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1.  HIV: mother-to-child transmission 
BMJ Clinical Evidence  2008;2008:0909.
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without anti-retroviral treatment, the risk of HIV transmission from infected mothers to their children is 15-30% during gestation or labour, and 15-20% during breast feeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads and/or advanced disease, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother to child transmission of HIV? We searched: Medline, Embase, The Cochrane Library and other important databases up to January 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breast feeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15-30% during pregnancy and labour, with an additional 10-20% transmission risk attributed to prolonged breast feeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads and/or advanced HIV disease.Without antiretroviral treatment (ART), 15-30% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the development of resistance, and adverse effects.From a paediatric perspective, successful prevention of MTCT remains the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, and/or to the baby immediately after birth, reduce the risk of MTCT of HIV-1.
Reductions in MTCT are possible using simple ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1-2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. RCTs demonstrate that short courses of antiretroviral drugs have proven efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.
Avoidance of breast feeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breast feeding-related HIV transmission needs to be balanced against the multiple benefits that breast feeding offers. In resource-poor countries, breast feeding is strongly associated with reduced infant morbidity and improved child survival. Modified breastfeeding practices may reduce the risk of HIV transmission while retaining some of its associated benefits.In settings where formula feeding is not feasible (no clean water, insufficient health education, significant cultural barriers) modified breastfeeding practices may offer the best compromise.Early breast feeding with weaning around age 4-6 months may offer an HIV-free survival benefit compared with either formula, mixed feeding, or prolonged breast feeding.Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin or immunoglobulin without HIV antibody does not reduce HIV-1 MTCT risk.
Vaginal microbiocides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that vitamin A or multivitamin supplementation reduces the risk of HIV-1 MTCT or infant mortality.
PMCID: PMC2907958  PMID: 19450331
2.  Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections 
BMC Oral Health  2013;13:47.
A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects.
Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression.
CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm.
Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response.
PMCID: PMC3849008  PMID: 24063298
Fulvic acid; Chlorhexidine; Biofilm; Antibacterial; Periodontitis; Inflammation
3.  Chemistry of Organophosphonate Scale Growth lnhibitors: 3. Physicochemical Aspects of 2-Phosphonobutane-1,2,4-Tricarboxylate (PBTC) And Its Effect on CaCO3 Crystal Growth 
Industrial water systems often suffer from undesirable inorganic deposits, such as calcium carbonate, calcium phosphates, calcium sulfate, magnesium silicate, and others. Synthetic water additives, such as phosphonates and phosphonocarboxylates, are the most important and widely utilized scale inhibitors in a plethora of industrial applications including cooling water, geothermal drilling, desalination, etc. The design of efficient and cost-effective inhibitors, as well as the study of their structure and function at the molecular level are important areas of research. This study reports various physicochemical aspects of the chemistry of PBTC (PBTC = 2-phosphonobutane-1,2,4-tricarboxylic acid), one of the most widely used scale inhibitors in the cooling water treatment industry. These aspects include its CaCO3 crystal growth inhibition and modification properties under severe conditions of high CaCO3 supersaturation, stability towards oxidizing microbiocides and tolerance towards precipitation with Ca2+. Results show that 15 ppm of PBTC can inhibit the formation of by ∼35 %, 30 ppm by ∼40 %, and 60 ppm by ∼44 %. PBTC is virtually stable to the effects of a variety of oxidizing microbiocides, including chlorine, bromine and others. PBTC shows excellent tolerance towards precipitation as its Ca salt. Precipitation in a 1000 ppm Ca2+ (as CaCO3) occurs after 185 ppm PBTC are present.
PMCID: PMC2267102  PMID: 18365095
phosphonates; carboxylates; PBTC; calcium carbonate; crystal modifiers; inhibition; biocides
4.  Antimicrobial efficacy of amine fluoride based tooth gels compared to a toothpaste in a phase 2/step 2 in-vitro test model 
Introduction: The aim of the present study was to determine the antimicrobial effect of various gel formulations on plaque formation; different tooth gels were compared to a toothpaste containing comparable antimicrobial ingredients with regard to its microbiocidal activity. The study was conducted under the assumption, that a chief requirement for the prevention of plaque formation is the combination of mechanical removal and antimicrobial activity, and not the sole capability of mechanical plaque removal.
Methods: Ledermix® fluoride gel as commercially available with preservative, and without preservative and perfume oils, Elmex® gelée, and Meridol® toothpaste were tested in a standardized in-vitro test modification of the quantitative suspension test EN 1040. Instead of testing in a suspension, the respective product was directly placed on a standardized contaminated sterile stainless steel disk without adding any bio-burden. 50% egg yolk in Aqua dest. was used as a neutralizer.
Results: Within 1 min, Elmex® gelée showed a RF >5 log10 against S. pyogenes and S. sanguinis. Against S. mutans, a log10 RF of ≥5 was achieved after 2 min, against C. albicans after 5 min, and against P. aeruginosa after 10 min S. aureus was the most difficult organisms to be reduced. After an application time of 10 min, only a log10 RF of 2.4 was achieved. Ledermix exceeded the antimicrobial efficacy of Elmex® gelée against S. mutans and C. albicans and was already effective against these organisms after 1 min, but did not show the same antimicrobial efficacy as Elmex® gelée against P. aeruginosa. Similar to Elmex® gelée, a required reduction of >5 log10 for antimicrobials under no organic challenge was not achieved against S. aureus. Ledermix® fluoride gel without preservatives and Ledermix® fluoride gel without preservatives and perfume oil did not show the antimicrobial efficacy of the standard Ledermix® fluoride gel formulation, indicating that the observed antimicrobial efficacy is chiefly based on the preservative, and possibly the perfume oil. Compared to the tested gels, Meridol® toothpaste was less effective and reached any antimicrobial effect >5 log10 only against S. sanguinis after 10 min.
Conclusion: All unmodified tested gels showed an antimicrobial effect. Because no relevant antimicrobial efficacy against plaque forming bacteria was achieved within 2 min, in practice, an anti-plaque forming effect based on the antimicrobial action of gels cannot be assumed when used in the oral cavity. However, the results of the present study indicate that the antimicrobial efficacy of gels is determined by their formulation and that for the prevention of plaque formation the combination of mechanical removal and antimicrobial activity is not the chief requirement only, but a sustained antimicrobial effect may be of greater importance.
PMCID: PMC3334950  PMID: 22558041
fluoride gels; toothpaste; amino fluoride; sodium monofluorophosphate; EN 1040; antimicrobial efficacy
5.  The effect of hydration state and energy balance on innate immunity of a desert reptile 
Frontiers in Zoology  2013;10:23.
Immune function is a vital physiological process that is often suppressed during times of resource scarcity due to investments in other physiological systems. While energy is the typical currency that has been examined in such trade-offs, limitations of other resources may similarly lead to trade-offs that affect immune function. Specifically, water is a critical resource with profound implications for organismal ecology, yet its availability can fluctuate at local, regional, and even global levels. Despite this, the effect of osmotic state on immune function has received little attention.
Using agglutination and lysis assays as measures of an organism’s plasma concentration of natural antibodies and capacity for foreign cell destruction, respectively, we tested the independent effects of osmotic state, digestive state, and energy balance on innate immune function in free-ranging and laboratory populations of the Gila monster, Heloderma suspectum. This desert-dwelling lizard experiences dehydration and energy resource fluctuations on a seasonal basis. Dehydration was expected to decrease innate immune function, yet we found that dehydration increased lysis and agglutination abilities in both lab and field studies, a relationship that was not simply an effect of an increased concentration of immune molecules. Laboratory-based differences in digestive state were not associated with lysis or agglutination metrics, although in our field population, a loss of fat stores was correlated with an increase in lysis.
Depending on the life history of an organism, osmotic state may have a greater influence on immune function than energy availability. Thus, consideration of osmotic state as a factor influencing immune function will likely improve our understanding of ecoimmunology and the disease dynamics of a wide range of species.
PMCID: PMC3660207  PMID: 23642164
Dehydration; Digestion; Energy balance; Hemagglutination; Hemolysis; Osmolality; Water
6.  New type of antibody-enzyme conjugate which specifically kills Candida albicans. 
Infection and Immunity  1980;27(2):690-692.
A new type of antibody-enzyme conjugate was made, and its possible application to Candida infection was studied. Both lactoperoxidase and xanthine oxidase were conjugated to specific antibody against Candida albicans. In vitro microbiocidal activity of the new antibody-enzyme conjugate, when incubated together with xanthine and minute amount of halides, showed a remarkable level of candidacidal ability. When the new antibody-enzyme conjugate was given to Candida-infected mice, followed by injecting xanthine and a minute amount of halides, about 50% of these heavily infected mice survived, whereas all control nontreated mice died. These data suggest that the further eleboration of this new antibody-enzyme conjugate might lead us to improve our therapeutic methods of clinical medicine.
PMCID: PMC550820  PMID: 6991424
7.  Quaternary ammonium silane-functionalized, methacrylate resin composition with antimicrobial activities and self-repair potential 
Acta biomaterialia  2012;8(9):3270-3282.
Design of antimicrobial polymers for enhancing healthcare issues and minimizing environmental problems is an important endeavor with both fundamental and practical implications. Quaternary ammonium silane-functionalized methacrylate (QAMS) represents an example of antimicrobial macromonomers synthesized by a sol-gel chemical route; these compounds possess flexible Si-O-Si bonds. In present work, a partially-hydrolyzed QAMS copolymerized with bis-GMA is introduced. This methacrylate resin was shown to possess desirable mechanical properties with both a high degree of conversion and minimal polymerization shrinkage. Kill-on-contact microbiocidal activities of this resin were demonstrated using single-species biofilms of Streptococcus mutans (ATCC 36558), Actinomyces naeslundii (ATCC 12104) and Candida albicans (ATCC 90028). Improved mechanical properties after hydration provided the proof-of-concept that QAMS-incorporated resin exhibits self-repair potential via water-induced condensation of organic modified silicate (ormosil) phases within the polymerized resin matrix.
PMCID: PMC3580770  PMID: 22659173
Quaternary ammonium; Organic modified silicate; Antimicrobial; Sol-gel technique; Self-repair
8.  Environments that Induce Synthetic Microbial Ecosystems 
PLoS Computational Biology  2010;6(11):e1001002.
Interactions between microbial species are sometimes mediated by the exchange of small molecules, secreted by one species and metabolized by another. Both one-way (commensal) and two-way (mutualistic) interactions may contribute to complex networks of interdependencies. Understanding these interactions constitutes an open challenge in microbial ecology, with applications ranging from the human microbiome to environmental sustainability. In parallel to natural communities, it is possible to explore interactions in artificial microbial ecosystems, e.g. pairs of genetically engineered mutualistic strains. Here we computationally generate artificial microbial ecosystems without re-engineering the microbes themselves, but rather by predicting their growth on appropriately designed media. We use genome-scale stoichiometric models of metabolism to identify media that can sustain growth for a pair of species, but fail to do so for one or both individual species, thereby inducing putative symbiotic interactions. We first tested our approach on two previously studied mutualistic pairs, and on a pair of highly curated model organisms, showing that our algorithms successfully recapitulate known interactions, robustly predict new ones, and provide novel insight on exchanged molecules. We then applied our method to all possible pairs of seven microbial species, and found that it is always possible to identify putative media that induce commensalism or mutualism. Our analysis also suggests that symbiotic interactions may arise more readily through environmental fluctuations than genetic modifications. We envision that our approach will help generate microbe-microbe interaction maps useful for understanding microbial consortia dynamics and evolution, and for exploring the full potential of natural metabolic pathways for metabolic engineering applications.
Author Summary
Microbial metabolism affects biogeochemical cycles and human health. In most natural environments, multiple microbial species interact with each other, forming complex ecosystems whose properties are poorly understood. In an effort to understand inter-microbial interactions, and to explore new metabolic engineering avenues, researchers have started building artificial microbial ecosystems, e.g. pairs of genetically engineered strains that require each other for survival. Here we computationally explore the possibility of creating artificial microbial ecosystems without re-engineering the microbes themselves, but rather by manipulating the environment in which they grow. Specifically, using the framework of flux balance analysis, we predict environments in which either one or both microbes in a pair would not be able to grow without the other, inducing commensal (one-way) or mutualistic (two-way) interactions, respectively. Our algorithms can successfully recapitulate known inter-microbial interactions, and predict millions of new ones across any pair amongst different microbial species. Surprisingly, we find that it is always possible to identify conditions that induce mutualistic or commensal interactions between any two species. Hence, our method should help in mapping naturally occurring microbe-microbe interactions, and in engineering new ones through a novel, environment-driven branch of synthetic ecology.
PMCID: PMC2987903  PMID: 21124952
9.  Toxicology in the Fast Lane: Application of High-Throughput Bioassays to Detect Modulation of Key Enzymes and Receptors 
Environmental Health Perspectives  2009;117(12):1867-1872.
Legislation at state, federal, and international levels is requiring rapid evaluation of the toxicity of numerous chemicals. Whole-animal toxicologic studies cannot yield the necessary throughput in a cost-effective fashion, leading to a critical need for a faster and more cost-effective toxicologic evaluation of xenobiotics.
We tested whether mechanistically based screening assays can rapidly provide information on the potential for compounds to affect key enzymes and receptor targets, thus identifying those compounds requiring further in-depth analysis.
A library of 176 synthetic chemicals was prepared and examined in a high-throughput screening (HTS) manner using nine enzyme-based and five receptor-based bioassays.
All the assays have high Z′ values, indicating good discrimination among compounds in a reliable fashion, and thus are suitable for HTS assays. On average, three positive hits were obtained per assay. Although we identified compounds that were previously shown to inhibit a particular enzyme class or receptor, we surprisingly discovered that triclosan, a microbiocide present in personal care products, inhibits carboxylesterases and that dichlone, a fungicide, strongly inhibits the ryanodine receptors.
Considering the need to rapidly screen tens of thousands of anthropogenic compounds, our study shows the feasibility of using combined HTS assays as a novel approach toward obtaining toxicologic data on numerous biological end points. The HTS assay approach is very useful to quickly identify potentially hazardous compounds and to prioritize them for further in-depth studies.
PMCID: PMC2799460  PMID: 20049205
bioassays; biomarkers; enzyme inhibition; high-throughput assays; triclocarban; triclosan
10.  Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection 
Virology Journal  2009;6:214.
Phosphorothioated oligonucleotides (PS-ONs) have a sequence-independent, broad spectrum antiviral activity as amphipathic polymers (APs) and exhibit potent in vitro antiviral activity against a broad spectrum of herpesviruses: HSV-1, HSV-2, HCMV, VZV, EBV, and HHV-6A/B, and in vivo activity in a murine microbiocide model of genital HSV-2 infection. The activity of these agents against animal cytomegalovirus (CMV) infections in vitro and in vivo was therefore investigated.
In vitro, a 40 mer degenerate AP (REP 9) inhibited both murine CMV (MCMV) and guinea pig CMV (GPCMV) with an IC50 of 0.045 μM and 0.16 μM, respectively, and a 40 mer poly C AP (REP 9C) inhibited MCMV with an IC50 of 0.05 μM. Addition of REP 9 to plaque assays during the first two hours of infection inhibited 78% of plaque formation whereas addition of REP 9 after 10 hours of infection did not significantly reduce the number of plaques, indicating that REP 9 antiviral activity against MCMV occurs at early times after infection. In a murine model of CMV infection, systemic treatment for 5 days significantly reduced virus replication in the spleens and livers of infected mice compared to saline-treated control mice. REP 9 and REP 9C were administered intraperitoneally for 5 consecutive days at 10 mg/kg, starting 2 days prior to MCMV infection. Splenomegaly was observed in infected mice treated with REP 9 but not in control mice or in REP 9 treated, uninfected mice, consistent with mild CpG-like activity. When REP 9C (which lacks CpG motifs) was compared to REP 9, it exhibited comparable antiviral activity as REP 9 but was not associated with splenomegaly. This suggests that the direct antiviral activity of APs is the predominant therapeutic mechanism in vivo. Moreover, REP 9C, which is acid stable, was effective when administered orally in combination with known permeation enhancers.
These studies indicate that APs exhibit potent, well tolerated antiviral activity against CMV infection in vivo and represent a new class of broad spectrum anti-herpetic agents.
PMCID: PMC2794273  PMID: 19954538
11.  Biomarkers of animal health: integrating nutritional ecology, endocrine ecophysiology, ecoimmunology, and geospatial ecology 
Ecology and Evolution  2015;5(3):557-566.
Diverse biomarkers including stable isotope, hormonal, and ecoimmunological assays are powerful tools to assess animal condition. However, an integrative approach is necessary to provide the context essential to understanding how biomarkers reveal animal health in varied ecological conditions. A barrier to such integration is a general lack of awareness of how shared extraction methods from across fields can provide material from the same animal tissues for diverse biomarker assays. In addition, the use of shared methods for extracting differing tissue fractions can also provide biomarkers for how animal health varies across time. Specifically, no study has explicitly illustrated the depth and breadth of spacial and temporal information that can be derived from coupled biomarker assessments on two easily collected tissues: blood and feathers or hair. This study used integrated measures of glucocorticoids, stable isotopes, and parasite loads in the feathers and blood of fall-migrating Northern saw-whet owls (Aegolius acadicus) to illustrate the wealth of knowledge about animal health and ecology across both time and space. In feathers, we assayed deuterium (δD) isotope and corticosterone (CORT) profiles, while in blood we measured CORT and blood parasite levels. We found that while earlier migrating owls had elevated CORT levels relative to later migrating birds, there was also a disassociation between plasma and feather CORT, and blood parasite loads. These results demonstrate how these tissues integrate time periods from weeks to seasons and reflect energetic demands during differing life stages. Taken together, these findings illustrate the potential for integrating diverse biomarkers to assess interactions between environmental factors and animal health across varied time periods without the necessity of continually recapturing and tracking individuals. Combining biomarkers from diverse research fields into an integrated framework hold great promise for advancing our understanding of environmental effects on animal health.
PMCID: PMC4328761
Bioindicators; birds; glucocorticoids; isoscapes; migration; stable isotopes; stress physiology
12.  A Short–Time Scale Colloidal System Reveals Early Bacterial Adhesion Dynamics 
PLoS Biology  2008;6(7):e167.
The development of bacteria on abiotic surfaces has important public health and sanitary consequences. However, despite several decades of study of bacterial adhesion to inert surfaces, the biophysical mechanisms governing this process remain poorly understood, due, in particular, to the lack of methodologies covering the appropriate time scale. Using micrometric colloidal surface particles and flow cytometry analysis, we developed a rapid multiparametric approach to studying early events in adhesion of the bacterium Escherichia coli. This approach simultaneously describes the kinetics and amplitude of early steps in adhesion, changes in physicochemical surface properties within the first few seconds of adhesion, and the self-association state of attached and free-floating cells. Examination of the role of three well-characterized E. coli surface adhesion factors upon attachment to colloidal surfaces—curli fimbriae, F-conjugative pilus, and Ag43 adhesin—showed clear-cut differences in the very initial phases of surface colonization for cell-bearing surface structures, all known to promote biofilm development. Our multiparametric analysis revealed a correlation in the adhesion phase with cell-to-cell aggregation properties and demonstrated that this phenomenon amplified surface colonization once initial cell-surface attachment was achieved. Monitoring of real-time physico-chemical particle surface properties showed that surface-active molecules of bacterial origin quickly modified surface properties, providing new insight into the intricate relations connecting abiotic surface physicochemical properties and bacterial adhesion. Hence, the biophysical analytical method described here provides a new and relevant approach to quantitatively and kinetically investigating bacterial adhesion and biofilm development.
Author Summary
When bacteria grow on solid surfaces, they can form three-dimensional communities called biofilms. Within these complex structures, bacteria can develop specific tolerance to different microbiocides, causing serious health and economic problems. Investigations of the key molecular events involved in biofilm formation have shown that surface-exposed adhesin proteins promote this process, but many questions remain regarding the mechanisms and biophysics of surface adhesion. We introduced an original approach to investigating the very early steps in bacterial adhesion that uses dispersed colloidal surfaces as microbial adhesion substrates. Using flow cytometry, we performed a quantitative real-time analysis of adhesion kinetics of several strains of the bacterium Escherichia coli, which were genetically engineered to produce well-characterized cell-surface adhesins that are known to promote biofilm development. We provide evidence for previously unknown adhesin-dependent behaviors, such as clear-cut differences in the very initial phases of surface colonization. We also demonstrate that initial adhesion correlates with almost instant surface property changes, and that cell-to-cell association might serve as an amplification mechanism for surface colonization. We therefore provide a new understanding of the intricate relationships between the physico-chemistry of abiotic surfaces and bacterial adhesion.
Combining micrometric colloidal beads as adhesion substrates with flow cytometric analysis allows for a high-resolution analysis that reveals adhesin-dependent behavior in the very first steps of surface colonization by bacteria.
PMCID: PMC2443189  PMID: 18613749
13.  Mammalian genes induce partially reprogrammed pluripotent stem cells in non-mammalian vertebrate and invertebrate species 
eLife  2013;2:e00036.
Cells are fundamental units of life, but little is known about evolution of cell states. Induced pluripotent stem cells (iPSCs) are once differentiated cells that have been re-programmed to an embryonic stem cell-like state, providing a powerful platform for biology and medicine. However, they have been limited to a few mammalian species. Here we found that a set of four mammalian transcription factor genes used to generate iPSCs in mouse and humans can induce a partially reprogrammed pluripotent stem cell (PRPSCs) state in vertebrate and invertebrate model organisms, in mammals, birds, fish, and fly, which span 550 million years from a common ancestor. These findings are one of the first to show cross-lineage stem cell-like induction, and to generate pluripotent-like cells for several of these species with in vivo chimeras. We suggest that the stem-cell state may be highly conserved across a wide phylogenetic range.
eLife digest
Stem cells are ‘pluripotent’—in other words, they have the potential to become many other cell types. This ability makes them extremely valuable for research. They also hold substantial promise for medical applications, since they can be used to replace cells lost or damaged by disease or injury.
Embryos represent a rich source of stem cells; however, obtaining these cells from human embryos raises obvious ethical and practical concerns, and they have also been difficult to isolate from many species. A recent discovery circumvented these issues for humans and several mammalian species commonly studied in the laboratory. This technique can turn cells from adult mammals into ‘induced pluripotent stem cells’, or iPSCs, by switching on four genes. Nevertheless, no analogous method has yet been established to create similar cell populations in non-mammalian organisms, which are also important models for human development and disease.
Now, Rosselló et al. have shown that cells from both invertebrate and non-mammalian vertebrate species—including birds, fish and insects—can be reprogrammed into cells that closely resemble iPSCs. Intriguingly, these cells were created by switching on the same four genes that generate iPSCs in mammals, even though vertebrates and invertebrates are separated by around 550 million years of evolution.
Rosselló et al. used a viral vector that carries the four stem-cell genes (from the mouse) into target cells from the different species. The genetically altered cells developed into iPSC-like cells with many of the characteristics of natural mammalian and bird stem cells. To confirm that the cells were pluripotent, Rossello et al. first showed that the cells could develop into primitive early embryos called embryoid bodies. For the vertebrate species tested, the embryoid bodies contained cells from each of the three main vertebrate embryo cell types. Secondly, iPSC-like cells from two organisms—chicks and zebrafish—formed various mature cell types when injected into developing chick or zebrafish embryos.
These results have two important implications. They suggest that the genetic mechanisms by which cells can be reprogrammed into a stem-like state have been conserved through 550 million years of evolution; additionally, they demonstrate that stem-like cells can be generated from important experimental organisms, and provide an important tool for both biological and biomedical research.
PMCID: PMC3762186  PMID: 24015354
iPS; quail; zebra finch; Drosophila; Chicken; Mouse; Zebrafish
14.  Semantics in Support of Biodiversity Knowledge Discovery: An Introduction to the Biological Collections Ontology and Related Ontologies 
PLoS ONE  2014;9(3):e89606.
The study of biodiversity spans many disciplines and includes data pertaining to species distributions and abundances, genetic sequences, trait measurements, and ecological niches, complemented by information on collection and measurement protocols. A review of the current landscape of metadata standards and ontologies in biodiversity science suggests that existing standards such as the Darwin Core terminology are inadequate for describing biodiversity data in a semantically meaningful and computationally useful way. Existing ontologies, such as the Gene Ontology and others in the Open Biological and Biomedical Ontologies (OBO) Foundry library, provide a semantic structure but lack many of the necessary terms to describe biodiversity data in all its dimensions. In this paper, we describe the motivation for and ongoing development of a new Biological Collections Ontology, the Environment Ontology, and the Population and Community Ontology. These ontologies share the aim of improving data aggregation and integration across the biodiversity domain and can be used to describe physical samples and sampling processes (for example, collection, extraction, and preservation techniques), as well as biodiversity observations that involve no physical sampling. Together they encompass studies of: 1) individual organisms, including voucher specimens from ecological studies and museum specimens, 2) bulk or environmental samples (e.g., gut contents, soil, water) that include DNA, other molecules, and potentially many organisms, especially microbes, and 3) survey-based ecological observations. We discuss how these ontologies can be applied to biodiversity use cases that span genetic, organismal, and ecosystem levels of organization. We argue that if adopted as a standard and rigorously applied and enriched by the biodiversity community, these ontologies would significantly reduce barriers to data discovery, integration, and exchange among biodiversity resources and researchers.
PMCID: PMC3940615  PMID: 24595056
15.  Automated Reporter Quantification In Vivo: High-Throughput Screening Method for Reporter-Based Assays in Zebrafish 
PLoS ONE  2012;7(1):e29916.
Reporter-based assays underlie many high-throughput screening (HTS) platforms, but most are limited to in vitro applications. Here, we report a simple whole-organism HTS method for quantifying changes in reporter intensity in individual zebrafish over time termed, Automated Reporter Quantification in vivo (ARQiv). ARQiv differs from current “high-content” (e.g., confocal imaging-based) whole-organism screening technologies by providing a purely quantitative data acquisition approach that affords marked improvements in throughput. ARQiv uses a fluorescence microplate reader with specific detection functionalities necessary for robust quantification of reporter signals in vivo. This approach is: 1) Rapid; achieving true HTS capacities (i.e., >50,000 units per day), 2) Reproducible; attaining HTS-compatible assay quality (i.e., Z'-factors of ≥0.5), and 3) Flexible; amenable to nearly any reporter-based assay in zebrafish embryos, larvae, or juveniles. ARQiv is used here to quantify changes in: 1) Cell number; loss and regeneration of two different fluorescently tagged cell types (pancreatic beta cells and rod photoreceptors), 2) Cell signaling; relative activity of a transgenic Notch-signaling reporter, and 3) Cell metabolism; accumulation of reactive oxygen species. In summary, ARQiv is a versatile and readily accessible approach facilitating evaluation of genetic and/or chemical manipulations in living zebrafish that complements current “high-content” whole-organism screening methods by providing a first-tier in vivo HTS drug discovery platform.
PMCID: PMC3251595  PMID: 22238673
16.  A Novel Nutritional Predictor Links Microbial Fastidiousness with Lowered Ubiquity, Growth Rate, and Cooperativeness 
PLoS Computational Biology  2014;10(7):e1003726.
Understanding microbial nutritional requirements is a key challenge in microbiology. Here we leverage the recent availability of thousands of automatically generated genome-scale metabolic models to develop a predictor of microbial minimal medium requirements, which we apply to thousands of species to study the relationship between their nutritional requirements and their ecological and genomic traits. We first show that nutritional requirements are more similar among species that co-habit many ecological niches. We then reveal three fundamental characteristics of microbial fastidiousness (i.e., complex and specific nutritional requirements): (1) more fastidious microorganisms tend to be more ecologically limited; (2) fastidiousness is positively associated with smaller genomes and smaller metabolic networks; and (3) more fastidious species grow more slowly and have less ability to cooperate with other species than more metabolically versatile organisms. These associations reflect the adaptation of fastidious microorganisms to unique niches with few cohabitating species. They also explain how non-fastidious species inhabit many ecological niches with high abundance rates. Taken together, these results advance our understanding microbial nutrition on a large scale, by presenting new nutrition-related associations that govern the distribution of microorganisms in nature.
Author Summary
Understanding microbial nutrition is critical for understanding microbial life, and thus has a major influence in many areas of biology. In recent years, the traditional methods of studying microbial nutrition, which rely on culturing bacteria and assessing their nutritional needs through extensive experiments, have been augmented by the development of genome-scale metabolic models, which enable in-depth analysis and prediction of nutrition for a few well-studied organisms. Recently, a pipeline was developed for generating genome-scale metabolic models automatically (the SEED). Here, we leverage models built from this pipeline in order to develop a novel predictor of microbial minimal medium requirements, which we then apply broadly for thousands of microbes across the tree of life. We first show that nutritional requirements are more similar among microorganisms that co-habit many ecological niches. We then use our medium predictions to examine the fastidiousness of organisms (i.e., their need for complex/specific media), and suggest an explanation for certain observed features of microbial abundance patterns. This study is one of the first to leverage genome-scale models on a large (>1000 species) scale, and sets the potential for a new host of strategies for understanding microbial nutrition and ecology in the future.
PMCID: PMC4102436  PMID: 25033033
17.  Condition, innate immunity and disease mortality of inbred crows 
Cooperatively breeding American crows (Corvus brachyrhynchos) suffer a severe disease-mediated survival cost from inbreeding, but the proximate mechanisms linking inbreeding to disease are unknown. Here, we examine indices of nestling body condition and innate immunocompetence in relationship to inbreeding and disease mortality. Using an estimate of microsatellite heterozygosity that predicts inbreeding in this population, we show that inbred crows were in relatively poor condition as nestlings, and that body condition index measured in the first 2–33 days after hatching, in addition to inbreeding index, predicted disease probability in the first 34 months of life. Inbred nestlings also mounted a weaker response along one axis of innate immunity: the proportion of bacteria killed in a microbiocidal assay increased as heterozygosity index increased. Relatively poor body condition and low innate immunocompetence are two mechanisms that might predispose inbred crows to ultimate disease mortality. A better understanding of condition-mediated inbreeding depression can guide efforts to minimize disease costs of inbreeding in small populations.
PMCID: PMC2981987  PMID: 20444716
American crows; body condition; disease; immunocompetence; inbreeding; inbreeding depression
18.  The Role of the Toxicologic Pathologist in the Post-Genomic Era# 
Journal of Toxicologic Pathology  2013;26(2):105-110.
An era can be defined as a period in time identified by distinctive character, events, or practices. We are now in the genomic era. The pre-genomic era: There was a pre-genomic era. It started many years ago with novel and seminal animal experiments, primarily directed at studying cancer. It is marked by the development of the two-year rodent cancer bioassay and the ultimate realization that alternative approaches and short-term animal models were needed to replace this resource-intensive and time-consuming method for predicting human health risk. Many alternatives approaches and short-term animal models were proposed and tried but, to date, none have completely replaced our dependence upon the two-year rodent bioassay. However, the alternative approaches and models themselves have made tangible contributions to basic research, clinical medicine and to our understanding of cancer and they remain useful tools to address hypothesis-driven research questions. The pre-genomic era was a time when toxicologic pathologists played a major role in drug development, evaluating the cancer bioassay and the associated dose-setting toxicity studies, and exploring the utility of proposed alternative animal models. It was a time when there was shortage of qualified toxicologic pathologists. The genomic era: We are in the genomic era. It is a time when the genetic underpinnings of normal biological and pathologic processes are being discovered and documented. It is a time for sequencing entire genomes and deliberately silencing relevant segments of the mouse genome to see what each segment controls and if that silencing leads to increased susceptibility to disease. What remains to be charted in this genomic era is the complex interaction of genes, gene segments, post-translational modifications of encoded proteins, and environmental factors that affect genomic expression. In this current genomic era, the toxicologic pathologist has had to make room for a growing population of molecular biologists. In this present era newly emerging DVM and MD scientists enter the work arena with a PhD in pathology often based on some aspect of molecular biology or molecular pathology research. In molecular biology, the almost daily technological advances require one’s complete dedication to remain at the cutting edge of the science. Similarly, the practice of toxicologic pathology, like other morphological disciplines, is based largely on experience and requires dedicated daily examination of pathology material to maintain a well-trained eye capable of distilling specific information from stained tissue slides - a dedicated effort that cannot be well done as an intermezzo between other tasks. It is a rare individual that has true expertise in both molecular biology and pathology. In this genomic era, the newly emerging DVM-PhD or MD-PhD pathologist enters a marketplace without many job opportunities in contrast to the pre-genomic era. Many face an identity crisis needing to decide to become a competent pathologist or, alternatively, to become a competent molecular biologist. At the same time, more PhD molecular biologists without training in pathology are members of the research teams working in drug development and toxicology. How best can the toxicologic pathologist interact in the contemporary team approach in drug development, toxicology research and safety testing? Based on their biomedical training, toxicologic pathologists are in an ideal position to link data from the emerging technologies with their knowledge of pathobiology and toxicology. To enable this linkage and obtain the synergy it provides, the bench-level, slide-reading expert pathologist will need to have some basic understanding and appreciation of molecular biology methods and tools. On the other hand, it is not likely that the typical molecular biologist could competently evaluate and diagnose stained tissue slides from a toxicology study or a cancer bioassay. The post-genomic era: The post-genomic era will likely arrive approximately around 2050 at which time entire genomes from multiple species will exist in massive databases, data from thousands of robotic high throughput chemical screenings will exist in other databases, genetic toxicity and chemical structure-activity-relationships will reside in yet other databases. All databases will be linked and relevant information will be extracted and analyzed by appropriate algorithms following input of the latest molecular, submolecular, genetic, experimental, pathology and clinical data. Knowledge gained will permit the genetic components of many diseases to be amenable to therapeutic prevention and/or intervention. Much like computerized algorithms are currently used to forecast weather or to predict political elections, computerized sophisticated algorithms based largely on scientific data mining will categorize new drugs and chemicals relative to their health benefits versus their health risks for defined human populations and subpopulations. However, this form of a virtual toxicity study or cancer bioassay will only identify probabilities of adverse consequences from interaction of particular environmental and/or chemical/drug exposure(s) with specific genomic variables. Proof in many situations will require confirmation in intact in vivo mammalian animal models. The toxicologic pathologist in the post-genomic era will be the best suited scientist to confirm the data mining and its probability predictions for safety or adverse consequences with the actual tissue morphological features in test species that define specific test agent pathobiology and human health risk.
PMCID: PMC3695332  PMID: 23914052
genomic era; history of toxicologic pathology; molecular biology
19.  A specialist-generalist classification of the arable flora and its response to changes in agricultural practices 
BMC Ecology  2010;10:20.
Theory in ecology points out the potential link between the degree of specialisation of organisms and their responses to disturbances and suggests that this could be a key element for understanding the assembly of communities. We evaluated this question for the arable weed flora as this group has scarcely been the focus of ecological studies so far and because weeds are restricted to habitats characterised by very high degrees of disturbance. As such, weeds offer a case study to ask how specialization relates to abundance and distribution of species in relation to the varying disturbance regimes occurring in arable crops.
We used data derived from an extensive national monitoring network of approximately 700 arable fields scattered across France to quantify the degree of specialisation of 152 weed species using six different ecological methods. We then explored the impact of the level of disturbance occurring in arable fields by comparing the degree of specialisation of weed communities in contrasting field situations.
The classification of species as specialist or generalist was consistent between different ecological indices. When applied on a large-scale data set across France, this classification highlighted that monoculture harbour significantly more specialists than crop rotations, suggesting that crop rotation increases abundance of generalist species rather than sets of species that are each specialised to the individual crop types grown in the rotation. Applied to a diachronic dataset, the classification also shows that the proportion of specialist weed species has significantly decreased in cultivated fields over the last 30 years which suggests a biotic homogenization of agricultural landscapes.
This study shows that the concept of generalist/specialist species is particularly relevant to understand the effect of anthropogenic disturbances on the evolution of plant community composition and that ecological theories developed in stable environments are valid in highly disturbed environments such as agro-ecosystems. The approach developed here to classify arable weeds according to the breadth of their ecological niche is robust and applicable to a wide range of organisms. It is also sensitive to disturbance regime and we show here that recent changes in agricultural practices, i.e. increased levels of disturbance have favoured the most generalist species, hence leading to biotic homogenisation in arable landscapes.
PMCID: PMC2939635  PMID: 20809982
20.  Correlates of Research Effort in Carnivores: Body Size, Range Size and Diet Matter 
PLoS ONE  2014;9(4):e93195.
Given the budgetary restrictions on scientific research and the increasing need to better inform conservation actions, it is important to identify the patterns and causes of biases in research effort. We combine bibliometric information from a literature review of almost 16,500 peer-reviewed publications on a well-known group of 286 species, the Order Carnivora, with global datasets on species' life history and ecological traits to explore patterns in research effort. Our study explores how species' characteristics influenced the degree to which they were studied (measured as the number of publications). We identified a wide variation in intensity of research effort at both Family and Species levels, with some of the least studied being those which may need protection in future. Our findings hint at the complex role of human perspectives in setting research agendas. We found that better-studied species tended to be large-bodied and have a large geographic range whilst omnivory had a negative relationship with research effort. IUCN threat status did not exhibit a strong relationship with research effort which suggests that the conservation needs of individual species are not major drivers of research interest. This work is the first to use a combination of bibliometric analysis and biological data to quantify and interpret gaps in research knowledge across an entire Order. Our results could be combined with other resources, such as Biodiversity Action Plans, to prioritise and co-ordinate future research effort, whilst our methods can be applied across many scientific disciplines to describe knowledge gaps.
PMCID: PMC3973602  PMID: 24695422
21.  What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review 
A knowledge synthesis attempts to summarize all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can identify gaps in research evidence to define future research agendas. Knowledge synthesis activities in healthcare have largely focused on systematic reviews of interventions. However, a wider range of synthesis methods has emerged in the last decade addressing different types of questions (e.g., realist synthesis to explore mediating mechanisms and moderators of interventions). Many different knowledge synthesis methods exist in the literature across multiple disciplines, but locating these, particularly for qualitative research, present challenges. There is a need for a comprehensive manual for synthesis methods (quantitative/qualitative or mixed), outlining how these methods are related, and how to match the most appropriate knowledge synthesis method to answer a research question. The objectives of this scoping review are to: 1) conduct a systematic search of the literature for knowledge synthesis methods across multi-disciplinary fields; 2) compare and contrast the different knowledge synthesis methods; and, 3) map out the specific steps to conducting the knowledge syntheses to inform the development of a knowledge synthesis methods manual/tool.
We will search relevant electronic databases (e.g., MEDLINE, CINAHL), grey literature, and discipline-based listservs. The scoping review will consider all study designs including qualitative and quantitative methodologies (excluding economic analysis or clinical practice guideline development), and identify knowledge synthesis methods across the disciplines of health, education, sociology, and philosophy. Two reviewers will pilot-test the screening criteria and data abstraction forms, and will independently screen the literature and abstract the data. A three-step synthesis process will be used to map the literature to our objectives.
This project represents the first attempt to broadly and systematically identify, define and classify knowledge synthesis methods (i.e., less traditional knowledge synthesis methods). We anticipate that our results will lead to an accepted taxonomy for less traditional knowledge synthesis methods, and to the development and implementation of a methods manual for these reviews which will be relevant to a wide range of knowledge users, including researchers, funders, and journal editors.
PMCID: PMC3477082  PMID: 22862833
22.  Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash 
To provide an evidence-based clinical practice guideline for the chiropractic cervical treatment of adults with acute or chronic neck pain not due to whiplash. This is a considerable health concern considered to be a priority by stakeholders, and about which the scientific information was poorly organized.
Cervical treatments: manipulation, mobilization, ischemic pressure, clinic- and home-based exercise, traction, education, low-power laser, massage, transcutaneous electrical nerve stimulation, pillows, pulsed electromagnetic therapy, and ultrasound.
The primary outcomes considered were improved (reduced and less intrusive) pain and improved (increased and easier) ranges of motion (ROM) of the adult cervical spine.
An “extraction” team recorded evidence from articles found by literature search teams using 4 separate literature searches, and rated it using a Table adapted from the Oxford Centre for Evidence-based Medicine. The searches were 1) Treatment; August, 2003, using MEDLINE, CINAHL, AMED, MANTIS, ICL, The Cochrane Library (includes CENTRAL), and EBSCO, identified 182 articles. 2) Risk management (adverse events); October, 2004, identified 230 articles and 2 texts. 3) Risk management (dissection); September, 2003, identified 79 articles. 4) Treatment update; a repeat of the treatment search for articles published between September, 2003 and November, 2004 inclusive identified 121 articles.
To enable the search of the literature, the authors (Guidelines Development Committee [GDC]) regarded chiropractic treatment as including elements of “conservative” care in the search strategies, but not in the consideration of the range of chiropractic practice. Also, knowledge based only on clinical experience was considered less valid and reliable than good-caliber evidence, but where the caliber of the relevant evidence was low or it was non-existent, unpublished clinical experience was considered to be equivalent to, or better than the published evidence.
The expected benefits from the recommendations include more rapid recovery from pain, impairment and disability (improved pain and ROM). The GDC identified evidence-based pain benefits from 10 unimodal treatments and more than 7 multimodal treatments. There were no pain benefits from magnets in necklaces, education or relaxation alone, occipital release alone, or head retraction-extension exercise combinations alone. The specificity of the studied treatments meant few studies could be generalized to more than a minority of patients.
Adverse events were not addressed in most studies, but where they were, there were none or they were minor. The theoretic harm of vertebral artery dissection (VAD) was not reported, but an analysis suggested that 1 VAD may occur subsequent to 1 million cervical manipulations.
Costs were not analyzed in this guideline, but it is the understanding of the GDC that recommendations limiting ineffective care and promoting a more rapid return of patients to full functional capacity will reduce patient costs, as well as increase patient safety and satisfaction.
For simplicity, this version of the guideline includes primarily data synthesized across studies (evidence syntheses), whereas the technical and the interactive versions of this guideline ( also include relevant data from individual studies (evidence extractions).
The GDC developed treatment, risk-management and research recommendations using the available evidence. Treatment recommendations addressing 13 treatment modalities revolved around a decision algorithm comprising diagnosis (or assessment leading to diagnosis), treatment and reassessment. Several specific variations of modalities of treatment were not recommended.
For adverse events not associated with a treatment modality, but that occur in the clinical setting, there was evidence to recommend reconsideration of treatment options or referral to the appropriate health services. For adverse events associated with a treatment modality, but not a known or observable risk factor, there was evidence to recommend heightened vigilance when a relevant treatment is planned or administered. For adverse events associated with a treatment modality and predicted by an observable risk factor, there was evidence to recommend absolute contraindications, and requirements for treatment modality modification or caution to minimize harm and maximize benefit. For managing the theoretic risk of dissection, there was evidence to recommend a systematic risk-management approach. For managing the theoretic risk of stroke, there was support to recommend minimal rotation in administering any modality of upper-cervical spine treatment, and to recommend caution in treating a patient with hyperhomocysteinemia, although the evidence was especially ambiguous in both of these areas.
Research recommendations addressed the poor caliber of many of the studies; the GDC concluded that the scientific base for chiropractic cervical treatment of neck pain was not of sufficient quality or scope to “cover” current chiropractic practice comprehensively, although this should not suggest other disciplines are more evidence-based.
This guideline was authored by the 10 members of the GDC (Elizabeth Anderson-Peacock, Jean-Sébastien Blouin, Roland Bryans, Normand Danis, Andrea Furlan, Henri Marcoux, Brock Potter, Rick Ruegg, Janice Gross Stein, Eleanor White) based on the work of 3 literature search teams and an evidence extraction team, and in light of feedback from a commentator (Donald R Murphy), a 5-person review panel (Robert R Burton, Andrea Furlan, Richard Roy, Steven Silk, Roy Till), a 6-person Task Force (Grayden Bridge, H James Duncan, Wanda Lee MacPhee, Bruce Squires, Greg Stewart, Dean Wright), and 2 national profession-wide critiques of complete drafts. Two professional editors with extensive guidelines experience were contracted (Thor Eglington, Bruce P Squires). Key contributors to the guideline included individuals with specialties or expert knowledge in chiropractic, medicine, research processes, literature analysis processes, clinical practice guideline processes, protective association affairs, regulatory affairs, and the public interest. This guideline has been formally peer reviewed.
PMCID: PMC1839918  PMID: 17549134
chiropractic; guideline; evidence-based; neck pain
23.  Healthcare associated infection: novel strategies and antimicrobial implants to prevent surgical site infection 
This report is based on a Hygienist Panel Meeting held at St Anne's Manor, Wokingham on 24–25 June 2009. The panel agreed that greater use should be made of antiseptics to reduce reliance on antibiotics with their associated risk of antibiotic resistance. When choosing an antiseptic for clinical use, the Biocompatibility Index, which considers both the microbiocidal activity and any cytotoxic effects of an antiseptic agent, was considered to be a useful tool. The need for longer and more proactive post-discharge surveillance of surgical patients was also agreed to be a priority, especially given the current growth of day-case surgery. The introduction of surgical safety checklists, such as the World Health Organization's Safe Surgery Saves Lives initiative, is a useful contribution to improving safety and prevention of SSIs and should be used universally. Considering sutures as ‘implants’, with a hard or non-shedding surface to which micro-organisms can form biofilm and cause surgical site infections, was felt to be a useful concept.
PMCID: PMC3182781  PMID: 20819330
Surgical site infection; Antimicrobial sutures; Biofilms
24.  Incorporating 16S Gene Copy Number Information Improves Estimates of Microbial Diversity and Abundance 
PLoS Computational Biology  2012;8(10):e1002743.
The abundance of different SSU rRNA (“16S”) gene sequences in environmental samples is widely used in studies of microbial ecology as a measure of microbial community structure and diversity. However, the genomic copy number of the 16S gene varies greatly – from one in many species to up to 15 in some bacteria and to hundreds in some microbial eukaryotes. As a result of this variation the relative abundance of 16S genes in environmental samples can be attributed both to variation in the relative abundance of different organisms, and to variation in genomic 16S copy number among those organisms. Despite this fact, many studies assume that the abundance of 16S gene sequences is a surrogate measure of the relative abundance of the organisms containing those sequences. Here we present a method that uses data on sequences and genomic copy number of 16S genes along with phylogenetic placement and ancestral state estimation to estimate organismal abundances from environmental DNA sequence data. We use theory and simulations to demonstrate that 16S genomic copy number can be accurately estimated from the short reads typically obtained from high-throughput environmental sequencing of the 16S gene, and that organismal abundances in microbial communities are more strongly correlated with estimated abundances obtained from our method than with gene abundances. We re-analyze several published empirical data sets and demonstrate that the use of gene abundance versus estimated organismal abundance can lead to different inferences about community diversity and structure and the identity of the dominant taxa in microbial communities. Our approach will allow microbial ecologists to make more accurate inferences about microbial diversity and abundance based on 16S sequence data.
Author Summary
Microbial ecologists cannot observe their study organisms directly, so they use molecular sequencing to measure the abundance of different microbes living in the wild. The most commonly used method for measuring the abundance of different microbes is to collect a DNA sample from an environment and sequence a particular gene, the 16S SSU rRNA gene (“16S”) from those samples. The abundance of 16S sequences from different microbes is then used as a surrogate measure of the abundance of the microbial taxa in the community. One problem with the use of the 16S gene as a measure of microbial abundance is that many microbes have multiple copies of the gene in their genome. Thus, variation in 16S gene abundances can be caused by both genomic copy number variation and variation in the abundance of organisms. In this study we present a computational method that allows estimation of the abundance and genomic 16S copy number of microbes based on environmental sequencing of the 16S gene. We use simulations and analysis of microbial community data sets to demonstrate that estimating the abundance of organisms from 16S data improves our ability to accurately measure the diversity and abundance of microbial communities.
PMCID: PMC3486904  PMID: 23133348
25.  Global Gradients in Vertebrate Diversity Predicted by Historical Area-Productivity Dynamics and Contemporary Environment 
PLoS Biology  2012;10(3):e1001292.
A novel hierarchical framework integrates the effects of time, area, productivity, and temperature at their respective relevant scales and successfully predicts the latitudinal gradient in global vertebrate diversity.
Broad-scale geographic gradients in species richness have now been extensively documented, but their historical underpinning is still not well understood. While the importance of productivity, temperature, and a scale dependence of the determinants of diversity is broadly acknowledged, we argue here that limitation to a single analysis scale and data pseudo-replication have impeded an integrated evolutionary and ecological understanding of diversity gradients. We develop and apply a hierarchical analysis framework for global diversity gradients that incorporates an explicit accounting of past environmental variation and provides an appropriate measurement of richness. Due to environmental niche conservatism, organisms generally reside in climatically defined bioregions, or “evolutionary arenas,” characterized by in situ speciation and extinction. These bioregions differ in age and their total productivity and have varied over time in area and energy available for diversification. We show that, consistently across the four major terrestrial vertebrate groups, current-day species richness of the world's main 32 bioregions is best explained by a model that integrates area and productivity over geological time together with temperature. Adding finer scale variation in energy availability as an ecological predictor of within-bioregional patterns of richness explains much of the remaining global variation in richness at the 110 km grain. These results highlight the separate evolutionary and ecological effects of energy availability and provide a first conceptual and empirical integration of the key drivers of broad-scale richness gradients. Avoiding the pseudo-replication that hampers the evolutionary interpretation of non-hierarchical macroecological analyses, our findings integrate evolutionary and ecological mechanisms at their most relevant scales and offer a new synthesis regarding global diversity gradients.
Author Summary
Understanding what determines the distribution of biodiversity across the planet remains one of the critical challenges in biology and has gained particular urgency in the face of environmental change and accelerating species extinctions. Our study develops a novel analytical framework to jointly evaluate historical and contemporary environmental predictors of the latitudinal gradient in the diversity of terrestrial vertebrates. The number of vertebrate species is greater in warm, productive biomes, such as tropical forests, that have both a large size and a long evolutionary history. Using just a few key predictor variables—time, area, productivity, and temperature—we are now able to explain more than 80% of the variability in biodiversity among bioregions. By integrating each of these factors at both the regional and local scale in a hierarchical model, we are able to provide a consensus explanation for broad-scale diversity gradients that encompasses both ecological and evolutionary mechanisms.
PMCID: PMC3313913  PMID: 22479151

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