An evaluation of DistillerSR's machine learning-based prioritization tool for title/abstract screening - impact on reviewer-relevant outcomes.

BACKGROUND: Systematic reviews often require substantial resources, partially due to the large number of records identified during searching. Although artificial intelligence may not be ready to fully replace human reviewers, it may accelerate and reduce the screening burden. Using DistillerSR (May 2020 release), we evaluated the performance of the prioritization simulation tool to determine the reduction in screening burden and time savings. METHODS: Using a true recall @ 95%, response sets from 10 completed systematic reviews were used to evaluate: (i) the reduction of screening burden; (ii) the accuracy of the prioritization algorithm; and (iii) the hours saved when a modified screening approach was implemented. To account for variation in the simulations, and to introduce randomness (through shuffling the references), 10 simulations were run for each review. Means, standard deviations, medians and interquartile ranges (IQR) are presented. RESULTS: Among the 10 systematic reviews, using true recall @ 95% there was a median reduction in screening burden of 47.1% (IQR: 37.5 to 58.0%). A median of 41.2% (IQR: 33.4 to 46.9%) of the excluded records needed to be screened to achieve true recall @ 95%. The median title/abstract screening hours saved using a modified screening approach at a true recall @ 95% was 29.8 h (IQR: 28.1 to 74.7 h). This was increased to a median of 36 h (IQR: 32.2 to 79.7 h) when considering the time saved not retrieving and screening full texts of the remaining 5% of records not yet identified as included at title/abstract. Among the 100 simulations (10 simulations per review), none of these 5% of records were a final included study in the systematic review. The reduction in screening burden to achieve true recall @ 95% compared to @ 100% resulted in a reduced screening burden median of 40.6% (IQR: 38.3 to 54.2%). CONCLUSIONS: The prioritization tool in DistillerSR can reduce screening burden. A modified or stop screening approach once a true recall @ 95% is achieved appears to be a valid method for rapid reviews, and perhaps systematic reviews. This needs to be further evaluated in prospective reviews using the estimated recall.

Host nuclear genotype influences phenotype of a conditional mutualist symbiont.

Arthropods commonly carry maternally inherited intracellular bacterial symbionts that may profoundly influence host biology and evolution. The intracellular symbiont Rickettsia sp. nr. bellii swept rapidly into populations of the sweetpotato whitefly Bemisia tabaci in the south-western USA. Previous laboratory experiments showed female-bias and fitness benefits were associated with Rickettsia infection, potentially explaining the high frequencies of infection observed in field populations, but the effects varied with whitefly genetic line. Here, we explored whether host extranuclear or nuclear genes influenced the variation in the Rickettsia-host phenotype in two genetic lines of the whitefly host, each with Rickettsia-infected and uninfected sublines. Introgression between the Rickettsia-infected subline of one genetic line and the Rickettsia-uninfected subline of the other was used to create two new sublines, each with the maternally inherited extranuclear genetic lineages of one line (Rickettsia, two other symbionts and the mitochondria) and the nuclear genotype of the other. Performance assays comparing the original and new lines showed that in addition to Rickettsia, the interaction of Rickettsia infection with host nuclear genotype influenced development time and the sex ratio of the progeny, whereas the extranuclear genotype did not. Host nuclear genotype, but not extranuclear genotype, also influenced the titre of Rickettsia. Our results support the hypothesis that differences in host nuclear genotype alone may explain considerable within-population variation in host-symbiont phenotype and may contribute to the observed variation in Rickettsia-whitefly interactions worldwide.

Reproductive interference and fecundity affect competitive interactions of sibling species with low mating barriers: experimental and theoretical evidence.

When allopatric species with incomplete prezygotic isolation come into secondary contact, the outcome of their interaction is not easily predicted. The parasitoid wasp Encarsia suzannae (iES), infected by Cardinium inducing cytoplasmic incompatibility (CI), and its sibling species E. gennaroi (EG), not infected by bacterial endosymbionts, may have diverged because of the complementary action of CI and asymmetric hybrid incompatibilities. Whereas postzygotic isolation is now complete because of sterility of F1 hybrid progeny, prezygotic isolation is still incipient. We set up laboratory population cage experiments to evaluate the outcome of the interaction between ES and EG in two pairwise combinations: iES vs EG and cured ES (cES, where Cardinium was removed with antibiotics) vs EG. We also built a theoretical model aimed at exploring the role of life-history differences and asymmetric mating on competitive outcomes. In three of four cages in each treatment, ES dominated the interaction. We found evidence for reproductive interference, driven by asymmetric mating preferences, that gave a competitive edge to ES, the species that better discriminated against heterospecifics. However, we did not find the fecundity cost previously shown to be associated with Cardinium infection in iES. The model largely supported the experimental results. The finding of only a slight competitive edge of ES over EG in population cages suggests that in a more heterogeneous environment the species could coexist. This is supported by evidence that the two species coexist in sympatry, where preliminary data suggest reproductive character displacement may have reinforced postzygotic isolation.

Locations of the hydrophobic side chains of lipoglycopeptides bound to the peptidoglycan of Staphylococcus aureus.

Glycopeptides whose aminosugars have been modified by attachment of hydrophobic side chains are frequently active against vancomycin-resistant microorganisms. We have compared the conformations of six such fluorinated glycopeptides (with side chains of varying length) complexed to cell walls labeled with d-[1-(13)C]alanine, [1-(13)C]glycine, and l-[ε-(15)N]lysine in whole cells of Staphylococcus aureus. The internuclear distances from (19)F of the bound drug to the (13)C and (15)N labels of the peptidoglycan, and to the natural abundance (31)P of lipid membranes and teichoic acids, were determined by rotational-echo double resonance NMR. The drugs did not dimerize, and their side chains did not form membrane anchors but instead became essential parts of secondary binding to pentaglycyl bridge segments of the cell-wall peptidoglycan.

Endosymbiont costs and benefits in a parasitoid infected with both Wolbachia and Cardinium.

Theory suggests that maternally inherited endosymbionts can promote their spread and persistence in host populations by enhancing the production of daughters by infected hosts, either by improving overall host fitness, or through reproductive manipulation. In the doubly infected parasitoid wasp Encarsia inaron, Wolbachia manipulates host reproduction through cytoplasmic incompatibility (CI), but Cardinium does not. We investigated the fitness costs and/or benefits of infection by each bacterium in differentially cured E. inaron as a potential explanation for persistence of Cardinium in this population. We introgressed lines infected with Wolbachia, Cardinium or both with the cured line to create a similar genetic background, and evaluated several parasitoid fitness parameters. We found that symbiont infection resulted in both fitness costs and benefits for E. inaron. The cost was lower initial egg load for all infected wasps. The benefit was increased survivorship, which in turn increased male production for wasps infected with only Cardinium. Female production was unaffected by symbiont infection; we therefore have not yet identified a causal fitness effect that can explain the persistence of Cardinium in the population. Interestingly, the Cardinium survivorship benefit was not evident when Wolbachia was also present in the host, and the reproduction of doubly infected individuals did not differ significantly from uninfected wasps. Therefore, the results of our study show that even when multiple infections seem to have no effect on a host, there may be a complex interaction of costs and benefits among symbionts.

Population dynamics and rapid spread of Cardinium, a bacterial endosymbiont causing cytoplasmic incompatibility in Encarsia pergandiella (Hymenoptera: Aphelinidae).

Cytoplasmic incompatibility (CI) is a common phenotype of maternally inherited bacterial symbionts of arthropods; in its simplest expression, uninfected females produce few or no viable progeny when mated to infected males. Infected females thus experience a reproductive advantage relative to that of uninfected females, with the potential for the symbiont to spread rapidly. CI population dynamics are predicted to depend primarily on the strength of incompatibility, the fitness cost of the infection and how faithfully symbionts are inherited. Although the bacterial symbiont lineage Wolbachia has been most identified with the CI phenotype, an unrelated bacterium, Cardinium may also cause CI. In the first examination of population dynamics of CI-inducing Cardinium, we used population cages of the parasitic wasp Encarsia pergandiella (Hymenoptera: Aphelinidae) with varying initial infection frequencies to test a model of invasion. Cardinium was found to spread rapidly in all populations, even in cases where the initial infection frequency was well below the predicted invasion threshold frequency. The discrepancy between the modeled and actual results is best explained by weaker CI than measured in the lab and a cryptic fitness benefit to the infection.

Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis.

As therapeutic agents of choice in the treatment of complicated infections, glycopeptide antibiotics are often preferentially used in cases of osteomyelitis, an infection located in bone and notoriously difficult to successfully manage. Yet frequent and heavy doses of these systemically administered antibiotics are conventionally prescribed to obtain higher antibiotic levels in the bone and reduce the high recurrence rates. Targeting antibiotics to the bone after systemic administration would present at least three potential advantages: (i) greater efficacy, by concentrating the therapeutic agent in bone; (ii) greater convenience, through a reduction in the frequency of administration; and (iii) greater safety, by reducing the levels of systemic drug exposure. We present here the design, synthesis and in vitro evaluation of eight prodrugs of the glycopeptide antibacterial agents vancomycin and oritavancin taking advantage of the affinity of the bisphosphonate group for bone for delivery to osseous tissues.

Cytoplasmic incompatibility in the parasitic wasp Encarsia inaron: disentangling the roles of Cardinium and Wolbachia symbionts.

Many bacterial endosymbionts of insects are capable of manipulating their host's reproduction for their own benefit. The most common strategy of manipulation is cytoplasmic incompatibility (CI), in which embryonic mortality results from matings between uninfected females and infected males. In contrast, embryos develop normally in infected females, whether or not their mate is infected, and infected progeny are produced. In this way, the proportion of infected females increases in the insect population, thereby promoting the spread of the maternally inherited bacteria. However, what happens when multiple endosymbionts inhabit the same host? The parasitoid wasp Encarsia inaron is naturally infected with two unrelated endosymbionts, Cardinium and Wolbachia, both of which have been documented to cause CI in other insects. Doubly infected wasps show the CI phenotype. We differentially cured E. inaron of each endosymbiont, and crossed hosts of different infection status to determine whether either or both bacteria caused the observed CI phenotype in this parasitoid, and whether the two symbionts interacted within their common host. We found that Wolbachia caused CI in E. inaron, but Cardinium did not. We did not find evidence that Cardinium was able to modify or rescue Wolbachia-induced CI, nor did we find that Cardinium caused progeny sex ratio distortion, leaving the role of Cardinium in E. inaron a mystery.

Bisphosphonated fluoroquinolone esters as osteotropic prodrugs for the prevention of osteomyelitis.

Osteomyelitis is a difficult to treat bacterial infection of the bone. Delivering antibacterial agents to the bone may overcome the difficulties in treating this illness by effectively concentrating the antibiotic at the site of infection and by limiting the toxicity that may result from systemic exposure to the large doses conventionally used. Using bisphosphonates as osteophilic functional groups, different forms of fluoroquinolone esters were synthesized and evaluated for their ability to bind bone and to release the parent antibacterial agent. Bisphosphonated glycolamide fluoroquinolone esters were found to present a profile consistent with effective and rapid bone binding and efficient release of the active drug moiety. They were assessed for their ability to prevent bone infection in vivo and were found to be effective when the free fluoroquinolones were not.

Zooplankton chitobiase activity as an endpoint of pharmaceutical effect.

Numerous human and veterinary pharmaceuticals are constantly entering surface waters, despite little understanding of their potential impacts on aquatic ecosystems. To address this concern, an attempt to create a simple, reproducible, inexpensive, and sublethal toxicity bioassay for freshwater zooplankton was initiated. The approach was centered on characterizing the response of a zooplankton enzyme, chitobiase, to the presence of a toxicant. The aim of the present research was to develop a reproducible laboratory-based assay for Daphnia magna chitobiase activity and to screen four commonly prescribed pharmaceuticals using that assay. The four pharmaceuticals tested for potential effects on D. magna chitobiase activity were atorvastatin, lovastatin, fluoxetine, and sertraline. We were able to detect exposure-associated differences in chitobiase activity at concentrations of 0.1 mug/L fluoxetine after 24 and 72 hours of exposure. Differences were also detected for the other compounds. The response of chitobiase was found to be promising as an assay to measure sublethal effects in D. magna and perhaps other zooplankton species.

Perturbation of chromatin architecture on ecdysterone induction of Drosophila melanogaster small heat shock protein genes.

Alterations in the pattern of DNase I hypersensitivity were observed on ecdysterone-stimulated transcription of Drosophila melanogaster small heat shock protein genes. Perturbations were induced near hsp27 and hsp22, coupled with an extensive domain of chromatin unfolding in the intergenic region between hsp23 and the developmentally regulated gene 1. These regions represent candidates for ecdysterone regulatory interactions.

The distribution of IgG subclasses in pemphigoid gestationis: PG factor is an IgG1 autoantibody.

Using monoclonal antibodies in immunofluorescence techniques, the subclass distribution of anti-basement membrane zone IgG antibodies was studied in the skin, placenta, and serum of patients with pemphigoid (herpes) gestationis. IgG1 was found to be the major IgG subclass in both serum and tissue, being detected in the sera of all pemphigoid gestationis patients studied. In pemphigoid and pemphigus, however, the distribution of IgG subclasses was heterogeneous, with IgG4 being the dominant autoantibody. Pemphigoid (herpes) gestationis factor, the circulating anti-basement membrane zone autoantibody thought to be pathogenic in pemphigoid gestationis, is therefore, an IgG1 antibody, with inferred complement binding capacity. Tissue damage in pemphigoid gestationis is apparently mediated by complement fixation which is detected via the classical complement cascade.

Characterization of spermidine synthase from Trypanosoma brucei brucei.

Spermidine synthase from Trypanosoma brucei brucei was characterized and found to be similar to spermidine synthase from other sources. The Km for putrescine was found to be 0.2 mM and the Km for decarboxylated S-adenosylmethionine 0.1 microM. The approximate molecular weight of the enzyme was 74 000 as determined by a combination of molecular sieve chromatography and sucrose density gradient centrifugation. Spermidine synthase activity was markedly inhibited in vitro by dicyclohexylamine (50% inhibition at 3 microM) and cyclohexylamine (50% inhibition at 15 microM); both being competitive inhibitors with respect to putrescine. S-Adenosyl-1,8-diamino-3-thiooctane, a nucleoside bisubstrate analog, was also a potent inhibitor of enzyme activity (50% inhibition at 25 microM). Administration of dicyclohexylamine to mice with trypanosomiasis resulted in no increase in survival time probably due to the lack of effect on trypanosome spermidine concentrations. Other possible inhibitors remain to be tested in vivo.

Probing the nature of chromosomal DNA-protein contacts by in vivo footprinting.

Of the various approaches employed to unravel the mechanisms of gene regulation, the method of in vivo footprinting seems likely to be increasingly perceived as indispensable. A clear knowledge of the actual pattern of DNA-protein interactions occurring at a given gene within a cell, gained from data obtained with a minimum of external perturbation, can provide a benchmark against which attempts at in vitro reconstruction of the relevant interactions can be judged. This appears particularly important given our current awareness of the degeneracy displayed by certain DNA sequences in terms of their in vitro ability to separately bind to more than one (sometimes several) species of protein factor present in a nuclear extract. The mutual pursuit of both in vivo and in vitro approaches will likely provide the best route to a detailed molecular description of regulatory interactions. Following the introduction of both improved and novel technical approaches, the possibility of probing chromosomal DNA-protein associations at nucleotide resolution is now well within the capacity of most laboratories. In this article the techniques of, probing reagents used for, and some important results obtained by in vivo footprinting are critically discussed.

Inhibition of Trypanosoma brucei brucei peptidyl transferase activity by sparsomycin analogs and effects on trypanosome protein synthesis and proliferation.

Peptidyl transferase activity of Trypanosoma brucei brucei polyribosomes was competitively inhibited by analogs of sparsomycin (Ki = 1-100 microM). The analogs were also potent inhibitors of [3H]-leucine and [3H]mannose incorporation into the proteins of intact trypanosomes with little or no effect on overall respiratory rate, suggesting a specific site of action for these analogs on protein synthesis. The peptidyl transferase inhibitors were effective at low concentrations at limiting the proliferation of trypanosomes both in vitro and in vivo. The potency of the compounds as inhibitors of cell proliferation was positively correlated with their efficacy as inhibitors of peptidyl transferase activity. One compound, MDL 20828 (1 mg/kg), increased the survival time of T. b. brucei-infected mice 4-fold in the absence of any overt drug toxicity to the hosts.

Regulation of growth and macromolecular synthesis by putrescine and spermidine in Pseudomonas aeruginosa.

Growth of P. aeruginosa, slowed by the addition of monofluoromethylornithine, difluoromethylarginine and dicyclohexylammonium sulfate, could be restored by addition of 0.1 mM putrescine plus 0.1 muM spermidine, or 0.1 mM spermidine or 5 mM putrescine by themselves. Lower concentrations of putrescine (0.1 mM - 1 mM) also partially reversed the growth inhibition. Conversion of putrescine to spermidine continued, although at a markedly reduced ratio, in the drug-inhibited cells, but intracellular spermidine concentrations remained depressed suggesting that reversal of inhibition by putrescine may be a direct effect. There was appreciable back-conversion of any added spermidine to putrescine with a demonstrable increase in total intracellular putrescine levels, making conclusions on the effects of spermidine ambiguous. Spermine (0.1 mM), a polyamine not present in bacteria, was also effective in reversing growth inhibition, probably because of its conversion into spermidine and putrescine. The effects of putrescine, spermidine and spermine were specific in that the non-physiological amines, 1,3-diaminopropane, 1,5-diaminopentane (cadaverine), 1,6-diaminohexane, or 1,7-diaminoheptane could not reverse the effects of the three drugs. Rates of total protein, RNA and DNA synthesis were all slowed to the same extent as growth rate and showed similar recovery with the addition of putrescine or spermidine. A role for putrescine in P. aeruginosa growth processes is suggested.

Ocular deviation following excimer laser photorefractive keratectomy.

We present a case of ocular deviation and diplopia that developed 9 months after monocular excimer laser photorefractive keratectomy. In this case, decompensation occurred because of a breakdown of fusion at distance. We suggest a cover test to assess the presence of significant phorias in all candidates for refractive surgery procedures.

The Genetic Knowledge Index: developing a standard measure of genetic knowledge.

This paper reports on the development of a unidimensional genetic knowledge index that has been tested and validated in a general population sample. The Index is intended to provide the basis for a standard measure of basic genetic knowledge that can be applied across diverse populations and research settings. The study group was composed of 330 European Americans selected randomly in the Louisville, KY, metropolitan area. The final version of the Genetic Knowledge Index (GKI) consisted of five items identified by principle components analysis, correlation coefficients, and the alpha measure of internal consistency. Construct validity of the GKI was determined by appropriate statistical correlations with educational attainment and attitudes toward genetic discrimination. The Index provides a numerical ranking of subjects' knowledge of practical genetics. Implications for research are discussed.

Defining dementia: social and historical background of Alzheimer disease.

Though Alzheimer disease (AD) has been recognized as a distinct entity since 1907, scientific understanding of, and public interest in, the disease remained very limited until the 1970s. The perception of AD as a significant problem has been substantially affected by cultural and demographic changes and by interest group and federal government initiatives. The recognition of AD has transformed senility from an expected stage of life into a "disease." It has also increased fear both of the individual effects of having AD and of the social consequences of AD in the population. Both the biotechnology industry and AD activist organizations will play a role in the social implications of genetic testing for AD.