podem aumentar a motivação ao aprender alemão no ambiente virtual de maneira positiva, enquanto as experiências negativas podem diminuir a motivação, principalmente quando a aula se constitui como atividade obrigatória, como aconteceu durante a pandemia

Purpose As data on this topic are sparse and contradictory, we aimed to ascertain the opinions of the members of the German Society of Gynecologic Endoscopy (AGE) regarding the use of robotic surgery in the treatment of ovarian malignancies. Methods In 2015, an anonymous questionnaire was sent to AGE members to assess their views on the treatment of ovarian malignancies by robotic surgery according to T stage and the current treatment practices in their facilities. Results Of the 228 respondents, 132 (58%) were fellows or attending physicians and 156 (68%) worked at university hospitals or tertiary referral centers. Most [n = 218 (96%)] respondents reported treating Conclusion The majority of AGE members surveyed considered robotic surgery to be an option for the treatment of T1 ovarian malignancies and borderline ovarian tumors. However, prospective randomized studies are needed to determine the relevance of robotic surgery in this context.

Increasing evidence suggests a role of the gut microbiota in patients’ response to medicinal drugs. In our recent study, we combined genomics of human gut commensals and gnotobiotic animal experiments to quantify microbiota and host contributions to drug metabolism. Informed by experimental data, we built a physiology-based pharmacokinetic model of drug metabolism that includes intestinal compartments with microbiome drug-metabolizing activity. This model successfully predicted serum levels of metabolites of three different drugs, quantified microbial contribution to systemic drug metabolite exposure, and simulated the effect of different parameters on host and microbiota drug metabolism. In this addendum, we expand these simulations to assess the effect of microbiota on the systemic drug and metabolite levels under conditions of altered host physiology, microbiota drug-metabolizing activity or physico-chemical properties of drugs. This work illustrates how and under which circumstances the gut microbiome may influence drug pharmacokinetics, and discusses broader implications of expanded pharmacokinetic models.

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features. ispartof: NATURE MEDICINE vol:28 issue:2 pages:303-+ ispartof: location:United States status: published

Purpose The purpose of this survey was to assess medical students’ opinions about online learning programs and their preferences for specific teaching formats during COVID 19 pandemic. Methods Between May and July 2020, medical students who took an online gynecology and obstetrics course were asked to fill in a questionnaire anonymously. The questionnaire solicited their opinions about the course, the teaching formats used (online lectures, video tutorials featuring real patient scenarios, and online practical skills training), and digital learning in general. Results Of 103 students, 98 (95%) submitted questionnaires that were included in the analysis. 84 (86%) students had no problem with the online course and 70 (72%) desired more online teaching in the future. 37 (38%) respondents preferred online to traditional lectures. 72 (74%) students missed learning with real patients. All digital teaching formats received good and excellent ratings from > 80% of the students. Conclusion The survey results show medical students’ broad acceptance of the online course during COVID 19 pandemic and indicates that digital learning options can partially replace conventional face-to-face teaching. For content taught by lecture, online teaching might be an alternative or complement to traditional education. However, bedside-teaching remains a key pillar of medical education.

The gut microbiota contributes to diverse aspects of host physiology, ranging from immunomodulation to drug metabolism. Changes in the gut microbiota composition are associated with various diseases as well as with the response to medications. It is therefore important to understand how different lifestyle and environmental factors shape gut microbiota composition. Beyond the commonly considered factor of diet, small-molecule drugs have recently been identified as major effectors of the microbiota composition. Other xenobiotics, such as environmental or chemical pollutants, can also impact gut bacterial communities. Here, we review the mechanisms of interactions between gut bacteria and antibiotics, host-targeted drugs, natural food compounds, food additives and environmental pollutants. While xenobiotics can impact bacterial growth and metabolism, bacteria in turn can bioaccumulate or chemically modify these compounds. These reciprocal interactions can manifest in complex xenobiotic-microbiota-host relationships. Our Review highlights the need to study mechanisms underlying interactions with pollutants and food additives towards deciphering the dynamics and evolution of the gut microbiota.

The Pseudomonas quinolone signal (PQS) is a multifunctional quorum sensing molecule of key importance to P. aeruginosa. Here, we report that the lytic Pseudomonas bacterial virus LUZ19 targets this population density-dependent signaling system by expressing quorum sensing targeting protein (Qst) early during infection. We demonstrate that Qst interacts with PqsD, a key host quinolone signal biosynthesis pathway enzyme, resulting in decreased levels of PQS and its precursor 2-heptyl-4(1H)-quinolone. The lack of a functional PqsD enzyme impairs LUZ19 infection but is restored by external supplementation of 2-heptyl-4(1H)-quinolone, suggesting that LUZ19 exploits the PQS system for successful infection. We establish a broad functional interaction network of Qst, which includes enzymes of cofactor biosynthesis pathways (CoaC/ThiD) and a non-ribosomal peptide synthetase pathway (PA1217). Qst therefore represents an exquisite example of intricate reprogramming of the bacterium by a phage, which may be further exploited as tool to combat antibiotic resistant bacterial pathogens., Cell Reports, 38 (7), ISSN:2666-3864, ISSN:2211-1247

BACKGROUND AND OBJECTIVES: To assess the concordance and discordance between the core Alzheimer disease (AD) CSF biomarkers and [(18)F]fluorodeoxyglucose (FDG)-PET patterns evaluated clinically in memory clinic patients who meet appropriate use criteria for AD biomarker investigations. METHODS: We retrospectively assessed participants with atypical and/or early-onset dementia evaluated at a tertiary care memory clinic. All individuals underwent CSF evaluations for Aβ42, phosphorylated tau (P-tau181) and total tau, and brain [(18)F]FDG-PET. [(18)F]FDG-PET data were visually interpreted by 2 nuclear medicine experts as being consistent with AD or non-AD. CSF biomarker results were similarly grouped into AD biomarker positive/negative. Contingency tables and Kappa coefficients were used to establish the level of agreement and disagreement between CSF and [(18)F]FDG-PET results in all individuals. RESULTS: One hundred thirty-six individuals had both [(18)F]FDG-PET and lumbar puncture performed as part of the early-onset and/or atypical dementia assessments. [(18)F]FDG-PET showed a pattern suggestive of AD in 43% of patients, while CSF biomarkers showed results consistent with AD in 57% of participants. In patients who met criteria for AD biomarker investigations, we found that [(18)F]FDG-PET was discordant with CSF AD biomarkers in nearly 20% of cases; 12% of individuals with [(18)F]FDG-PET scans consistent with AD had AD-negative CSF results; and 7% of individuals with [(18)F]FDG-PET scans not consistent with AD had AD-positive CSF results, potentially suggesting atypical AD variants or less advanced neurodegeneration. [(18)F]FDG-PET discriminated patients with an AD-positive CSF profile from patients with an AD-negative profile with a sensitivity and specificity higher than 80% (sensitivity: 81%, 95% CI = 71–88%, SP: 81%, 95% CI = 68–89%). Furthermore, [(18)F]FDG-PET had a positive predictive value of 87% (95% CI = 78–93%) and a negative predictive value of 72% (95% CI = 60–82%). DISCUSSION: CSF and [(18)F]FDG-PET disagreed in nearly 20% of the cases studied in this clinical series. While CSF Aβ42 and P-tau181 biomarkers are specific for AD, the topographical information from [(18)F]FDG-PET may provide complementary information.

Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing evidence implicates the gut microbiome in this variability, the molecular mechanisms involved remain largely unknown. Here we show, by measuring the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs, that many drugs are chemically modified by microorganisms. We combined high-throughput genetic analyses with mass spectrometry to systematically identify microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents. These causal links between the gene content and metabolic activities of the microbiota connect interpersonal variability in microbiomes to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.

To assess the change of body mass index (BMI), muscle mass, visceral and subcutaneous fat in patients with metastatic breast cancer. In this retrospective chart analysis, patients with metastatic breast cancer as initial diagnosis between 2012 and 2016 were analyzed. Patients had received either chemotherapy (CTH) or endocrine therapy (ETH) according to the German S3 Guideline. BMI was calculated from the patients’ weight and height. Change of muscle mass, visceral and subcutaneous fat was determined by comparing the surface area of these tissues on transverse CT images at the level of the third lumbar vertebrae (L3) at baseline and during treatment. A total of 45 patients were included in the study, 29 on CTH and 16 on ETH. BMI, visceral and subcutaneous fat remained stable over time for both treatment groups. When taking both treatment groups together, muscle mass decreased significantly by 5.0 ± 2.5 cm2 per year (p

Alzheimer9s disease (AD) is a multifactorial pathology responsible for most cases of dementia worldwide. Only a small percentage of AD cases are due to autosomal dominant mutations, while the vast majority have a sporadic presentation. Yet, preclinical research studies relied for decades on animal models that overexpress human genes found in AD autosomal dominant patients. Thus, one could argue that these models do not recapitulate sporadic AD. To avoid human gene overexpression artifacts, knock-in (KI) models have been developed, such as the novel hAβ-KI mouse model, which are still in early phases of characterization. We hypothesize that comparisons at the transcriptomic level may elucidate critical similarities and differences between transgenic/KI models and AD patients. Thus, we aimed at comparing the hippocampal transcriptomic profiling of overexpression (5xFAD and APP/PS1) and KI (hAβ-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. We first evaluated differentially expressed genes (DEGs) and Gene Ontology biological processes (GOBP) overlapping cross-species. After, we explored a network-based strategy to identify master regulators (MR) and the similarities of such elements among models and AD subtypes. A multiple sclerosis (MS) dataset was included to test the molecular specificity of the mouse models to AD. Our analysis revealed that all three mouse models presented more DEGs, GOBP terms and enriched signaling pathways in common with LOAD than with EOAD subjects. Furthermore, semantic similarity of enriched GOBP terms showed mouse model-specific biological alterations, and protein-protein interaction analysis of DEGs identified clusters of genes exclusively shared between hAβ-KI mice and LOAD. Furthermore, we identified 17 transcription factor candidates potentially acting as MR of AD in all three models. Finally, though all mouse models showed transcriptomic similarities to LOAD, hAβ-KI mice presented a remarkable specificity to this AD subtype, which might support the use of the novel hAβ-KI mouse model to advance our understanding of sporadic LOAD.

Background In the COVID-19 pandemic, Switzerland introduced broad nationwide face mask mandates only by October 2020, later than other Western European countries. This study aims to assess the underlying values and considerations of individuals to wear face masks in the absence of face mask mandates in the COVID-19 pandemic in German-speaking Switzerland. Methods As part of the “Solidarity in times of a pandemic” (SolPan) research commons, we interviewed 31 participants living in the German-speaking part of Switzerland in April 2020 and 25 of them again in October 2020. Qualitative inductive thematic analysis was applied for data analysis and interpretation. Public health ethics principles guided the interpretation and organization of findings. Results Five themes were identified: Trust and governmental policy; perceived benefits of mask-wearing; perceived risks of mask-wearing; social exclusion and prejudice; and decision-making in the absence of mandates. In light of increasing infection rates in October 2020, many participants started to consider the benefits higher than the risks and were willing to accept face mask mandates in that context, despite earlier reservations. Conclusions The absence of face mask mandates underline individual autonomy but may also suppress personal responsibility due to social influence. Face masks are only temporarily acceptable in liberal Western societies and face mask mandates should be enforced only when epidemiologically necessary. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-021-12215-4.

OBJECTIVE Previous positron emission tomography (PET) studies using [11 C]ABP688 show reduced metabotropic glutamate receptor type 5 (mGluR5) allosteric binding site availability in the epileptogenic hippocampus of mesial temporal lobe epilepsy (MTLE) patients. However, the link between mGluR5 abnormalities and postsurgical outcomes remains unclear. Here, we test whether reduced PET [11 C]ABP688 binding in cornu ammonis (CA) sectors more vulnerable to glutamatergic excitotoxicity relates to surgical outcomes. METHODS We obtained magnetic resonance imaging (MRI) and [11 C]ABP688-PET from 31 unilateral MTLE patients and 30 healthy controls. MRI hippocampal subfields were segmented using FreeSurfer. To respect the lower PET special resolution, MRI-derived anatomical subfields were combined into CA1-3, CA4/dentate gyrus, and Subiculum. Partial volume corrected [11 C]ABP688 nondisplaceable binding potential (BPND ) values were averaged across each subfield, and Z-scores were calculated. Subfield [11 C]ABP688-BPND was compared between seizure-free and non-seizure-free patients. In addition, we also assessed subfield volumes and [18 F]fluorodeoxyglucose (FDG) uptake in each clinical group. RESULTS MTLE [11 C]ABP688-BPND was reduced in ipsilateral (epileptogenic) CA1-3 and CA4/dentate-gyrus (p

Purpose The aims of this study were to determine the incidence of intraoperative and postoperative complications of laparoscopic gynecological interventions and to identify risk factors for such complications. Methods All patients who underwent laparoscopic interventions from September 2013 to September 2017 at the Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital were identified retrospectively using a prospectively compiled clinical database. Binary logistic regression analysis was used to identify independent risk factors for intra- and postoperative complications. Results Data from 3351 patients were included in the final analysis. Overall, 188 (5.6%) intraoperative and 219 (6.5%) postoperative complications were detected. On multivariate analysis, age [odds ratio (OR), 1.03; 95% confidence interval (CI) 1.01–1.04], surgery duration (OR, 1.02; 95% CI 1.02–1.03), carbon dioxide use (OR, 0.99; 95% CI 0.99–1.00), and surgical indication (all p ≤ 0.01) were independent risk factors for intraoperative and duration of surgery (OR, 1.01; 95% CI 1.01–1.02; p ≤ 0.01), carbon dioxide use (OR, 0.99; 95% CI 0.99–1.00; p ≤ 0.01), hemoglobin drop (OR, 1.41; 95% CI 1.21–1.65; p ≤ 0.01), and ASA status (p = 0.04) for postoperative complications. Conclusion In this large retrospective analysis with a generally low incidence of complications (5.6% intraoperative and 6.5% postoperative complications), a representative risk collective was identified: Patients aged > 38 years, surgery duration > 99 min, benign or malignant adnex findings were at higher risk for intraoperative and patients with surgery duration > 94 min, hemoglobin drop > 2 g/dl and ASA status III at higher risk for postoperative complications.

Purpose Vaginal cuff dehiscence (VCD) is one of the major surgical complications following hysterectomy with data on incidence rates varying largely and studies assessing risk factors being sparse with contradictive results. The aim of this study was to assess the incidence rate of and risk factors for VCD in a homogenous cohort of women treated for benign uterine pathologies via total laparoscopic hysterectomy (TLH) with standardized follow-up. Methods All patients undergoing TLH at the Department of Gynecology and Obstetrics, Saarland University Hospital between November 2010 and February 2019 were retrospectively identified from a prospectively maintained service database. Results VCD occurred in 18 (2.9%) of 617 patients included. In univariate and multivariate analyses, a lower level of surgeon laparoscopic expertise (odds ratio 3.19, 95% confidence interval (CI) 1.0–9.38; p = 0.03) and lower weight of removed uterus (odds ratio 0.99, 95% CI 0.98–0.99; p = 0.02) were associated positively with the risk of VCD. Conclusion In this homogenous cohort undergoing TLH, laparoscopic expertise and uterine weight influenced the risk of postoperative VCD. These findings might help to further reduce the rate of this complication.

Mobile applications for digital contact tracing have been developed and introduced around the world in response to the COVID-19 pandemic. Proposed as a tool to support 'traditional' forms of contact-tracing carried out to monitor contagion, these apps have triggered an intense debate with respect to their legal and ethical permissibility, social desirability and general feasibility. Based on a large-scale study including qualitative data from 349 interviews conducted in nine European countries (Austria, Belgium, France, Germany, Ireland, Italy, the Netherlands, German-speaking Switzerland, the United Kingdom), this paper shows that the binary framing often found in surveys and polls, which contrasts privacy concerns with the usefulness of these interventions for public health, does not capture the depth, breadth, and nuances of people's positions towards COVID-19 contact-tracing apps. The paper provides a detailed account of how people arrive at certain normative positions by analysing the argumentative patterns, tropes and (moral) repertoires underpinning people's perspectives on digital contact-tracing. Specifically, we identified a spectrum comprising five normative positions towards the use of COVID-19 contact-tracing apps: opposition, scepticism of feasibility, pondered deliberation, resignation, and support. We describe these stances and analyse the diversity of assumptions and values that underlie the normative orientations of our interviewees. We conclude by arguing that policy attempts to develop and implement these and other digital responses to the pandemic should move beyond the reiteration of binary framings, and instead cater to the variety of values, concerns and expectations that citizens voice in discussions about these types of public health interventions. ispartof: Critical Public Health vol:32 issue:1 pages:5-18 ispartof: location:England status: Published online

Early sensory deprivation, such as deafness, shapes brain development in multiple ways. Deprived auditory areas become engaged in the processing of stimuli from the remaining modalities and in high-level cognitive tasks. Yet, structural and functional changes were also observed in non-deprived brain areas, which may suggest the whole-brain network changes in deaf individuals. To explore this possibility, we compared the resting-state functional network organization of the brain in early deaf adults and hearing controls and examined global network segregation and integration. Relative to hearing controls, deaf adults exhibited decreased network segregation and an altered modular structure. In the deaf, regions of the salience network were coupled with the fronto-parietal network, while in the hearing controls, they were coupled with other large-scale networks. Deaf adults showed weaker connections between auditory and somatomotor regions, stronger coupling between the fronto-parietal network and several other large-scale networks (visual, memory, cingulo-opercular and somatomotor), and an enlargement of the default mode network. Our findings suggest that brain plasticity in deaf adults is not limited to changes in the auditory cortex but additionally alters the coupling between other large-scale networks and the development of functional brain modules. These widespread functional connectivity changes may provide a mechanism for the superior behavioral performance of the deaf in visual and attentional tasks. Electronic supplementary material The online version of this article (10.1007/s11682-020-00346-y) contains supplementary material, which is available to authorized users.

It has been proposed that the auditory cortex in the deaf humans might undergo task-specific reorganization. However, evidence remains scarce as previous experiments used only two very specific tasks (temporal processing and face perception) in visual modality. Here, congenitally deaf/hard of hearing and hearing women and men were enrolled in an fMRI experiment as we sought to fill this evidence gap in two ways. First, we compared activation evoked by a temporal processing task performed in two different modalities, visual and tactile. Second, we contrasted this task with a perceptually similar task that focuses on the spatial dimension. Additional control conditions consisted of passive stimulus observation. In line with the task specificity hypothesis, the auditory cortex in the deaf was activated by temporal processing in both visual and tactile modalities. This effect was selective for temporal processing relative to spatial discrimination. However, spatial processing also led to significant auditory cortex recruitment which, unlike temporal processing, occurred even during passive stimulus observation. We conclude that auditory cortex recruitment in the deaf and hard of hearing might involve interplay between task-selective and pluripotential mechanisms of cross-modal reorganization. Our results open several avenues for the investigation of the full complexity of the cross-modal plasticity phenomenon.SIGNIFICANCE STATEMENTPrevious studies suggested that the auditory cortex in the deaf may change input modality (sound to vision) while keeping its function (e.g., rhythm processing). We investigated this hypothesis by asking deaf or hard of hearing and hearing adults to discriminate between temporally and spatially complex sequences in visual and tactile modalities. The results show that such function-specific brain reorganization, as has previously been demonstrated in the visual modality, also occurs for tactile processing. On the other hand, they also show that for some stimuli (spatial) the auditory cortex activates automatically, which is suggestive of a take-over by a different kind of cognitive function. The observed differences in processing of sequences might thus result from an interplay of task-specific and pluripotent plasticity.