1. Infectious diseases have a large impact on poultry health and economics. Elucidating the pathogenesis of a certain disease is crucial to implement control strategies.
2. Multiplication of a ...pathogen and its characterisation in vitro are basic requirements to perform experimental studies. However, passaging of the pathogen in vitro can influence the pathogenicity, a process targeted for live vaccine development, but limits the reproduction of clinical signs.
3. Numerous factors can influence the outcome of experimental infections with some importance on the pathogen, application route and host as exemplarily outlined for Histomonas meleagridis, Gallibacterium anatis and fowl aviadenoviruses (FAdVs).
4. In future, more comprehensive and detailed settings are needed to obtain as much information as possible from animal experiments. Processing of samples with modern diagnostic tools provides the option to closely monitor the host-pathogen interaction.
How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, ...demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease.
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Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment ...of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.
Machine learning is a broad term encompassing a number of methods that allow the investigator to learn from the data. These methods may permit large real-world databases to be more rapidly translated ...to applications to inform patient-provider decision making.
This systematic literature review was conducted to identify published observational research of employed machine learning to inform decision making at the patient-provider level. The search strategy was implemented and studies meeting eligibility criteria were evaluated by two independent reviewers. Relevant data related to study design, statistical methods and strengths and limitations were identified; study quality was assessed using a modified version of the Luo checklist.
A total of 34 publications from January 2014 to September 2020 were identified and evaluated for this review. There were diverse methods, statistical packages and approaches used across identified studies. The most common methods included decision tree and random forest approaches. Most studies applied internal validation but only two conducted external validation. Most studies utilized one algorithm, and only eight studies applied multiple machine learning algorithms to the data. Seven items on the Luo checklist failed to be met by more than 50% of published studies.
A wide variety of approaches, algorithms, statistical software, and validation strategies were employed in the application of machine learning methods to inform patient-provider decision making. There is a need to ensure that multiple machine learning approaches are used, the model selection strategy is clearly defined, and both internal and external validation are necessary to be sure that decisions for patient care are being made with the highest quality evidence. Future work should routinely employ ensemble methods incorporating multiple machine learning algorithms.
Prebiotic dietary fiber supplements are commonly consumed to help meet fiber recommendations and improve gastrointestinal health by stimulating beneficial bacteria and the production of short-chain ...fatty acids (SCFAs), molecules beneficial to host health. The objective of this research project was to compare potential prebiotic effects and fermentability of five commonly consumed fibers using an in vitro fermentation system measuring changes in fecal microbiota, total gas production and formation of common SCFAs. Fecal donations were collected from three healthy volunteers. Materials analyzed included: pure beta-glucan, Oatwell (commercially available oat-bran containing 22% oat β-glucan), xylooligosaccharides (XOS), WholeFiber (dried chicory root containing inulin, pectin, and hemi/celluloses), and pure inulin. Oatwell had the highest production of propionate at 12 h (4.76 μmol/mL) compared to inulin, WholeFiber and XOS samples (
< 0.03). Oatwell's effect was similar to those of the pure beta-glucan samples, both samples promoted the highest mean propionate production at 24 h. XOS resulted in a significant increase in the genus
after 24 h of fermentation (0 h:0.67 OTUs (operational taxonomic unit); 24 h:5.22 OTUs;
= 0.038). Inulin and WholeFiber increased the beneficial genus
, consistent with findings in clinical studies. All analyzed compounds were fermentable and promoted the formation of beneficial SCFAs.
Following the dynamic capabilities perspective, we suggest that antecedents to innovation can be found at the individual, firm, and network levels. Thus, we challenge two assumptions common in prior ...research: (1) that significant variance exists at the focal level of analysis, whereas other levels of analysis are assumed to be homogeneous, and (2) that the focal level of analysis is independent from other levels of analysis. Accordingly, we advance a set of hypotheses to simultaneously assess the direct effects of antecedents at the individual, firm, and network levels on innovation output. We then investigate whether a firm's antecedents to innovation lie across different levels. To accomplish this, we propose two competing interaction hypotheses. We juxtapose the hypothesis that the individual-, firm-, and network-level antecedents to innovation are substitutes versus the proposition that these innovation mechanisms are complements. We test our multilevel theoretical model using an unusually comprehensive and detailed panel data set that documents the innovation attempts of global pharmaceutical companies within biotechnology over a 22-year time period (1980-2001). We find evidence that the antecedents to innovation lie across different levels of analysis and can have compensating or reinforcing effects on firm-level innovative output.
Mineral particles, in general, are not spheres and so the assumption of spherical particles, instead of more realistic shapes, has significant effects on modeled optical properties and therefore on ...remote-sensing procedures for desert aerosol and the derived radiative forcing. Thus, in a new version of the database OPAC (Optical Properties of Aerosols and Clouds; Hess et al., 1998), the optical properties of the mineral particles are modeled describing the particles as spheroids with size dependent aspect ratio distributions, but with the size distributions and the spectral refractive indices not changed against the previous version of OPAC. The spheroid assumption is known to substantially improve the scattering functions but pays regard to the limited knowledge on particle shapes in an actual case. The relative deviations of the optical properties of non-spherical mineral particles from those of spherical particles are for the phase function in the solar spectral range up to +60% at scattering angles of about 130° and up to -60% in the backscatter region, but less than 2% for the asymmetry parameter. The deviations are generally small in the thermal infrared and for optical properties that are independent of the scattering angle. The improved version of OPAC (4.0) is freely available at www.rascin.net.
Summary
Background
Proton pump inhibitors (PPIs) are a mainstay therapy for all gastric acid‐related diseases. Clinical concerns arise from a small but growing number of case reports presenting ...PPI‐induced hypomagnesaemia (PPIH) as a consequence of long‐term PPI use. Current opinion is that reduced intestinal magnesium absorption might be involved, but nothing is known on the molecular mechanism underlying PPIH.
Aim
To investigate whether or not PPIH is a true, long‐term drug‐class effect of all PPIs and to scrutinise a possible role of comorbidity in its aetiology. Therefore, the primary objective in particular was to investigate serum magnesium dynamics in trials drug withdrawal and re‐challenge. The secondary objective was to profile the ‘patient at risk’.
Methods
We reviewed systematically all currently available case reports on the subject and performed a statistical analysis on extracted data.
Results
Proton pump inhibitor‐induced hypomagnesaemia PPIH is a drug‐class effect and occurred after 5.5 years (median) of PPI use, onset was broad and ranged from 14 days to 13 years. Discontinuation of PPIs resulted in fast recovery from PPIH in 4 days and re‐challenge led to reoccurrence within 4 days. Histamine‐2‐receptor antagonists were the preferable replacement therapy in PPIH and prevented reoccurrence of hypomagnesaemia. In PPIH no specific risk profile was identified that was linked to the hypomagnesaemia.
Conclusions
The cases of PPIH show severe symptoms of magnesium depletion and identification of its causation was only possible through withdrawal of the PPI. Clinical awareness of PPIH is key to avoid putting patients at risk.
Understanding and conceptualizing the complexities of the contemporary global economy is a challenging but vitally important task. In this article, we critically evaluate the potential of one ...interpretive framework—the global production networks (GPN) perspective—for analysing the global economy and its impacts on territorial development. After situating the approach in relation to other cognate chain/network approaches, the article proceeds to review and evaluate a number of underdeveloped areas that need to be understood and incorporated more fully if the framework is to deliver on its early potential. The article concludes with a consideration of the key research issues facing work in this area.
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