A Text Mining Approach to Explore IFNε Literature and Biological Mechanisms.

Interferons (IFN) constitute a primary line of protection against mucosal infection, with IFN research spanning over 60 years and encompassing a vast ever-expanding amount of literature. Most of what is currently understood has been derived from extensive research defining the roles of "classical" type I IFNs, IFNα and IFNß. However, little is known regarding responses elicited by less well-characterized IFN subtypes such as IFNε. In this paper, we combined a deductive text mining analysis of IFNε literature characterizing literature-derived knowledge with a comparative analysis of other type I and type III IFNs. Utilizing these approaches, three clusters of terms were extracted from the literature covering different aspects of IFNε research and a set of 47 genes uniquely cited in the context of IFNε. The use of these "in silico" approaches support the expansion of current understanding and the creation of new knowledge surrounding IFNε.

Digital Interventions and Their Unexpected Outcomes - Time for Digitalovigilance?

The application of digital interventions in healthcare beyond research has been translated in the development of software as a medical device. Along with corresponding regulations for medical devices, there is a need for assessing adverse events to conduct post-market surveillance and to appropriately label digital health interventions to ensure proper use and patient safety. To date unexpected consequences of digital health interventions are neglected or ignored, or at least remain undescribed in literature. This paper is intended to raise awareness across the research community about these upcoming challenges. We recommend that - together with developing a new research field of digitalovigilance - a systematic assessment and monitoring of adverse events and unexpected interactions be included in clinical trials, along with the reporting of such events and the conduct of meta-analyses on critical aspects.

Distribution and diversity of type VI secretion system clusters in Enterobacter bugandensis and Enterobacter cloacae.

Gram-negative bacteria use type VI secretion systems (T6SSs) to antagonize neighbouring cells. Although primarily involved in bacterial competition, the T6SS is also implicated in pathogenesis, biofilm formation and ion scavenging. Enterobacter species belong to the ESKAPE pathogens, and while their antibiotic resistance has been well studied, less is known about their pathogenesis. Here, we investigated the distribution and diversity of T6SS components in isolates of two clinically relevant Enterobacter species, E. cloacae and E. bugandensis. T6SS clusters are grouped into four types (T6SSi-T6SSiv), of which type i can be further divided into six subtypes (i1, i2, i3, i4a, i4b, i5). Analysis of a curated dataset of 31 strains demonstrated that most of them encode T6SS clusters belonging to the T6SSi type. All T6SS-positive strains possessed a conserved i3 cluster, and many harboured one or two additional i2 clusters. These clusters were less conserved, and some strains displayed evidence of deletion. We focused on a pathogenic E. bugandensis clinical isolate for comprehensive in silico effector prediction, with comparative analyses across the 31 isolates. Several new effector candidates were identified, including an evolved VgrG with a metallopeptidase domain and a Tse6-like protein. Additional effectors included an anti-eukaryotic catalase (KatN), M23 peptidase, PAAR and VgrG proteins. Our findings highlight the diversity of Enterobacter T6SSs and reveal new putative effectors that may be important for the interaction of these species with neighbouring cells and their environment.

Preparation and Characterization of Extruded PLA Films Coated with Polyaniline or Polypyrrole by In Situ Chemical Polymerization.

Conductive polymers, such as polypyrrole and polyaniline, have been extensively studied for their notable intrinsic electronic and ionic conductivities, rendering them suitable for a range of diverse applications. In this study, in situ chemical polymerization was employed to coat extruded PLA films with PPy and PANi. Morphological analysis reveals a uniform and compact deposition of both polyaniline and polypyrrole after polymerization periods of 3 and 1 h, respectively. Furthermore, the PLA-PANi-3h and PLA-PPy-1h composites exhibited the highest electrical conductivity, with values of 0.042 and 0.022 S cm-1, respectively. These findings were in agreement with the XPS results, as the polyaniline-coated film showed a higher proportion of charge carriers compared to the polypyrrole composite. The elastic modulus of the coated films showed an increase compared with that of pure PLA films. Additionally, the inflection temperatures for the PLA-PANi-3h and PLA-PPy-1h composites were 368.7 and 367.2 °C, respectively, while for pure PLA, it reached 341.47 °C. This improvement in mechanical and thermal properties revealed the effective interfacial adhesion between the PLA matrix and the conducting polymer. Therefore, this work demonstrates that coating biopolymeric matrices with PANi or PPy enables the production of functional and environmentally friendly conductive materials suitable for potential use in the removal of heavy metals in water treatment.

Transcriptome and Secretome Analyses of Endophyte Methylobacterium mesophilicum and Pathogen Xylella fastidiosa Interacting Show Nutrient Competition.

Xylella fastidiosa is the causal agent of several plant diseases affecting fruit and nut crops. Methylobacterium mesophilicum strain SR1.6/6 was isolated from Citrus sinensis and shown to promote plant growth by producing phytohormones, providing nutrients, inhibiting X. fastidiosa, and preventing Citrus Variegated Chlorosis. However, the molecular mechanisms involved in the interaction among these microbes are still unclear. The present work aimed to analyze physiological and molecular aspects of M. mesophilicum SR1.6/6 and X. fastidiosa 9a5c in co-culture. The transcriptome and secretome analyses indicated that X. fastidiosa down-regulates cell division and transport genes and up-regulates stress via induction of chaperones and pathogenicity-related genes including, the lipase-esterase LesA, a protease, as well as an oligopeptidase in response to M. mesophilicum competition. On the other hand, M. mesophilicum also down-regulated transport genes, except for iron uptake, which was up-regulated. Secretome analysis identified four proteins in M. mesophilicum exclusively produced in co-culture with X. fastidiosa, among these, three are related to phosphorous uptake. These results suggest that M. mesophilicum inhibits X. fastidiosa growth mainly due to nutrient competition for iron and phosphorous, thus promoting X. fastidiosa starvation, besides producing enzymes that degrade X. fastidiosa cell wall, mainly hydrolases. The understanding of these interactions provides a direction for control and management of the phytopathogen X. fastidiosa, and consequently, helps to improve citrus growth and productivity.

Assessing the Potential Risks of Digital Therapeutics (DTX): The DTX Risk Assessment Canvas.

MOTIVATION: Digital therapeutics (DTX), i.e., health interventions that are provided through digital means, are increasingly available for use; in some countries, physicians can even prescribe selected DTX following a reimbursement by health insurances. This results in an increasing need for methodologies to consider and monitor DTX's negative consequences, their risks to patient safety, and possible adverse events. However, it is completely unknown which aspects should be subject to surveillance given the missing experiences with the tools and their negative impacts. OBJECTIVE: Our aim is to develop a tool-the DTX Risk Assessment Canvas-that enables researchers, developers, and practitioners to reflect on the negative consequences of DTX in a participatory process. METHOD: Taking the well-established business model canvas as a starting point, we identified relevant aspects to be considered in a risk assessment of a DTX. The aspects or building blocks of the canvas were constructed in a two-way process: first, we defined the aspects relevant for discussing and reflecting on how a DTX might bring negative consequences and risks for its users by considering ISO/TS 82304-2, the scientific literature, and by reviewing existing DTX and their listed adverse effects. The resulting aspects were grouped into thematic blocks and the canvas was created. Second, six experts in health informatics and mental health provided feedback and tested the understandability of the initial canvas by individually applying it to a DTX of their choice. Based on their feedback, the canvas was modified. RESULTS: The DTX Risk Assessment Canvas is organized into 15 thematic blocks which are in turn grouped into three thematic groups considering the DTX itself, the users of the DTX, and the effects of the DTX. For each thematic block, questions have been formulated to guide the user of the canvas in reflecting on the single aspects. Conclusions: The DTX Risk Assessment Canvas is a tool to reflect the negative consequences and risks of a DTX by discussing different thematic blocks that together constitute a comprehensive interpretation of a DTX regarding possible risks. Applied during the DTX design and development phase, it can help in implementing countermeasures for mitigation or means for their monitoring.

Transcriptomics reveals shared immunosuppressive landscapes in ventilator-associated lower respiratory tract infections (VA-LRTI) patients.

BACKGROUND: Ventilator-associated pneumonia (VAP) represents a transitory status of immunoparalysis, and we hypothesized that ventilator-associated tracheobronchitis (VAT) could share also some degree of immune response to a respiratory infection. RESEARCH DESIGN AND METHODS: A prospective observational study in five medical ICUs to evaluate immunological alterations of patients with VA-LRTI. Immunological gene expression profiles in the blood using whole transcriptome microarrays in the first 24 hours following diagnosis. The area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of mRNA levels to differentiate VA-LRTI and lack of infection. A principal component analysis (PCA) was employed for analyzing the impact of each genetic expression footprint variable in explaining the variance of the cohort. RESULTS: There was overlapping between the three classes of patients encompassing gene expression levels of 8 genes (i.e. HLA, IL2RA, CD40LG, ICOS, CCR7, CD1C, CD3E). HLA-DRA was equally low among VAT and VAP patients characterizing immune depression, and significantly lower than the control group. CONCLUSIONS: Our findings suggest that VAP and VAT are not so different regarding gene expression levels suggesting a degree of immunosuppression. Our results indicate a state of immunoparalysis in respiratory infections in critically ill patients.

Draft genome sequence of Enterobacter cloacae ST473 harbouring blaCMH-3 isolated from a human patient diagnosed with recurrent bacteriuria in Nigeria.

Enterobacter cloacae is among the most frequently isolated species described in clinical infections and is commonly associated with a multidrug resistance (MDR) phenotype. We present the draft genome sequence of a MDR E. cloacae isolated in Nigeria from the urine sample of an adult male outpatient diagnosed with symptomatic recurrent bacteriuria. The isolate was found to be resistant to ceftriaxone, cefotaxime, cefepime and levofloxacin. Genome analysis revealed the presence of the beta-lactamase chromosomal gene blaCMH-3, which may be responsible for the antibiotic resistance observed in the recurrent E. cloacae urinary tract infection.

Quantitative Representativeness and Constituency of the Long-Term Agroecosystem Research Network and Analysis of Complementarity with Existing Ecological Networks.

Studies conducted at sites across ecological research networks usually strive to scale their results to larger areas, trying to reach conclusions that are valid throughout larger enclosing regions. Network representativeness and constituency can show how well conditions at sampling locations represent conditions also found elsewhere and can be used to help scale-up results over larger regions. Multivariate statistical methods have been used to design networks and select sites that optimize regional representation, thereby maximizing the value of datasets and research. However, in networks created from already established sites, an immediate challenge is to understand how well existing sites represent the range of environments in the whole area of interest. We performed an analysis to show how well sites in the USDA Long-Term Agroecosystem Research (LTAR) Network represent all agricultural working lands within the conterminous United States (CONUS). Our analysis of 18 LTAR sites, based on 15 climatic and edaphic characteristics, produced maps of representativeness and constituency. Representativeness of the LTAR sites was quantified through an exhaustive pairwise Euclidean distance calculation in multivariate space, between the locations of experiments within each LTAR site and every 1 km cell across the CONUS. Network representativeness is from the perspective of all CONUS locations, but we also considered the perspective from each LTAR site. For every LTAR site, we identified the region that is best represented by that particular site-its constituency-as the set of 1 km grid locations best represented by the environmental drivers at that particular LTAR site. Representativeness shows how well the combination of characteristics at each CONUS location was represented by the LTAR sites' environments, while constituency shows which LTAR site was the closest match for each location. LTAR representativeness was good across most of the CONUS. Representativeness for croplands was higher than for grazinglands, probably because croplands have more specific environmental criteria. Constituencies resemble ecoregions but have their environmental conditions "centered" on those at particular existing LTAR sites. Constituency of LTAR sites can be used to prioritize the locations of experimental research at or even within particular sites, or to identify the extents that can likely be included when generalizing knowledge across larger regions of the CONUS. Sites with a large constituency have generalist environments, while those with smaller constituency areas have more specialized environmental combinations. These "specialist" sites are the best representatives for smaller, more unusual areas. The potential of sharing complementary sites from the Long-Term Ecological Research (LTER) Network and the National Ecological Observatory Network (NEON) to boost representativeness was also explored. LTAR network representativeness would benefit from borrowing several NEON sites and the Sevilleta LTER site. Later network additions must include such specialist sites that are targeted to represent unique missing environments. While this analysis exhaustively considered principal environmental characteristics related to production on working lands, we did not consider the focal agronomic systems under study, or their socio-economic context.

Electromagnetic Fields Literature Analysis for Precision Medicine.

During the last century technological advances have increased the number of anthropogenic electromagnetic fields (EMFs) and therefore human exposures. In this work we have mined from more than 30,000 EMF-related publications the genes, diseases and molecular mechanisms associated with the exposure to six different subsets of EMFs. Results show 3653 unique disease MeSH terms and 9966 unique genes identified of which only 4340 genes are human. Overall, our approach highlights the molecular aspects of the increasing exposure to EMFs.

Mapping Exposome Derived Phenotypes into SNOMED Codes.

Human phenotypes define the healthy or diseased status of an individual and they arise from the complex interactions between environmental and genetic factors. The whole set of human exposures constitute the human exposome. These exposures have multiple sources including physical and socioeconomic factors. In this manuscript we have used text mining techniques to retrieve 1295 and 1903 Human Phenotype Ontology terms associated with these exposome factors and we have subsequently mapped 83% and 90% of the HPO terms respectively) into SNOMED as a clinically actionable code. We have developed a proof-of-concept approach to facilitate the integration of exposomic and clinical data.

Somatodendritic orientation determines tDCS-induced neuromodulation of Purkinje cell activity in awake mice.

Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits in vivo. In this study, we observe that tDCS induces a heterogeneous polarity-dependent modulation of the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex. Using a combination of juxtacellular labeling and high-density Neuropixels recordings, we demonstrate that the apparently heterogeneous effects of tDCS on PC activity can be explained by taking into account the somatodendritic orientation relative to the electric field. Our findings emphasize the importance of considering neuronal orientation and morphological aspects to increase the predictive power of tDCS computational models, enhance the reliability of current stimulation protocols and optimize desired effects in basic and clinical human applications.

Defining and Scoping Participatory Health Informatics: An eDelphi Study.

BACKGROUND: Health care has evolved to support the involvement of individuals in decision making by, for example, using mobile apps and wearables that may help empower people to actively participate in their treatment and health monitoring. While the term "participatory health informatics" (PHI) has emerged in literature to describe these activities, along with the use of social media for health purposes, the scope of the research field of PHI is not yet well defined. OBJECTIVE: This article proposes a preliminary definition of PHI and defines the scope of the field. METHODS: We used an adapted Delphi study design to gain consensus from participants on a definition developed from a previous review of literature. From the literature we derived a set of attributes describing PHI as comprising 18 characteristics, 14 aims, and 4 relations. We invited researchers, health professionals, and health informaticians to score these characteristics and aims of PHI and their relations to other fields over three survey rounds. In the first round participants were able to offer additional attributes for voting. RESULTS: The first round had 44 participants, with 28 participants participating in all three rounds. These 28 participants were gender-balanced and comprised participants from industry, academia, and health sectors from all continents. Consensus was reached on 16 characteristics, 9 aims, and 6 related fields. DISCUSSION: The consensus reached on attributes of PHI describe PHI as a multidisciplinary field that uses information technology and delivers tools with a focus on individual-centered care. It studies various effects of the use of such tools and technology. Its aims address the individuals in the role of patients, but also the health of a society as a whole. There are relationships to the fields of health informatics, digital health, medical informatics, and consumer health informatics. CONCLUSION: We have proposed a preliminary definition, aims, and relationships of PHI based on literature and expert consensus. These can begin to be used to support development of research priorities and outcomes measurements.

Modelling the Gastrointestinal Carriage of Klebsiella pneumoniae Infections.

Klebsiella pneumoniae is a leading cause of nosocomial and community acquired infections, making K. pneumoniae the pathogen that is associated with the second largest number of deaths attributed to any antibiotic resistant infection. K. pneumoniae colonizes the nasopharynx and the gastrointestinal tract in an asymptomatic manner without dissemination to other tissues. Importantly, gastrointestinal colonization is a requisite for infection. Our understanding of K. pneumoniae colonization is still based on interrogating mouse models in which animals are pretreated with antibiotics to disturb the colonization resistance imposed by the gut microbiome. In these models, infections disseminate to other tissues. Here, we report a murine model to allow for the study of the gastrointestinal colonization of K. pneumoniae without tissue dissemination. Hypervirulent and antibiotic resistant strains stably colonize the gastrointestinal tract of in an inbred mouse population without antibiotic treatment. The small intestine is the primary site of colonization and is followed by a transition to the colon over time, without dissemination to other tissues. Our model recapitulates the disease dynamics of the metastatic K. pneumoniae strains that are able to disseminate from the gastrointestinal tract to other sterile sites. Colonization is associated with mild to moderate histopathology, no significant inflammation, and no effect on the richness of the microbiome. Our model sums up the clinical scenario in which antibiotic treatment disturbs the colonization of K. pneumoniae and results in dissemination to other tissues. Finally, we establish that the capsule polysaccharide is necessary for the colonization of the large intestine, whereas the type VI secretion system contributes to colonization across the gastrointestinal tract. IMPORTANCE Klebsiella pneumoniae is one of the pathogens that is sweeping the world in the antibiotic resistance pandemic. Klebsiella colonizes the nasopharynx and the gut of healthy subjects in an asymptomatic manner, making gut colonization a requisite for infection. This makes it essential to understand the gastrointestinal carriage in preventing Klebsiella infections. Current research models rely on the perturbation of the gut microbiome by antibiotics, resulting in an invasive infection. Here, we report a new model of K. pneumoniae gut colonization that recapitulates key features of the asymptomatic human gastrointestinal tract colonization. In our model, there is no need to disturb the microbiota to achieve stable colonization, and there is no dissemination to other tissues. Our model sums up the clinical scenario in which antibiotic treatment triggers invasive infection. We envision that our model will be an excellent platform upon which to investigate factors enhancing colonization and invasive infections and to test therapeutics to eliminate Klebsiella asymptomatic colonization.

Transoral flexible laser surgery of the upper aerodigestive tract with blue laser.

PURPOSE: The introduction of fiber-guided lasers was a breakthrough in laryngology practice, opening the path for treating different pathologies with minimally invasive procedures, both in the operating room and in the office. The most recent technology in the area is the blue laser, which combines photoangiolytic and cutting properties, characteristics that make this equipment suitable for its use in upper aerodigestive tract surgery. However, there is not enough experience in this area. The authors present a case series of patients with different pharyngeal, laryngeal, and tracheal pathologies who were treated by means of transoral procedures using fiber-guided blue laser. METHODS: The surgical records of patients with different upper aerodigestive tract pathologies who were treated with fiber-guided blue laser in the operating room, under general anesthesia with jet ventilation or supraglottic ventilation using suspension laryngotracheoscopy techniques between February 2018 and March 2022 were reviewed. RESULTS: A total of 80 surgical interventions in a group of 38 patients were performed. A wide variety of procedures was executed, either using the laser alone or in combination with other techniques to treat different pathologies of the aero-digestive tract safely and effectively, with adequate functional results. CONCLUSIONS: Following all necessary precautions, blue laser is a reliable tool to perform minimally invasive surgeries in the operating room using TOFLS techniques. It can be used alone or in combination with other devices to achieve the desired goals.

Histamine Produced by Gram-Negative Bacteria Impairs Neutrophil's Antimicrobial Response by Engaging the Histamine 2 Receptor.

We found that histamine (10-9 M) did not have any effect on the in vitro capture of Escherichia coli by neutrophils but accelerated its intracellular killing. In contrast, histamine (10-6 M) delayed the capture of Escherichia coli by neutrophils and reduced the amounts of pHrodo zymosan particles inside acidic mature phagosomes. Histamine acted through the H4R and the H2R, which are coupled to the Src family tyrosine kinases or the cAMP/protein kinase A pathway, respectively. The protein kinase A inhibitor H-89 abrogated the delay in bacterial capture induced by histamine (10-6 M) and the Src family tyrosine kinase inhibitor PP2 blocked histamine (10-9 M) induced acceleration of bacterial intracellular killing and tyrosine phosphorylation of proteins. To investigate the role of histamine in pathogenicity, we designed an Acinetobacter baumannii strain deficient in histamine production (hdc::TOPO). Galleria mellonella larvae inoculated with the wild-type Acinetobacter baumannii ATCC 17978 strain (1.1 × 105 CFU) died rapidly (100% death within 40 h) but not when inoculated with the Acinetobacter baumannii hdc::TOPO mutant (10% mortality). The concentration of histamine rose in the larval haemolymph upon inoculation of the wild type but not the Acinetobacter baumannii hdc::TOPO mutant, such concentration of histamine blocks the ability of hemocytes from Galleria mellonella to capture Candida albicans in vitro. Thus, bacteria-producing histamine, by maintaining high levels of histamine, may impair neutrophil phagocytosis by hijacking the H2R.

Informed consent for suspension microlaryngoscopy: what should we tell the patient? A consensus statement of the European Laryngological Society.

INTRODUCTION: Informed consent for any surgical intervention is necessary, as only well-informed patients can actively participate in the decision-making process about their care, and better understand the likely or potential outcomes of their treatment. No consensus exists on informed consent for suspension microlaryngoscopy (SML). MATERIALS AND METHODS: Informed consent procedures in nine countries on five continents were studied. RESULTS: Several risks can be discerned: risks of SML as procedure, anesthesiologic risks of SML, specific risks of phonosurgery, risks of inadequate glottic exposure or unexpected findings, risks of not treating. SML has recognized potential complications, that can be divided in temporary (minor) complications, and lasting (major) complications. CONCLUSION: SML is a safe procedure with low morbidity, and virtually no mortality. Eleven recommendations are provided.

Machine Learning Based Microbiome Signature to Predict Inflammatory Bowel Disease Subtypes.

Inflammatory bowel disease (IBD) is a chronic disease with unknown pathophysiological mechanisms. There is evidence of the role of microorganims in this disease development. Thanks to the open access to multiple omics data, it is possible to develop predictive models that are able to prognosticate the course and development of the disease. The interpretability of these models, and the study of the variables used, allows the identification of biological aspects of great importance in the development of the disease. In this work we generated a metagenomic signature with predictive capacity to identify IBD from fecal samples. Different Machine Learning models were trained, obtaining high performance measures. The predictive capacity of the identified signature was validated in two external cohorts. More precisely a cohort containing samples from patients suffering Ulcerative Colitis and another from patients suffering Crohn's Disease, the two major subtypes of IBD. The results obtained in this validation (AUC 0.74 and AUC = 0.76, respectively) show that our signature presents a generalization capacity in both subtypes. The study of the variables within the model, and a correlation study based on text mining, identified different genera that play an important and common role in the development of these two subtypes.

A Comparative Analysis of Phenotypes Derived from Genes or Biomedical Literature in COVID-19.

Since the emergence of SARS-CoV-2 in November 2019, there has been an exponential production of literature due to worldwide efforts to understand the interactions between the virus and the human body. Using an "in-house" developed script we retrieved gene annotations and identified phenotype enrichments. Human Phenotype Ontology terms were retrieved from the literature using the Onassis R package. This produced both disease-gene and disease-phenotype data as well as data for gene-phenotype interactions. Overall, we retrieved 181 human phenotypes that were identified by both approaches. Further in-depth analysis of these relationships could provide further insights in the molecular mechanisms related with the observed phenotypes, answers and hypotheses for key concepts within COVID-19 research.