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Given the equivocal literature on the relationship between internalizing symptoms and early adolescent alcohol use (AU) and AU disorder (AUD), the present study took a developmental perspective to understand how internalizing and externalizing symptoms may operate together in the etiology of AU and AUD. We pit the delayed onset and rapid escalation hypothesis (Hussong et al., 2011) against a synthesis of the dual failure model and the stable co-occurring hypothesis (Capaldi, 1992; Colder et al., 2013, 2018) to test competing developmental pathways to adolescent AU and AUD involving problem behavior, peer delinquency, and early initiation of AU. A latent transactional and mediational framework was used to test pathways to AUD spanning developmental periods before AU initiation (Mage = 11) to early and high risk for AUD (Mage = 14–15 and Mage = 17–18). The results supported three pathways to AUD. The first started with “pure” externalizing symptoms in early childhood and involved multiple mediators, including the subsequent development of co-occurring symptoms and peer delinquency. The second pathway involved stable co-occurring symptoms. Interestingly, chronically elevated pure internalizing symptoms did not figure prominently in pathways to AUD. Selection and socialization effects between early AU and peer delinquency constituted a third pathway.
We report daptomycin minimum inhibitory concentrations (MICs) for vancomycin-resistant Enterococcus faecium isolated from bloodstream infections over a 4-year period. The daptomycin MIC increased over time hospital-wide for initial isolates and increased over time within patients, culminating in 40% of patients having daptomycin-nonsusceptible isolates in the final year of the study.
There is increasing recognition that perinatal anxiety disorders are both common and potentially serious for mother and child. Obsessive–compulsive disorder (OCD) can be triggered or exacerbated in the postpartum period, with mothers reporting significant effects on parenting tasks. However, there is little evidence concerning their effective treatment or the impact of successful treatment on parenting.
A total of 34 mothers with OCD and a baby of 6 months old were randomized into either time-intensive cognitive–behaviour therapy (iCBT) or treatment as usual (TAU). iCBT took place after randomization at 6 months postpartum and was completed by 9 months. Maternal symptomatology, sensitivity in mother–infant interactions and parenting were assessed at baseline and reassessed at 12 months postpartum. At 12 months attachment was also assessed using Ainsworth's Strange Situation Procedure. A healthy control group of mothers and infants (n = 37) underwent the same assessments as a benchmark.
iCBT was successful in ameliorating maternal symptoms of OCD (controlled effect size = 1.31–1.90). However, mother–infant interactions were unchanged by treatment and remained less sensitive in both OCD groups than a healthy control group. The distribution of attachment categories was similar across both clinical groups and healthy controls with approximately 72% classified as secure in each group.
iCBT is an effective intervention for postpartum OCD. Sensitive parenting interactions are affected by the presence of postpartum OCD and this is not improved by successful treatment of OCD symptoms. However, the overall attachment bond appears to be unaffected. Longitudinal studies are needed to explore the impact of postpartum OCD as the child develops.
The rapid rise in syphilis cases has prompted a number of public health campaigns to assist men who have sex with men (MSM) recognize and present early with symptoms. This study aimed to investigate the temporal trend of the duration of self-report symptoms and titre of rapid plasma reagin (RPR) in MSM with infectious syphilis. Seven hundred and sixty-one syphilis cases in MSM diagnosed at the Melbourne Sexual Health Centre (MSHC) from 2007–2013 were reviewed. Median duration of symptoms and RPR titres in each year were calculated. The median durations of symptoms with primary and secondary syphilis were 9 [interquartile range (IQR) 6–14] days and 14 (IQR 7–30) days, respectively. The overall median titre of RPR in secondary syphilis (median 128, IQR 64–256) was higher than in primary syphilis (median 4, IQR 1–32) and in early latent syphilis (median 32, IQR 4–64). The median duration of symptoms for primary syphilis, secondary syphilis and titre of RPR level did not change over time. Public health campaigns were not associated with a significant shorter time from onset of symptoms to treatment. Alternative strategies such as more frequent testing of MSM should be promoted to control the syphilis epidemic in Australia.
The group G streptococcus has generally not been considered a prominent pathogen. In a 1982 study of the colonization rate by β-haemoly tic streptococci in apparently healthy children, age 5–11 years, 25 of 69 isolates belonged to group G. This surprisingly high rate of group G colonization (14·3%) led to a retrospective study of school surveys in 1967 which showed that the colonization rate with this organism was 2·3% (range 1·3–3·5%). A review of bacitracin-sensitive streptococcal isolates from hospital admissions of patients with acute glomerulonephritis (AGN), rheumatic fever, and their siblings, between January 1967 and July 1980, was conducted. Of 1063 bacitracin-sensitive isolates, 63 were group G, and 52 of these were isolated from AGN patients and their siblings, i.e. 7 from skin lesions of AGN patients, 40 from the throats of siblings and only 5 from the skins of the siblings. The other 11 group G isolates were from rheumatic-fever patients and their siblings. Thus, the group G colonization rate fluctuates in the population. The isolation of only group G streptococci from skin lesions of patients with AGN suggests a possible association between group G streptococcal pyoderma and acute post-streptococcal glomerulonephritis.
Cryptosporidium is an important cause of diarrhoeal disease worldwide and, as several recent waterborne outbreaks have shown, poses a significant threat to public health in Ireland. We identified the Cryptosporidium spp. in 199 positive human stool samples by PCR–RFLP of the 18S rRNA and COWP gene loci. Subspecies were identified in 104 samples by sequence analysis of the 60 kDa glycoprotein (gp60) gene fragment. Overall C. parvum was identified in 80%, and C. hominis in 20% of cases. No other Cryptosporidium spp. were detected. C. parvum was by far the most common species in the rural, more sparsely populated west of Ireland and exhibited a pronounced spring peak coincident with a peak in the national cryptosporidiosis incidence rate. Our data indicated a trend towards higher proportions of C. hominis in older age groups. Ninety-nine per cent of all subtyped C. parvum isolates belonged to allele family IIa, of which allele IIaA18G3R1 was by far the most common (63%). According to a recent study by Thompson and colleagues [Parasitology Research (2007), 100, 619–624] this allele is also the most common in Irish cattle. Subtyping of the C. hominis isolates indicated that they belonged to a geographically widely distributed allele (IbA10G2) known to have caused several water- and foodborne outbreaks around the world. The predominance of C. parvum, its geographic and seasonal distribution and the IIaA18G3R1 subtype underlines the importance of zoonotic Cryptosporidium transmission in Ireland.
Infection caused by parasitic nematodes of humans and livestock can have significant health and economic costs. Treatments aimed at alleviating these costs, such as chemotherapy and vaccination, alter parasite survival and reproduction, the main selective pressures shaping life-history traits such as age to maturity, size and fecundity. Most authors have argued that the life-history evolution prompted by animal and public health programmes would be clinically beneficial, generating smaller, less fecund worms, and several mathematical models support this view. However, using mathematical models of long-lasting interventions, such as vaccination, and regularly repeated short interventions, such as drenching, we show here that the expected outcome actually depends on how mortality rates vary as a function of worm size and developmental status. Interventions which change mortality functions can exert selection pressure to either shorten or extend the time to maturity, and thus increase or decrease worm fecundity and size. The evolutionary trajectory depends critically on the details of the mortality functions with and without the intervention. Earlier optimism that health interventions would always prompt the evolution of smaller, less fecund and hence clinically less damaging worms is premature.
The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) is associated with malaria virulence (disease severity) in both rodents and humans. We are interested in whether parasite genetic diversity influences TNF-mediated effects on malaria virulence. Here, primary infections with genetically distinct Plasmodium chabaudi chabaudi (P.c.c.) clones varied in the virulence and cytokine responses induced in female C57BL/6 mice. Even when parasitaemia was controlled for, a greater day 7 TNF-α response was induced by infection with more virulent P.c.c. clones. Since many functions of TNF-α are exerted through TNF receptor 1 (TNFR1), a TNFR-1 fusion protein (TNFR-Ig) was used to investigate whether TNFR1 blockade eliminated clone virulence differences. We found that TNFR-1 blockade ameliorated the weight loss but not the anaemia induced by malaria infection, regardless of P.c.c. clone. We show that distinct P.c.c. infections induced significantly different plasma interferon gamma (IFN-γ), interleukin 6 (IL-6) and interleukin 10 (IL-10) levels. Our results demonstrate that regardless of P.c.c. genotype, blocking TNFR1 signalling protected against weight loss, but had negligible effects on both anaemia and asexual parasite kinetics. Thus, during P.c.c. infection, TNF-α is a key mediator of weight loss, independent of parasite load and across parasite genotypes.
The status of kinematic observations in Local Group dwarf spheroidal
galaxies (dSphs) is reviewed. Various approaches to the dynamical
modelling of these data are discussed and some general features of
dSph dark matter haloes based on simple mass models are presented.
The observational evidence for kinematic substructure in Local Group dSphs is reviewed. The properties of these substructures are consistent with their being disrupted star clusters. The persistence of cold substructure argues strongly against the presence of dark matter cusps in the haloes of dSphs. A formation scenario for dSphs is described involving the merger of star clusters in the potential well of a low-mass dark matter halo.
Thin films of sputtered aluminum were deformed by two different experimental techniques. One experiment comprised passing high electrical AC current density through patterned Al interconnect lines deposited on SiO2/Si substrates. The other consisted of uniaxial mechanical tensile deformation of a 1 μm thick by 5 μm wide free standing Al line. In the electrical tests approximately 2 x 107 W/cm2 was dissipated at 200 Hz resulting in cyclic Joule heating, which developed a total thermomechanical strain of about 0.3 % per cycle. The tension test showed a gauge length fracture strain of only 0.5 % but did display ductile chisel point fracture. In both experiments, certain grains exhibited large, > 30°, rotation away from an initial <111> normal orientation toward <001>, based on electron backscatter diffraction (EBSD) measurements in the scanning electron microscope (SEM). Transmission electron microscopy (TEM) analysis of specimens from both experiments showed an unusually high density of prismatic dislocation loops. In the mechanically-tested samples, a high density of loops was seen in the chisel point fracture zone. In cross sections of highly deformed regions of the electrical test specimens, very high densities, > 1015/cm3, of small, > 10 nm diameter, prismatic loops were observed. In both cases the presence of a high density of prismatic loops shows that a very high density of vacancies was created in the deformation. On the other hand, in both cases the density of dislocations in the deformed areas was relatively low. These results suggest very high incidence of intersecting dislocations creating jogs and subsequently vacancies before exiting the sample.
We demonstrate the evolution of microstructure and deformation associated with the use of electrical methods for evaluating mechanical reliability of patterned interconnects on rigid substrates. Thermomechanical fatigue in aluminum and copper interconnects was induced by means of low frequency (100 Hz), high density (> 10 MA/cm2) alternating currents, which caused cyclic Joule heating and associated thermal expansion strains between the metal lines and oxidized silicon substrate. The failure mechanism involved formation of localized plasticity, which caused topography changes on the free surfaces of the metal, leading to open circuit eventually taking place by melting at a region of severely reduced cross-sectional area. Both aluminum and copper responded to power cycling by deforming in a manner highly dependent upon variations in grain size and orientation. Isolated patches of damage appeared early within individual grains or clusters of grains, as determined by a quasi in situ scanning electron microscopy and automated electron backscatter diffraction measurement. With increased cycling, the extent of damage became more severe and widespread. We document some examples of the types of damage that mechanically confined interconnects exhibited when subjected to thousands of thermal cycles, including growth and re-orientation of grains in a systematic manner. We observed in the case of Al-1Si certain grains increasing by nearly an order of magnitude in size, and reorienting by greater than 30°. The suitability of electrical methods for accelerated testing of mechanical reliability is also discussed.
We demonstrate the potential of X-ray photo-emission electron microscopy (XPEEM) to reveal valence-state images of the spatial distribution and relative concentration of metals in specific oxidation states. Additionally, XPEEM allows X-ray absorption spectra to be extracted from chosen pixel areas of the images. Using an in-house-built XPEEM instrument we show an application of the method in providing valence-state images of complex mineral intergrowths. The image resolution achieved with this instrument of simple design was ∼5 μm and reasonable quality X-ray absorption spectra were extracted from areas of ∼5×5 μm. These initial results suggest that by using commercial XPEEM instruments on 3rd generation, high-brightness synchrotron sources a spatial resolution of 100 nm or better could be achieved, with the ability to extract high-quality X-ray absorption spectra from areas of 0.1 μm2. Given that standard thin sections or polished blocks can be studied by XPEEM, and that each XPEEM image records ∼1000 μm2, XPEEM can be used in conjunction with other analytical methods such as EMPA and TEM-EELS/PEELS.
Andrew F. Read, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK,
Sylvain Gandon, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK,
Sean Nee, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK,
Margaret J. Mackinnon, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK
Pathogen evolution poses the critical challenge for infectious disease management in the twenty-first century. As is already painfully obvious in many parts of the world, the spread of drug-resistant and vaccine-escape (epitope) mutants can impair and even debilitate public and animal health programs. But there may also be another way in which pathogen evolution can erode the effectiveness of medical and veterinary interventions. Virulence- and transmission-related traits are intimately linked to pathogen fitness and are almost always genetically variable in pathogen populations. They can therefore evolve. Moreover, virulence and infectiousness are the target of medical and veterinary interventions. Here, we focus on vaccination and ask whether large-scale immunization programs might impose selection that results in the evolution of more-virulent pathogens.
The word virulence is used in a variety of ways in different disciplines. We take a parasite-centric view as follows. We use “disease severity” (morbidity and/or mortality) to mean the harm to the host following infection. Disease severity is thus a phenotype measured at the whole-organism (host) level that is determined by host genes, parasite genes, environmental effects, and the interaction between those factors. One component of this is virulence, a phenotypic trait of the pathogen whose expression depends on the host. Thus, virulence is the component of disease severity that is due to pathogen genes, and it can be measured only on a given host. We assume no specificity in the interaction between host and pathogen (more-virulent strains are always more virulent, whatever host they infect).
The sex ratios of malaria and related Apicomplexan parasites play a major role in transmission success. Here, we address 2 fundamental issues in the sex ratios of the rodent malaria parasite, Plasmodium chabaudi. First we test the accuracy of empirical methods for estimating sex ratios in malaria parasites, and show that sex ratios made with standard thin smears may overestimate the proportion of female gametocytes. Secondly, we test whether the mortality rate differs between male and female gametocytes, as assumed by sex ratio theory. Conventional application of sex ratio theory to malaria parasites assumes that the primary sex ratio can be accurately determined from mature gametocytes circulating in the peripheral circulation. We stopped gametocyte production with chloroquine in order to study a cohort of gametocytes in vitro. The mortality rate was significantly higher for female gametocytes, with an average half-life of 8 h for female gametocytes and 16 h for male gametocytes.
In theory, the age at which maturation occurs in parasitic nematodes is inversely related to pre-maturational mortality rate, and cross-species data on mammalian nematodes are consistent with this prediction. Immunity is a major source of parasite mortality and parasites stand to gain sizeable fitness benefits through short-term adjustments of maturation time in response to variation in immune-mediated mortality. The effects of thymus-dependent immune responses on maturation in the nematode parasites Strongyloides ratti and Nippostrongylus brasiliensis were investigated using congenitally thymus-deficient (nude) rats. As compared with worms in normal rats, reproductive maturity of parasites (presence of eggs in utero) in nude rats occurred later in S. ratti but earlier in N. brasiliensis. Immune-mediated differences in maturation time were not associated with differences in worm length. Thymus-dependent immunity had no effect on pre-maturational mortality. Results are discussed in relation to theoretical expectations and possible explanations for the observed patterns in parasite maturation.