The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim ...(COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.
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Highlights • EMT is important for embryonic development, wound healing, and placentation. • Some cancers appear to exploit this process for increased metastatic potential. • Therefore, this pathway ...is of great therapeutic interest in the treatment of cancer.
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Abstract Objective We reviewed data on the epidemiology of epilepsy in the United States and estimated the prevalence and incidence of drug-resistant temporal lobe epilepsy (TLE) due to hippocampal ...sclerosis (HS) based on extrapolation from the available data drawn from the literature. Methods We searched the electronic database PubMed on December 14, 2016 using the following search terms in the title: “epilepsy” OR “temporal lobe” OR “hippocampal sclerosis” AND “epidemiology” OR “prevalence” OR “incidence”. Relevant original studies were included. We also reviewed several previous systematic reviews, meta-analyses, and their references. Results We concluded that the estimated current U.S. prevalence of drug-resistant HS-TLE is 0.51 – 0.66 cases per 1,000 people, and the estimated U.S. incidence is 3.1 – 3.4 cases per 100,000 people per year. Based on a U.S. population of 324 million, we estimate that as many as 143,000 - 191,000 U.S. patients still suffer from drug-resistant HS-TLE and are in need of surgery or other therapeutic options. Conclusions Although full scale epidemiological studies on drug resistant HS-TLE are needed, several observational studies allow adequate estimates of the range for the incidence and prevalence of this condition. Given the morbidity and mortality associated with poorly controlled seizures, this relatively large and growing patient population is a matter of concern. Considering the variety of treatment options that are available or in the pipeline to treat drug resistant epilepsy, future efforts should focus on advocating for early referral of patients with drug-resistant HS-TLE for more comprehensive epilepsy management.
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4.
Altered calcium signaling in cancer cells Stewart, Teneale A.; Yapa, Kunsala T.D.S.; Monteith, Gregory R.
Biochimica et biophysica acta,
10/2015, Volume:
1848, Issue:
10
Journal Article
Peer reviewed
Open access
It is the nature of the calcium signal, as determined by the coordinated activity of a suite of calcium channels, pumps, exchangers and binding proteins that ultimately guides a cell's fate. ...Deregulation of the calcium signal is often deleterious and has been linked to each of the ‘cancer hallmarks’. Despite this, we do not yet have a full understanding of the remodeling of the calcium signal associated with cancer. Such an understanding could aid in guiding the development of therapies specifically targeting altered calcium signaling in cancer cells during tumorigenic progression. Findings from some of the studies that have assessed the remodeling of the calcium signal associated with tumorigenesis and/or processes important in invasion and metastasis are presented in this review. The potential of new methodologies is also discussed. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
•Deregulated Ca2+ signaling is linked to each of the ‘cancer hallmarks’.•Altered Ca2+ transporter protein expression is associated with some cancers.•Specific aspects of the Ca2+ signal appear to be altered in some cancer cells.•The nature of altered Ca2+ signaling in cancer is not completely understood.•Understanding altered Ca2+ signaling in cancer may guide therapeutic targeting.
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Acquisition and development of the gut microbiome are vital for immune education in neonates, especially those born preterm. As such, microbial communities have been extensively studied in the ...context of postnatal health and disease. Bacterial communities have been the focus of research in this area due to the relative ease of targeted bacterial sequencing and the availability of databases to align and validate sequencing data. Recent increases in high-throughput metagenomic sequencing accessibility have facilitated research to investigate bacteriophages within the context of neonatal gut microbial communities. Focusing on unexplored viral diversity, has identified novel bacteriophage species and previously uncharacterised viral diversity. In doing so, studies have highlighted links between bacteriophages and bacterial community structure in the context of health and disease. However, much remains unknown about the complex relationships between bacteriophages, the bacteria they infect and their human host. With a particular focus on preterm infants, this review highlights opportunities to explore the influence of bacteriophages on developing microbial communities and the tripartite relationships between bacteriophages, bacteria and the neonatal human host. We suggest a focus on expanding collections of isolated bacteriophages that will further our understanding of the growing numbers of bacteriophages identified in metagenomes.
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A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is ...important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.
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Recent advancements have been made toward understanding the diagnostic and therapeutic potential of cerebrospinal fluid (CSF) and related hydrodynamics. Increased understanding of CSF dynamics may ...lead to improved detection of central nervous system (CNS) diseases and optimized delivery of CSF based CNS therapeutics, with many proposed therapeutics hoping to successfully treat or cure debilitating neurological conditions. Before significant strides can be made toward the research and development of interventions designed for human use, additional research must be carried out with representative subjects such as non-human primates (NHP). This study presents a geometric and hydrodynamic characterization of CSF in eight cynomolgus monkeys (Macaca fascicularis) at baseline and two-week follow-up. Results showed that CSF flow along the entire spine was laminar with a Reynolds number ranging up to 80 and average Womersley number ranging from 4.1-7.7. Maximum CSF flow rate occurred ~25 mm caudal to the foramen magnum. Peak CSF flow rate ranged from 0.3-0.6 ml/s at the C3-C4 level. Geometric analysis indicated that average intrathecal CSF volume below the foramen magnum was 7.4 ml. The average surface area of the spinal cord and dura was 44.7 and 66.7 cm2 respectively. Subarachnoid space cross-sectional area and hydraulic diameter ranged from 7-75 mm2 and 2-3.7 mm, respectively. Stroke volume had the greatest value of 0.14 ml at an axial location corresponding to C3-C4.
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Phages and lipids in human milk (HM) may benefit preterm infant health by preventing gastrointestinal pathobiont overgrowth and microbiome modulation. Lipid association may promote vertical ...transmission of phages to the infant. Despite this, interrelationships between lipids and phages are poorly characterized in preterm HM. Shotgun metagenomics and untargeted lipidomics of phage and lipid profiles from 99 preterm HM samples reveals that phages are abundant and prevalent from the first week and throughout the first 100 days of lactation. Phage-host richness of preterm HM increases longitudinally. Core phage communities characterized by Staphylococcus- and Propionibacterium-infecting phages are significantly correlated with long-chain fatty acid abundances over lactational age. We report here a phage-lipid interaction in preterm HM, highlighting the potential importance of phage carriage in preterm HM. These results reveal possible strategies for phage carriage in HM and their importance in early-life microbiota development.
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•Preterm human milk harbors core bacteriophage communities from the first week of lactation•Preterm human milk bacteriophages mostly infect skin-commensal bacteria•Core viruses and lipids/fatty acids are interrelated in preterm human milk (in vivo)•Associations between fatty acid chain length and phage morphotype can be replicated in vitro
Yew et al. highlight that core viromes of preterm human milk develop over time and are dominated by bacteriophages infecting human skin commensals. Co-occurrence networks and in vitro association studies link phage morphotypes with fatty acid chain length. This highlights potential vehicles for vertical transmission of bacteriophages from mother to infant.
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infection (CDI) is responsible for around 300,000 hospitalizations yearly in the United States, with the associated monetary cost being billions of dollars. Gut microbiome dysbiosis is known to be ...important to CDI. To the best of our knowledge, metatranscriptomics (MT) has only been used to characterize gut microbiome composition and function in one prior study involving CDI patients. Therefore, we utilized MT to investigate differences in active community diversity and composition between CDI+ (
= 20) and CDI- (
= 19) samples with respect to microbial taxa and expressed genes. No significant (Kruskal-Wallis,
> 0.05) differences were detected for richness or evenness based on CDI status. However, clustering based on CDI status was significant for both active microbial taxa and expressed genes datasets (PERMANOVA,
≤ 0.05). Furthermore, differential feature analysis revealed greater expression of the opportunistic pathogens
and
in CDI+ compared to CDI- samples. When only fungal sequences were considered, the family Saccharomycetaceae expressed more genes in CDI-, while 31 other fungal taxa were identified as significantly (Kruskal-Wallis
≤ 0.05, log(LDA) ≥ 2) associated with CDI+. We also detected a variety of genes and pathways that differed significantly (Kruskal-Wallis
≤ 0.05, log(LDA) ≥ 2) based on CDI status. Notably, differential genes associated with biofilm formation were expressed by
. This provides evidence of another possible contributor to
's resistance to antibiotics and frequent recurrence
. Furthermore, the greater number of CDI+ associated fungal taxa constitute additional evidence that the mycobiome is important to CDI pathogenesis. Future work will focus on establishing if
is actively producing biofilms during infection and if any specific fungal taxa are particularly influential in CDI.
The fecal metabolome in early life has seldom been studied. We investigated its evolution in pre-term babies during their first weeks of life. Multiple (n = 152) stool samples were studied from 51 ...babies, all <32 weeks gestation. Volatile organic compounds (VOCs) were analyzed by headspace solid phase microextraction gas chromatography mass spectrometry. Data were interpreted using Automated Mass Spectral Deconvolution System (AMDIS) with the National Institute of Standards and Technology (NIST) reference library. Statistical analysis was based on linear mixed modelling, the number of VOCs increased over time; a rise was mainly observed between day 5 and day 10. The shift at day 5 was associated with products of branched-chain fatty acids. Prior to this, the metabolome was dominated by aldehydes and acetic acid. Caesarean delivery showed a modest association with molecules of fungal origin. This study shows how the metabolome changes in early life in pre-term babies. The shift in the metabolome 5 days after delivery coincides with the establishment of enteral feeding and the transition from meconium to feces. Great diversity of metabolites was associated with being fed greater volumes of milk.
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