Characteristics of the 100 largest modern zoonotic disease outbreaks.

Zoonotic disease outbreaks are an important threat to human health and numerous drivers have been recognized as contributing to their increasing frequency. Identifying and quantifying relationships between drivers of zoonotic disease outbreaks and outbreak severity is critical to developing targeted zoonotic disease surveillance and outbreak prevention strategies. However, quantitative studies of outbreak drivers on a global scale are lacking. Attributes of countries such as press freedom, surveillance capabilities and latitude also bias global outbreak data. To illustrate these issues, we review the characteristics of the 100 largest outbreaks in a global dataset (n = 4463 bacterial and viral zoonotic outbreaks), and compare them with 200 randomly chosen background controls. Large outbreaks tended to have more drivers than background outbreaks and were related to large-scale environmental and demographic factors such as changes in vector abundance, human population density, unusual weather conditions and water contamination. Pathogens of large outbreaks were more likely to be viral and vector-borne than background outbreaks. Overall, our case study shows that the characteristics of large zoonotic outbreaks with thousands to millions of cases differ consistently from those of more typical outbreaks. We also discuss the limitations of our work, hoping to pave the way for more comprehensive future studies. This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.

What factors explain the geographical range of mammalian parasites?

Free-living species vary substantially in the extent of their spatial distributions. However, distributions of parasitic species have not been comprehensively compared in this context. We investigated which factors most influence the geographical extent of mammal parasites. Using the Global Mammal Parasite Database we analysed 17 818 individual geospatial records on 1806 parasite species (encompassing viruses, bacteria, protozoa, arthropods and helminths) that infect 396 carnivore, ungulate and primate host species. As a measure of the geographical extent of each parasite species we quantified the number and area of world ecoregions occupied by each. To evaluate the importance of variables influencing the summed area of ecoregions occupied by a parasite species, we used Bayesian network analysis of a subset ( n = 866) of the parasites in our database that had at least two host species and complete information on parasite traits. We found that parasites that covered more geographical area had a greater number of host species, higher average phylogenetic relatedness between host species and more sampling effort. Host and parasite taxonomic groups had weak and indirect effects on parasite ecoregion area; parasite transmission mode had virtually no effect. Mechanistically, a greater number of host species probably increases both the collective abundance and habitat breadth of hosts, providing more opportunities for a parasite to have an expansive range. Furthermore, even though mammals are one of the best-studied animal classes, the ecoregion area occupied by their parasites is strongly sensitive to sampling effort, implying mammal parasites are undersampled. Overall, our results support that parasite geographical extent is largely controlled by host characteristics, many of which are subsumed within host taxonomic identity.

Characterizing the phylogenetic specialism-generalism spectrum of mammal parasites.

The distribution of parasites across mammalian hosts is complex and represents a differential ability or opportunity to infect different host species. Here, we take a macroecological approach to investigate factors influencing why some parasites show a tendency to infect species widely distributed in the host phylogeny (phylogenetic generalism) while others infect only closely related hosts. Using a database on over 1400 parasite species that have been documented to infect up to 69 terrestrial mammal host species, we characterize the phylogenetic generalism of parasites using standard effect sizes for three metrics: mean pairwise phylogenetic distance (PD), maximum PD and phylogenetic aggregation. We identify a trend towards phylogenetic specialism, though statistically host relatedness is most often equivalent to that expected from a random sample of host species. Bacteria and arthropod parasites are typically the most generalist, viruses and helminths exhibit intermediate generalism, and protozoa are on average the most specialist. While viruses and helminths have similar mean pairwise PD on average, the viruses exhibit higher variation as a group. Close-contact transmission is the transmission mode most associated with specialism. Most parasites exhibiting phylogenetic aggregation (associating with discrete groups of species dispersed across the host phylogeny) are helminths and viruses.

Performance of the plant-based repellent TT-4302 against mosquitoes in the laboratory and field and comparative efficacy to 16 mosquito repellents against Aedes aegypti (Diptera: Culicidae).

Repellent efficacy of the plant-based repellent, TT-4302 (5% geraniol), was compared with 16 other products in laboratory arm-in-cage trials against Aedes aegypti (L). Eight repellents (Badger, BioUD, Burt's bees, California Baby, Cutter Natural, EcoSMART, Herbal Armor, and SkinSmart) exhibited a mean repellency below 90% to Ae. aegypti at 0.5 h after application. Three repellents (Buzz Away Extreme, Cutter Advanced, and OFF! Botanicals lotion) fell below 90% repellency 1.5 h after application. TT-4302 exhibited 94.7% repellency 5 h posttreatment, which was a longer duration than any of the other repellents tested. The positive control, 15% DEET (OFF! Active), was repellent for 3 h before activity dropped below 90%. Additional arm-in-cage trials comparing TT-4302 with 15% DEET were carried out against Anopheles quadrimaculatus Say. At 6 h after treatment, TT-4302 provided 95.2% repellency while DEET exhibited 72.2%. In North Carolina field trials, TT-4302 provided 100% repellency 5 h after application against Aedes albopictus Skuse while DEET provided 77.6% repellency. These results demonstrate that TT-4302 is an efficacious plant-based repellent that provides an extended duration of protection compared with many other commercially available products.

Activity of the plant-based repellent, TT-4302 against the ticks Amblyomma americanum, Dermacentor variabilis, Ixodes scapularis and Rhipicephalus sanguineus (Acari: Ixodidae).

The plant-based repellent TT-4302 (5 % geraniol) was compared to deet (15 %) in laboratory two-choice bioassays against the ticks Amblyomma americanum, Dermacentor variabilis, Ixodes scapularis, and Rhipicephalus sanguineus. At 2.5 and 3.5 h after treatment of filter paper with TT-4302, 100 % repellency was observed for all species at both time points with the exception of I. scapularis at the 3.5 h evaluation where repellency was 95.8 %. Deet was 100 % repellent at both time points for D. variabilis and R. sanguineus and was 100 % repellent at the 2.5 h evaluation for I. scapularis. Repellency of deet to A. americanum was 88.9 and 95.8 % at 2.5 and 3.5 h, respectively which was not significantly different than that of TT-4302. No significant difference against I. scapularis was observed between TT-4302 and deet at 3.5 h after treatment where deet was 87.5 % repellent. A variant of TT-4302, TT-4228 was tested in the laboratory against A. americanum and was compared to deet (15 %) in field trials against wild populations of ticks in North Carolina, USA. In the laboratory, TT-4228 was 94.4 and 87.5 % repellent at 2.5 and 3.5 h after treatment, respectively. In the field where the predominant tick species was A. americanum, significantly fewer ticks were collected from socks worn by human volunteers that were treated with TT-4228 compared to those treated with deet 2.5 or 3.5 h after treatment. Significantly fewer ticks were recovered from socks treated with TT-4228 than their paired untreated controls 2.5 or 3.5 h after treatment and repellencies were 90 and 70 %, respectively. Fewer ticks were collected from deet-treated compared to their paired untreated socks 2.5 h after application; however, no significant difference was found in the number of ticks collected from deet-and untreated socks 3.5 h after treatment.

In situ measurements of nitrate leaching implicate poor nitrogen and irrigation management on sandy soils.

Minimizing the risk of nitrate contamination along the waterways of the U.S. Great Plains is essential to continued irrigated corn production and quality water supplies. The objectives of this study were to quantify nitrate (NO(3)) leaching for irrigated sandy soils (Pratt loamy fine sand [sandy, mixed, mesic Lamellic Haplustalfs]) and to evaluate the effects of N fertilizer and irrigation management strategies on NO(3) leaching in irrigated corn. Two irrigation schedules (1.0x and 1.25x optimum) were combined with six N fertilizer treatments broadcast as NH(4)NO(3) (kg N ha(-1)): 300 and 250 applied pre-plant; 250 applied pre-plant and sidedress; 185 applied pre-plant and sidedress; 125 applied pre-plant and sidedress; and 0. Porous-cup tensiometers and solution samplers were installed in each of the four highest N treatments. Soil solution samples were collected during the 2001 and 2002 growing seasons. Maximum corn grain yield was achieved with 125 or 185 kg N ha(-1), regardless of the irrigation schedule (IS). The 1.25x IS exacerbated the amount of NO(3) leached below the 152-cm depth in the preplant N treatments, with a mean of 146 kg N ha(-1) for the 250 and 300 kg N preplant applications compared with 12 kg N ha(-1) for the same N treatments and 1.0x IS. With 185 kg N ha(-1), the 1.25x IS treatment resulted in 74 kg N ha(-1) leached compared with 10 kg N ha(-1) for the 1.0x IS. Appropriate irrigation scheduling and N fertilizer rates are essential to improving N management practices on these sandy soils.

An algorithm for approximate tandem repeats.

A perfect single tandem repeat is defined as a nonempty string that can be divided into two identical substrings, e.g., abcabc. An approximate single tandem repeat is one in which the substrings are similar, but not identical, e.g., abcdaacd. In this paper we consider two criterions of similarity: the Hamming distance (k mismatches) and the edit distance (k differences). For a string S of length n and an integer k our algorithm reports all locally optimal approximate repeats, r = umacro û, for which the Hamming distance of umacro and û is at most k, in O(nk log (n/k)) time, or all those for which the edit distance of umacro and û is at most k, in O(nk log k log (n/k)) time. This paper concentrates on a more general type of repeat called multiple tandem repeats. A multiple tandem repeat in a sequence S is a (periodic) substring r of S of the form r = u(a)u', where u is a prefix of r and u' is a prefix of u. An approximate multiple tandem repeat is a multiple repeat with errors; the repeated subsequences are similar but not identical. We precisely define approximate multiple repeats, and present an algorithm that finds all repeats that concur with our definition. The time complexity of the algorithm, when searching for repeats with up to k errors in a string S of length n, is O(nka log (n/k)) where a is the maximum number of periods in any reported repeat. We present some experimental results concerning the performance and sensitivity of our algorithm. The problem of finding repeats within a string is a computational problem with important applications in the field of molecular biology. Both exact and inexact repeats occur frequently in the genome, and certain repeats occurring in the genome are known to be related to diseases in the human.

Synthesis and evaluation of nitroheterocyclic phosphoramidates as hypoxia-selective alkylating agents.

A series of novel nitroheterocyclic phosphoramidates has been prepared, and the cytotoxicity of these compounds has been evaluated in clonogenic assays against B16, wild-type and cyclophosphamide-resistant MCF-7, and HT-29 cells under aerobic conditions and HT-29 cells under hypoxic conditions. All compounds were comparable in toxicity to wild-type and resistant MCF-7 cells and were also selectively toxic to HT-29 cells under hypoxic conditions (selectivity ratios 1.7 to >20). Analogues lacking the nitro group were not cytotoxic. Electron-withdrawing substituents increased cytotoxicity under aerobic conditions and thereby decreased hypoxic selectivity. In contrast, an electron-donating substituent markedly decreased both aerobic and hypoxic cytotoxicity but enhanced hypoxic selectivity. Chemical reduction of the nitro group resulted in rapid expulsion of the cytotoxic phosphoramide mustard. The most potent of these compounds show significant cytotoxicity under both aerobic and hypoxic conditions.

A surface measure for probabilistic structural computations.

Computing three-dimensional structures from sparse experimental constraints requires method for combining heterogeneous sources of information, such as distances, angles, and measures of total volume, shape, and surface. For some types of information, such as distances between atoms, numerous methods are available for computing structures that satisfy the provided constraints. It is more difficult, however, to use information about the degree to which an atom is on the surface or buried as a useful constraint during structure computations. Surface measures have been used as accept/reject criteria for previously computed structures, but this is not an efficient strategy. In this paper, we investigate the efficacy of applying a surface measure in the computation of molecular structure, using a method of probabilistic least square computations which facilitates the introduction of multiple, noisy, heterogeneous data sources. For this purpose, we introduce a simple purely geometrical measure of surface proximity called maximal conic view (MCV). MCV is efficiently computable and differentiable, and is hence well suited to driving a structural optimization method based, in part, on surface data. As an initial validation, we show that MCV correlates well with known measures for total exposed surface area. We use this measure in our experiments to show that information about surface proximity (derived from theory or experiment, for example) can be added to a set of distance measurements to increase significantly the quality of the computed structure. In particular, when 30 to 50 percent of all possible short-range distances are provided, the addition of surface information improves the quality of the computed structure (as measured by RMS fit) by as much as 80 percent. Our results demonstrate that knowledge of which atoms are on the surface and which are buried can be used as a powerful constraint in estimating molecular structure.

An information theoretic view of gapped and other alignments.

We use an information theoretical framework to estimate the probability of the score of gapped alignments. With appropriate scaling, the score of a global (and with some adjustments also the score of a local) alignment of two sequences can be viewed as the difference in the number of bits needed to transmit the two sequences T1 and T2 under two different encoding schemes C1 and C2. C1 is an idealized scheme, assumed to achieve an optimal encoding with respect to a distribution p, and the assumption that T1 and T2 are independent. C2 is an alternate scheme, that will transmit T1 and T2 while taking advantage of the optimal alignment between the two. That is under C1, the strings T1 and T2 (with respective probabilities p(T1) and p(T2)), are assumed to be encoded using C1(T1, T2) = log [formula: see text] bits. By slightly modifying a known Theorem we show that the probability (under p) that two independent sequences T1, T2 can be transmitted with an alternate encoding scheme (C2) with no more than C1(T1, T2)-r bits is bounded by 2-r. We then show how to use this bound to derive upper bounds for the probability of gapped alignment scores between two sequences.

Nitrobenzyl phosphorodiamidates as potential hypoxia-selective alkylating agents.

A series of novel nitrobenzyltetrakis(chloroethyl)phosphorodiamidates has been prepared, and its cytotoxicity has been evaluated against HT-29 cells under aerobic and hypoxic conditions and against murine bone marrow progenitor cells under aerobic conditions. All compounds were selectively toxic to HT-29 cells under hypoxic conditions, and the selectivity ratios varied from 1.6 to > 90. Analogs lacking either the nitro group or the tetrakis(chloroethyl) moiety were not cytotoxic, confirming that the presence of both nitro and incipient alkylating groups are essential for activity. Surprisingly, some analogs were far more toxic to bone marrow progenitors than to HT-29 cells under aerobic conditions, suggesting that other activation mechanisms must exist in these hematopoietic cells. Cytotoxicity increased with increasing depth in the HT-29 spheroid model, consistent with the preferential hypoxic toxicity of these compounds. Alkaline elution experiments showed a greater number of DNA interstrand cross-links under hypoxic compared to aerobic conditions. The extent of cross-linking in hypoxic cells was essentially identical to that produced by an equitoxic dose of melphalan, suggesting that the cytotoxicity of these compounds results from phosphorodiamidate release and alkylation of DNA.

Integration Of SiON waveguides and photodiodes on silicon substrates.

Two methods of coupling integrated optical waveguides to photodetectors are investigated. As waveguides, SiON layers were deposited by low-pressure chemical vapor deposition on a thick isolation layer of thermally grown SiO(2) on silicon substrates. Lateral p-i-n diode photodetectors were fabricated by standard processing in the silicon substrates. Structures for end-fire and leaky-wave coupling were fabricated. Coupling efficiencies of up to 84% for end-fire and 88% for leaky-wave coupling were obtained. The fabrication steps are described, and the resulting optoelectrical behavior is discussed.

Factors affecting the survival and growth of bacteria introduced into lake water.

The populations of Pseudomonas sp. B4, Escherichia coli, Klebsiella pneumoniae, Micrococcus flavus, and Rhizobium leguminosarum biovar phaseoli declined rapidly in lake water. The initially rapid decline of the two pseudomonads and R. phaseoli was followed by a period of slow loss of viability, but viable cells of the other species were not found after 10 days. The rapid initial phase of decline was not a result of Bdellovibrio spp., bacteriophages, or toxins in the water since Bdellovibrio spp. were not present and passage of the lake water through filters that should not have removed bacteriophages or soluble toxins led to the elimination of the rapid phase of decline. The addition of 250 micrograms of cycloheximide and 30 micrograms of nystatin per ml eliminated viable protozoa form the lake water, and the population of Pseudomonas sp. B4 did not fall and the decline of E. coli and K. pneumoniae was delayed or slowed under these conditions. Pseudomonas sp. L2 proliferated rapidly in lake water amended with glucose, phosphate, and NH4NO3, but its numbers subsequently fell abruptly; however, in water amended with cycloheximide and nystatin, which killed indigenous protozoa, the population density was higher and the fall in numbers was delayed. Of the nutrients, the chief response was to carbon, but when glucose was added, phosphorus and nitrogen stimulated growth further. Removing other bacteria by filtering the lake water before inoculation with Pseudomonas sp. L2 suggested that competition reduced the extent of response of the pseudomonad to added nutrients.(ABSTRACT TRUNCATED AT 250 WORDS)

Factorial analysis of the MMPI profiles of low back pain patients.

To examine the interrelationships of MMPI scale scores among low back pain patients, 50 profiles were scored on the traditional 13 scales, Hanvik's Lb scale and seven subscales derived from Scales 1 and 3. The profiles were randomly divided into two equal samples and factor analyzed. Comparison of the two samples yielded three common factors. The first factor measured severity of the symptoms, the second assessed the level of anger and aggression and the third assessed the psychogenic components of the syndrome. The implications of the factors are discussed.

Issues in psychiatric day-care programs in non-urban areas: a case study.

As community mental health continues to grow in credibility, it has expanded, not only into new areas of treatment (e.g., child abuse), but also into new geographical areas, such as rural Canada. However, transplantation of urban-based community mental health models into the rural community poses major problems. To illustrate such problems as well as possible solutions, this paper describes a day-care program in a non-urban area, the overall settings of the program, a description of its structure and the issues facing it, as well as some of the ways we have dealt with them. We then discuss some recent changes we made in the program and how we evaluated these, to illustrate how such a program can institute an ongoing program evaluation. Finally, some data on the outcome of the program is presented.

Ambiversion: characteristics of midrange responders on the Introversion-Extraversion continuum.

Sixty-nine midrange responders on the Introversion-Extroversion (IE) scale of the Eysenck Personality Questionnaire (EPQ) were given an experimental measure to assess tendency toward ambivalence (i.e., both strongly introverted and strongly extraverted responses) vs. moderation (i.e., midrange responses), and degree of importance given to IE types of activities. The participants were divided into those showing ambivalence vs. those showing moderate responses, and into those reporting high vs. low importance of such activities. As was predicted, the ambivalent group showed significantly higher scores on the neuroticism scale of the EPQ, while the low importance group tended to show more psychoticism, but not to a significant degree. Both of the midrange scores were unrelated to the Bem Sex Role Inventory. Based on the findings, at least two groups are posited in the midrange of the IE dimension: an ambivalent group with mixed strong introversive and extraversive tendencies, and an ambiverted group with midrange scores.

A behavioral approach to patient compliance.

A behavioral program for increasing a patient's compliance with a drug regimen can be administered by a physician or by trained health care personnel. The program focuses first on the development of a strong external cue to the timing of medication and then on helping the patient to have realistic expectations and to establish an appropriate self-reward for compliance. Monitoring of degree of compliance is essential to the success of the program, as is development of a cooperative, rather than authoritatian, relationship between physician and patient.