Evaluation of a system for enhancing mobile telephone communication for people with hearing loss.

Objective: To evaluate a system - "the service" - designed to improve mobile telephone communication for people with hearing loss. Design: Each participant registered online and took an online hearing test using their own mobile telephone held in the position of their choice. The test assessed the combined effects of the telephone, the hearing loss of the participant and the hearing aid of the participant (if worn). The results were stored as a "hearing profile" and used to set up frequency-dependent amplification and multichannel amplitude compression. The signal processing was performed in the telephone network and applied to all calls of the participant. Participants completed four questionnaires about their listening experiences using the telephone, one before using the service, two while using the service and one after using the service. Also, the ability to understand speech was measured using challenging sentences. Study sample: Fifty-three participants with varying degrees of hearing loss. Results: The great majority of participants indicated that call clarity was improved and that listening difficulty was reduced when using the service. Speech intelligibility scores were significantly improved when using the service. Conclusions: The service appears to be effective in improving phone communication for people with hearing loss.

Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.

Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8(+) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8(+) T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8(+)  CD45RA(+)  CD27(-) T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8(+) T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8(+) T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8(+) T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.

A global synthesis of survival estimates for microbats.

Accurate survival estimates are needed to construct robust population models, which are a powerful tool for understanding and predicting the fates of species under scenarios of environmental change. Microbats make up 17% of the global mammalian fauna, yet the processes that drive differences in demographics between species are poorly understood. We collected survival estimates for 44 microbat species from the literature and constructed a model to determine the effects of reproductive, feeding and demographic traits on survival. Our trait-based model indicated that bat species which produce more young per year exhibit lower apparent annual survival, as do males and juveniles compared with females and adults, respectively. Using 8 years of monitoring data for two Australian species, we demonstrate how knowledge about the effect of traits on survival can be incorporated into Bayesian survival analyses. This approach can be applied to any group and is not restricted to bats or even mammals. The incorporation of informative priors based on traits can allow for more timely construction of population models to support management decisions and actions.

Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA.

The mechanisms regulating memory CD8(+) T cell function and homeostasis during aging are unclear. CD8(+) effector memory T cells that re-express CD45RA increase considerably in older humans and both aging and persistent CMV infection are independent factors in this process. We used MHC class I tetrameric complexes that were mutated in the CD8 binding domain to identify CMV-specific CD8(+) T cells with high Ag-binding avidity. In individuals who were HLA-A*0201, CD8(+) T cells that expressed CD45RA and were specific for the pp65 protein (NLVPMVATV epitope) had lower avidity than those that expressed CD45RO and demonstrated decreased cytokine secretion and cytolytic potential after specific activation. Furthermore, low avidity NLVPMVATV-specific CD8(+) T cells were significantly increased in older individuals. The stimulation of blood leukocytes with CMV lysate induced high levels of IFN-α that in turn induced IL-15 production. Moreover, the addition of IL-15 to CD45RA(-)CD45RO(+) CMV-specific CD8(+) T cells induced CD45RA expression while Ag activated cells remained CD45RO(+). This raises the possibility that non-specific cytokine-driven accumulation of CMV-specific CD8(+)CD45RA(+) T cells with lower Ag-binding avidity may exacerbate the effects of viral reactivation on skewing the T cell repertoire in CMV-infected individuals during aging.

Tree-hugging koalas demonstrate a novel thermoregulatory mechanism for arboreal mammals.

How climate impacts organisms depends not only on their physiology, but also whether they can buffer themselves against climate variability via their behaviour. One of the way species can withstand hot temperatures is by seeking out cool microclimates, but only if their habitat provides such refugia. Here, we describe a novel thermoregulatory strategy in an arboreal mammal, the koala Phascolarctos cinereus. During hot weather, koalas enhanced conductive heat loss by seeking out and resting against tree trunks that were substantially cooler than ambient air temperature. Using a biophysical model of heat exchange, we show that this behaviour greatly reduces the amount of heat that must be lost via evaporative cooling, potentially increasing koala survival during extreme heat events. While it has long been known that internal temperatures of trees differ from ambient air temperatures, the relevance of this for arboreal and semi-arboreal mammals has not previously been explored. Our results highlight the important role of tree trunks as aboveground 'heat sinks', providing cool local microenvironments not only for koalas, but also for all tree-dwelling species.

Hypersalinity reduces the risk of cyanide toxicosis to insectivorous bats interacting with wastewater impoundments at gold mines.

Wildlife and livestock that ingest bioavailable cyanide compounds in gold mining tailings dams are known to experience cyanide toxicosis. Elevated levels of salinity in open impoundments have been shown to prevent wildlife cyanide toxicosis by reducing drinking and foraging. This finding appears to be consistent for diurnal wildlife interacting with open impoundments, however the risks to nocturnal wildlife of cyanide exposure are unknown. We investigated the activity of insectivorous bats in the airspace above both fresh (potable to wildlife) and saline water bodies at two gold mines in the goldfields of Western Australian. During this study, cyanide-bearing solutions stored in open impoundments at both mine sites were hypersaline (range=57,000-295,000 mg/L total dissolved solids (TDS)), well above known physiological tolerance of any terrestrial vertebrate. Bats used the airspace above each water body monitored, but were more active at fresh than saline water bodies. In addition, considerably more terminal echolocation buzz calls were recorded in the airspace above fresh than saline water bodies at both mine sites. However, it was not possible to determine whether these buzz calls corresponded to foraging or drinking bouts. No drinking bouts were observed in 33 h of thermal video footage recorded at one hypersaline tailings dam, suggesting that this water is not used for drinking. There is no information on salinity tolerances of bats, but it could be assumed that bats would not tolerate salinity in drinking water at concentrations greater than those documented as toxic for saline-adapted terrestrial wildlife. Therefore, when managing wastewater impoundments at gold mines to avoid wildlife mortalities, adopting a precautionary principle, bats are unlikely to drink solutions at salinity levels ≥50,000 mg/L TDS.

A light-exploiting insectivorous bat shows no melatonin disruption under lights with different spectra.

Natural light-dark cycles synchronize an animal's internal clock with environmental conditions. The introduction of artificial light into the night-time environment masks natural light cues and has the potential to disrupt this well-established biological rhythm. Nocturnal animal species, such as bats, are adapted to low light conditions and are therefore among the most vulnerable to the impacts of artificial light at night (ALAN). The behaviour and activity of insectivorous bats is disrupted by short-wavelength artificial light at night, while long-wavelength light is less disruptive. However, the physiological consequences of this lighting have not been investigated. Here, we examine the effect of LEDs with different spectra on urinary melatonin in an insectivorous bat. We collected voluntarily voided urine samples from Gould's wattled bats (Chalinolobus gouldii) and measured melatonin-sulfate under ambient night-time conditions (baseline) and under red (λP 630 nm), amber (λP 601 nm), filtered warm white (λP 586 nm) and cool white (λP 457 nm) LEDs. We found no effect of light treatment on melatonin-sulfate irrespective of spectra. Our findings suggest that short-term exposure to LEDs at night do not disrupt circadian physiology in the light-exploiting Gould's wattled bat.

Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation.

Background: Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk time period. Methods: We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We derived a model in 270 patients using NONMEM (version 7.5.1) and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and multivariable analysis was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of mean prediction error (PE). Results: We developed a one-compartment base model with a fixed rate absorption constant. Significant covariates in multivariable analysis were postoperative day, hematocrit, transplant type, CYP3A5 genotype, total body weight, and time-varying postoperative day, hematocrit, and CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR -29.3%-70.53%). Conclusion: Postoperative day was the strongest predictor of tacrolimus exposure in the early post-lung transplant period. Future multicenter studies employing intensive sampling to examine a broad set of variables related to critical illness physiology are needed to understand determinants of clearance, volume of distribution and absorption in this population.

Cytomegalovirus infection reduces telomere length of the circulating T cell pool.

Short telomeres of circulating leukocytes are a risk factor for age-related diseases, such as atherosclerosis, but the exact mechanisms generating variations in telomere length are unknown. We hypothesized that induction of differentiated T cells during chronic CMV infection would affect T cell telomere length. To test this, we measured the amount of differentiated T cells and telomere length of lymphocytes during primary CMV infection as well as CMV-seropositive and -seronegative healthy individuals. After primary CMV infection, we observed an increase in highly differentiated cells that coincided with a steep drop in telomere length. Moreover, we found in a cohort of 159 healthy individuals that telomere shortening was more rapid in CMV-seropositive individuals and correlated with the amount of differentiated T cells in both CD4(+) T cells and CD8(+) T cells. Finally, we found that telomere length measured in blood leukocytes is correlated with lymphocyte telomere length. Thus, CMV infection induces a strong decrease in T cell telomere length, which can be explained by changes in the composition of the circulating lymphocyte pool.

KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells.

Highly differentiated CD8+CD28-CD27- T cells have short telomeres, defective telomerase activity, and reduced capacity for proliferation, indicating that they are close to replicative senescence. In addition, these cells express increased levels of the senescence-associated inhibitory receptor KLRG1 and have poor capacity for IL-2 synthesis and defective Akt (ser(473)) phosphorylation after activation. It is not known whether signaling via KLRG1 contributes to any of the attenuated differentiation-related functional changes in CD8+ T cells. To address this, we blocked KLRG1 signaling during T-cell receptor activation using antibodies against its major ligand, E-cadherin. This resulted in a significant enhancement of Akt (ser(473)) phosphorylation and T-cell receptor-induced proliferative activity of CD8+CD28-CD27- T cells. Furthermore, the increase of proliferation was directly linked to the Akt-mediated induction of cyclin D and E and reduction in the cyclin inhibitor p27 expression. In contrast, the reduced telomerase activity in highly differentiated CD8+CD28(-)CD27- T cells was not altered by KLRG1 blockade, indicating the involvement of other mechanisms. This is the first demonstration of a functional role for KLRG1 in primary human CD8+ T cells and highlights that certain functional defects that arise during progressive T-cell differentiation toward replicative senescence are maintained actively by inhibitory receptor signaling.

Report from the second cytomegalovirus and immunosenescence workshop.

The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vaccination. This commentary summarizes the major findings of these presentations and references subsequently published work from the presenter laboratory where appropriate and draws together major themes that were subsequently discussed along with new areas of interest that were highlighted by this discussion.

Predictions of U.K. regulated power station contributions to regional air pollution and deposition: a model comparison exercise.

Contributions of the emissions from a U.K. regulated fossil-fuel power station to regional air pollution and deposition are estimated using four air quality modeling systems for the year 2003. The modeling systems vary in complexity and emphasis in the way they treat atmospheric and chemical processes, and include the Community Multiscale Air Quality (CMAQ) modeling system in its versions 4.6 and 4.7, a nested modeling system that combines long- and short-range impacts (referred to as TRACK-ADMS [Trajectory Model with Atmospheric Chemical Kinetics-Atmospheric Dispersion Modelling System]), and the Fine Resolution Atmospheric Multi-pollutant Exchange (FRAME) model. An evaluation of the baseline calculations against U.K. monitoring network data is performed. The CMAQ modeling system version 4.6 data set is selected as the reference data set for the model footprint comparison. The annual mean air concentration and total deposition footprints are summarized for each modeling system. The footprints of the power station emissions can account for a significant fraction of the local impacts for some species (e.g., more than 50% for SO2 air concentration and non-sea-salt sulfur deposition close to the source) for 2003. The spatial correlation and the coefficient of variation of the root mean square error (CVRMSE) are calculated between each model footprint and that calculated by the CMAQ modeling system version 4.6. The correlation coefficient quantifies model agreement in terms of spatial patterns, and the CVRMSE measures the magnitude of the difference between model footprints. Possible reasons for the differences between model results are discussed. Finally, implications and recommendations for the regulatory assessment of the impact of major industrial sources using regional air quality modeling systems are discussed in the light of results from this case study.

Low-Cost Automated Flight Intercept Trap for the Temporal Sub-Sampling of Flying Insects Attracted to Artificial Light at Night.

Sampling methods are selected depending on the targeted species or the spatial and temporal requirements of the study. However, most methods for passive sampling of flying insects have a poor temporal resolution because it is time-consuming, costly and/or logistically difficult to perform. Effective sampling of flying insects attracted to artificial light at night (ALAN) requires sampling at user-defined time points (nighttime only) across well-replicated sites resulting in major time and labor-intensive survey effort or expensive automated technologies. Described here is a low-cost automated intercept trap that requires no specialist equipment or skills to construct and operate, making it a viable option for studies that require temporal sub-sampling across multiple sites. The trap can be used to address a wide range of other ecological questions that require a greater temporal and spatial scale than is feasible with previous trap technology.

Assessment of downstream effectors of BCR/ABL protein tyrosine kinase using combined proteomic approaches.

Leukaemic transformation is frequently associated with the aberrant activity of a protein tyrosine kinase (PTK). As such it is of clinical relevance to be able to map the effects of these leukaemogenic PTKs on haemopoietic cells at the level of phosphorylation modulation. In this paradigm study we have employed a range of proteomic approaches to analyse the effects of one such PTK, BCR/ABL. We have employed phosphoproteome enrichment techniques allied to peptide and protein quantification to identify proteins and pathways involved in cellular transformation. Amongst the proteins shown to be regulated at the post-translational level were cofilin, an actin-severing protein thus linked to altered motility and Cbl an E3 ubiquitin ligase integrally linked to the control of tyrosine kinase signalling (regulated by 5 and 6 PTKs respectively). The major class of proteins identified however were molecular chaperones. We also showed that HSP90 phosphorylation is altered by BCR/ABL action and that HSP90 plays a crucial role in oncogene stability. Further investigation with another six leukaemogenic PTKs demonstrates that this HSP90 role in oncogene stability appears to be a common phenomenon in a range of leukaemias. This opens up the potential opportunity to treat different leukaemias with HSP90 inhibitors.

Eight-channel iTRAQ enables comparison of the activity of six leukemogenic tyrosine kinases.

There are a number of leukemogenic protein-tyrosine kinases (PTKs) associated with leukemic transformation. Although each is linked with a specific disease their functional activity poses the question whether they have a degree of commonality in their effects upon target cells. Exon array analysis of the effects of six leukemogenic PTKs (BCR/ABL, TEL/PDGFRbeta, FIP1/PDGFRalpha, D816V KIT, NPM/ALK, and FLT3ITD) revealed few common effects on the transcriptome. It is apparent, however, that proteome changes are not directly governed by transcriptome changes. Therefore, we assessed and used a new generation of iTRAQ tagging, enabling eight-channel relative quantification discovery proteomics, to analyze the effects of these six leukemogenic PTKs. Again these were found to have disparate effects on the proteome with few common targets. BCR/ABL had the greatest effect on the proteome and had more effects in common with FIP1/PDGFRalpha. The proteomic effects of the four type III receptor kinases were relatively remotely related. The only protein commonly affected was eosinophil-associated ribonuclease 7. Five of six PTKs affected the motility-related proteins CAPG and vimentin, although this did not correspond to changes in motility. However, correlation of the proteomics data with that from the exon microarray not only showed poor levels of correlation between transcript and protein levels but also revealed alternative patterns of regulation of the CAPG protein by different oncogenes, illustrating the utility of such a combined approach.

Nest boxes do not cause a shift in bat community composition in an urbanised landscape.

Nest boxes are often used to provide supplementary roosts for cavity-dependent wildlife, but little is known about if they influence faunal community composition. Long-term monitoring of bat boxes in south-eastern Australia indicated that their use was dominated by one generalist species (Chalinolobus gouldii), causing concern that installing bat boxes could cause a shift toward less diverse bat communities. To test this, we conducted a large-scale before-after control-impact experiment at 18 sites, over five years. Sites were either: (1) those with existing bat boxes, (2) those where boxes were added during the study, or (3) controls without boxes. We used echolocation call data from 9035 bat detector nights to compare community composition, diversity, and species' relative activity between the sites. Chalinolobus gouldii continued to dominate the use of existing boxes, but we found little difference in community composition between sites based on the presence, absence, or addition of boxes. Our study is the first to explore the influence installing artificial hollows has on localized faunal assemblages over spatio-temporal scales relevant to management. We conclude that there is cause for optimism that bat boxes might not have perverse outcomes on local community composition in the short- to medium-term, as we had feared.

Ventricular Catheter Tract Hemorrhage as a Risk Factor for Ventriculostomy-Related Infection.

BACKGROUND: Ventriculostomy-related infection (VRI) is a feared complication of external ventricular drain (EVD) placement. Although many contributing factors to VRI have been examined, little is known whether there is an association between ventriculostomy-related catheter tract hemorrhage (VCTH) and VRI. OBJECTIVE: To evaluate risk factors for VRI and assess possible correlations with VCTH. METHODS: We performed a retrospective analysis of patients with EVD placement in a neurocritical care unit between 2011 and 2015. VRI was defined as clinical signs of infection with a positive cerebrospinal fluid gram stain and isolation of cerebrospinal fluid culture. VCTH was diagnosed by computed tomography immediately after EVD insertion. RESULTS: A total of 247 patients with EVD were identified during the 5-yr study period. An association between VCTH and gram-negative VRI was identified (P = .02). Ten percent (25 of 247 patients) developed a VRI, and 7% (18 of 247 patients) had a VCTH. Of the 25 patients with VRI, 20% (n = 5) had a VCTH, compared to 6% (n = 13) of 222 patients who had an EVD placed but did not develop VRI. There were no significant differences in demographic and clinical factors except for multiple EVD insertions (P < .00001), EVD duration (P < .001), and hospital length of stay (P < .001). CONCLUSION: VCTH is a potentially significant risk factor for VRI. Further analysis will be needed to confirm the strength of this association, and to delineate the possible mechanisms by which tract hemorrhage may serve as a nidus for bacterial penetration into the central nervous system.

Factors influencing the risk of wildlife cyanide poisoning on a tailings storage facility in the Eastern Goldfields of Western Australia.

Patterns of wildlife visitation and interaction with cyanide-bearing tailings slurry and solutions at the Fimiston tailings storage facility (TSF) have been reported in a previously published ecological study. The above-mentioned findings are extended in this paper by the examination of additional wildlife survey data, along with process water chemistry data collected during the same study period. Analysis of the combined results revealed that the primary wildlife protective mechanism in operation was effective management of tailings cyanide concentration. Nevertheless, tailings discharge concentration exceeded the industry standard wildlife protective limit of 50mg/L weak acid dissociable (WAD) cyanide episodically during the study period. Wildlife that interacted with habitats close to the spigot outlet during brief periods of increased discharge concentration were likely to have been exposed to bioavailable cyanide at concentrations greater than the industry standard protective limit. However, no wildlife deaths were recorded. These results appear to support the hypothesis that hypersalinity of process solutions (unique to the Kalgoorlie district of Western Australia) and a lack of aquatic food resources represent secondary protective mechanisms that operated to prevent cyanide-related wildlife mortality during the project. The proposed protective mechanisms are discussed in the context of their potential application as proactive management procedures to minimise wildlife exposure to cyanide.

The EMCOOLs surface cooling system for fever control in neurocritical care patients: A pilot study.

OBJECTIVES: Fever occurs in up to 50% of critically-ill patients with acute neurological injury. Small temperature elevations have been correlated with increased morbidity and mortality in this patient population. We sought to evaluate a novel single-use surface cooling system for the treatment of fever in patients with acute brain injury. PATIENTS AND METHODS: We conducted a retrospective analysis of a prospective product evaluation using the EMCOOLS Flex.Pad™ system for acute fever (≥38.3 °C) in our 16-bed neuro-ICU. Four refrigerated pads (-18 °C) were applied to the chest, back, and anterior thighs. Core temperature (bladder) was continuously recorded over 4 h, and the highest Bedside Shivering Assessment Scale (BSAS) score was recorded hourly. RESULTS: Twelve subjects were included in the analysis. Mean age was 55 ±â€¯9 years, 9 patients were men, and mean weight was 85 ±â€¯12 kg. The most common primary diagnoses were subarachnoid (N = 5) and intracerebral (N = 4) hemorrhage. Application of the EMCOOLS system resulted in a linear 1.3 ±â€¯0.6 °C drop (T0avg = 38.9 °C, T90avg = 37.6 °C, P = 0.0032) in mean temperature over 90 min, followed by a plateau with only one subject rebounding to >38 °C within 4 h. Normothermia (<38.0 °C) was achieved in all but one patient (92%) in an average of 65 min. Comatose patients displayed a non-significantly higher degree of cooling at 90 min than did awake subjects (ΔTcoma = 1.74 °C vs ΔTawake = 0.74 °C hr-1, P = 0.067). There was no observed skin irritation upon removal of the device for any patients. CONCLUSION: The EMCOOLs system is a well-tolerated, safe and effective short-term intervention for control of fever in neurological patients. Future studies are needed to compare efficacy of the EMCOOLs to other devices and interventions.