Evaluating hospital infection control measures for antimicrobial-resistant pathogens using stochastic transmission models: Application to vancomycin-resistant enterococci in intensive care units

Nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) are the cause of significant morbidity and mortality among hospital patients. It is important to be able to assess the efficacy of control measures using data on patient outcomes. In this paper, we describe methods for analysing such data using patient-level stochastic models which seek to describe the underlying unobserved process of transmission. The methods are applied to detailed longitudinal patient-level data on vancomycin-resistant Enterococci from a study in a US hospital with eight intensive care units (ICUs). The data comprise admission and discharge dates, dates and results of screening tests, and dates during which precautionary measures were in place for each patient during the study period. Results include estimates of the efficacy of the control measures, the proportion of unobserved patients colonized with vancomycin-resistant Enterococci, and the proportion of patients colonized on admission. </jats:p

Tracking Holocene palaeostratification and productivity changes in the Western Irish Sea: A multi-proxy record

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.The Western Irish Sea preserves an exceptionally thick (ca. 40 m) Holocene succession that is ideally suited to understanding the pattern of palaeostratification and water mass productivity changes in the region, and their relationship with sea level, sedimentation, and biota. Additionally, the presence of shallow-buried methane provides an opportunity to explore its potential impact on the local pattern of Holocene marine environmental change. Multi-proxy investigation of a cored borehole succession through the Holocene interval tracks changes from mixed to seasonally stratified conditions. In the earliest Holocene (11.2–10 ka), high productivity, mixed water conditions prevailed, with abundant and diverse foraminifera and dominant heterotrophic dinoflagellate cysts. Productivity was probably driven by high nutrient fluxes related to high rates of sedimentation (>1600 cm/kyr), in turn influenced by relatively low sea level and restricted sediment accommodation space across shelf areas to the east of the borehole site (eastern Irish Sea Basin). With rising sea level in the later part of the Early Holocene, the region evolved into a relatively lower productivity mixed water mass system, with significant changes in ecology revealed by dinoflagellate cysts and foraminifera. In the latest Early Holocene and earliest Mid Holocene (ca. 8.4–8.2 ka) a return to higher productivity is signalled by dinoflagellate cyst data; a result of seasonal stratification becoming established, evidenced by sharply increased summer sea surface temperature estimates (typically 16–17 °C) that contrast with an opposite (more positive) trend in δ18O values for benthic foraminifera. Reductions in turbulent mixing associated with stratification might have exacerbated the palaeoecological impact of shallow-buried methane associated with the borehole site, potentially evidenced by a significant change in dominant benthic foraminifera and strong, localised excursions in the benthic δ13C/δ18O record

Evaluation of the health-related quality of life of children in Schistosoma haematobium-endemic communities in Kenya: a cross-sectional study.

BACKGROUND: Schistosomiasis remains a global public health challenge, with 93% of the ~237 million infections occurring in sub-Saharan Africa. Though rarely fatal, its recurring nature makes it a lifetime disorder with significant chronic health burdens. Much of its negative health impact is due to non-specific conditions such as anemia, undernutrition, pain, exercise intolerance, poor school performance, and decreased work capacity. This makes it difficult to estimate the disease burden specific to schistosomiasis using the standard DALY metric. METHODOLOGY/PRINCIPAL FINDINGS: In our study, we used Pediatric Quality of Life Inventory (PedsQL), a modular instrument available for ages 2-18 years, to assess health-related quality of life (HrQoL) among children living in a Schistosoma haematobium-endemic area in coastal Kenya. The PedsQL questionnaires were administered by interview to children aged 5-18 years (and their parents) in five villages spread across three districts. HrQoL (total score) was significantly lower in villages with high prevalence of S. haematobium (-4.0%, p<0.001) and among the lower socioeconomic quartiles (-2.0%, p<0.05). A greater effect was seen in the psychosocial scales as compared to the physical function scale. In moderate prevalence villages, detection of any parasite eggs in the urine was associated with a significant 2.1% (p<0.05) reduction in total score. The PedsQL reliabilities were generally high (Cronbach alphas ≥0.70), floor effects were acceptable, and identification of children from low socioeconomic standing was valid. CONCLUSIONS/SIGNIFICANCE: We conclude that exposure to urogenital schistosomiasis is associated with a 2-4% reduction in HrQoL. Further research is warranted to determine the reproducibility and responsiveness properties of QoL testing in relation to schistosomiasis. We anticipate that a case definition based on more sensitive parasitological diagnosis among younger children will better define the immediate and long-term HrQoL impact of Schistosoma infection

A bi-directional relationship between obesity and health-related quality of life : evidence from the longitudinal AusDiab study

Objective: To assess the prospective relationship between obesity and health-related quality of life, including a novel assessment of the impact of health-related quality of life on weight gain.Design and setting: Longitudinal, national, population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study, with surveys conducted in 1999/2000 and 2004/2005.Participants: A total of 5985 men and women aged 25 years at study entry.Main outcome measure(s): At both time points, height, weight and waist circumference were measured and self-report data on health-related quality of life from the SF-36 questionnaire were obtained. Cross-sectional and bi-directional, prospective associations between obesity categories and health-related quality of life were assessed.Results: Higher body mass index (BMI) at baseline was associated with deterioration in health-related quality of life over 5 years for seven of the eight health-related quality of life domains in women (all P0.01, with the exception of mental health, P&gt;0.05), and six out of eight in men (all P&lt;0.05, with the exception of role-emotional, P=0.055, and mental health, P&gt;0.05). Each of the quality-of-life domains related to mental health as well as the mental component summary were inversely associated with BMI change (all P&lt;0.0001 for women and P0.01 for men), with the exception of vitality, which was significant in women only (P=0.008). For the physical domains, change in BMI was inversely associated with baseline general health in women only (P=0.023).Conclusions: Obesity was associated with a deterioration in health-related quality of life (including both physical and mental health domains) in this cohort of Australian adults followed over 5 years. Health-related quality of life was also a predictor of weight gain over 5 years, indicating a bi-directional association between obesity and health-related quality of life. The identification of those with poor health-related quality of life may be important in assessing the risk of future weight gain, and a focus on health-related quality of life may be beneficial in weight management strategies.<br /

A review of physical supply and EROI of fossil fuels in China

This paper reviews China’s future fossil fuel supply from the perspectives of physical output and net energy output. Comprehensive analyses of physical output of fossil fuels suggest that China’s total oil production will likely reach its peak, at about 230 Mt/year (or 9.6 EJ/year), in 2018; its total gas production will peak at around 350 Bcm/year (or 13.6 EJ/year) in 2040, while coal production will peak at about 4400 Mt/year (or 91.9 EJ/year) around 2020 or so. In terms of the forecast production of these fuels, there are significant differences among current studies. These differences can be mainly explained by different ultimately recoverable resources assumptions, the nature of the models used, and differences in the historical production data. Due to the future constraints on fossil fuels production, a large gap is projected to grow between domestic supply and demand, which will need to be met by increasing imports. Net energy analyses show that both coal and oil and gas production show a steady declining trend of EROI (energy return on investment) due to the depletion of shallow-buried coal resources and conventional oil and gas resources, which is generally consistent with the approaching peaks of physical production of fossil fuels. The peaks of fossil fuels production, coupled with the decline in EROI ratios, are likely to challenge the sustainable development of Chinese society unless new abundant energy resources with high EROI values can be found

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection

Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Goya, María Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

BDNF Facilitates L-LTP Maintenance in the Absence of Protein Synthesis through PKMζ

Late-phase long term potentiation (L-LTP) is thought to be the cellular basis for long-term memory (LTM). While LTM as well as L-LTP is known to depend on transcription and translation, it is unclear why brain-derived neurotrophic factor (BDNF) could sustain L-LTP when protein synthesis is inhibited. The persistently active protein kinase ζ (PKMζ) is the only molecule implicated in perpetuating L-LTP maintenance. Here, in mouse acute brain slices, we show that inhibition of PKMζ reversed BDNF-dependent form of L-LTP. While BDNF did not alter the steady-state level of PKMζ, BDNF together with the L-LTP inducing theta-burst stimulation (TBS) increased PKMζ level even without protein synthesis. Finally, in the absence of de novo protein synthesis, BDNF maintained TBS-induced PKMζ at a sufficient level. These results suggest that BDNF sustains L-LTP through PKMζ in a protein synthesis-independent manner, revealing an unexpected link between BDNF and PKMζ

TRPM2 channel deficiency prevents delayed cytosolic Zn²⁺ accumulation and CA1 pyramidal neuronal death after transient global ischemia

Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn²⁺ level ([Zn²⁺]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn²⁺]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn²⁺]c but abolished the cytosolic Zn²⁺ accumulation during reperfusion as well as ROS-elicited increases in the [Zn²⁺]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn²⁺]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury