Rapid turnover of T cells in acute infectious mononucleosis.

During acute infectious mononucleosis (AIM), large clones of Epstein-Barr virus-specific T lymphocytes are produced. To investigate the dynamics of clonal expansion, we measured cell proliferation during AIM using deuterated glucose to label DNA of dividing cells in vivo, analyzing cells according to CD4, CD8 and CD45 phenotype. The proportion of labeled CD8(+)CD45R0(+) T lymphocytes was dramatically increased in AIM subjects compared to controls (mean 17.5 versus 2.8%/day; p<0.005), indicating very rapid proliferation. Labeling was also increased in CD4(+)CD45R0(+) cells (7.1 versus 2.1%/day; p<0.01), but less so in CD45RA(+) cells. Mathematical modeling, accounting for death of labeled cells and changing pool sizes, gave estimated proliferation rates in CD8(+)CD45R0(+) cells of 11-130% of cells proliferating per day (mean 47%/day), equivalent to a doubling time of 1.5 days and an appearance rate in blood of about 5 x 10(9) cells/day (versus 7 x 10(7) cells/day in controls). Very rapid death rates were also observed amongst labeled cells (range 28-124, mean 57%/day),indicating very short survival times in the circulation. Thus, we have shown direct evidence for massive proliferation of CD8(+)CD45R0(+) T lymphocytes in AIM and demonstrated that rapid cell division continues concurrently with greatly accelerated rates of cell disappearance

Alaska Volcano Observatory Alert and Forecasting Timeliness: 1989–2017

The Alaska Volcano Observatory (AVO) monitors volcanoes in Alaska and issues notifications and warnings of volcanic unrest and eruption. We evaluate the timeliness and accuracy of eruption forecasts for 53 eruptions at 20 volcanoes, beginning with Mount Redoubt's 1989–1990 eruption. Successful forecasts are defined as those where AVO issued a formal warning before eruption onset. These warning notifications are now part of AVO's Aviation Color Code and Volcanic Alert Level. This analysis considers only the start of an eruption, although many eruptions have multiple phases of activity. For the 21 eruptions at volcanoes with functioning local seismic networks, AVO has high forecasting success at volcanoes with: &gt;15 years repose intervals and magmatic eruptions (4 out of 4, 100%); or larger eruptions (Volcanic Explosivity Index (VEI) 3 or greater; 6 out of 10, 60%). Therefore, AVO successfully forecast all four monitored, longer-repose period, VEI 3+ eruptions: Redoubt 1989–1990 and 2009, Spurr 1992, and Augustine 2005–2006. For volcanoes with functioning seismic monitoring networks, success rates are lower for: volcanoes with shorter repose periods (3 out of 16, 19%); more mafic compositions (3 out of 18, 17%); or smaller eruption size (VEI 2 or less, 1 out of 11, 9%). These eruptions (Okmok, Pavlof, Veniaminof, and Shishaldin) often lack detectable precursory signals. For 32 eruptions at volcanoes without functioning local seismic networks, the forecasting success rate is much lower (2, 6%; Kasatochi 2008 and Shishaldin 2014). For remote volcanoes where the main hazard is to aviation, rapid detection is a goal in the absence of in situ monitoring. Eruption detection has improved in recent years, shown by a decrease in the time between eruption onset and notification. Even limited seismic monitoring can detect precursory activity at volcanoes with certain characteristics (intermediate composition, longer repose times, larger eruptions), but difficulty persists in detecting subtle precursory activity at frequently active volcanoes with more mafic compositions. This suggests that volcano-specific characteristics should be considered when designing monitoring programs and evaluating forecasting success. More proximally-located sensors and data types are likely needed to forecast eruptive activity at frequently-active, more mafic volcanoes that generally produce smaller eruptions

US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with preexisting inflammatory lung disease such as cystic fibrosis(CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition

Hemodynamic Effects of Anthrax Toxins in the Rabbit Model and the Cardiac Pathology Induced by Lethal Toxin

Anthrax lethal toxin (LeTx) and edema toxin (EdTx) have been shown to alter hemodynamics in the rodent model, while LeTx primarily is reported to induce extensive tissue pathology. However, the rodent model has limitations when used for comparison to higher organisms such as humans. The rabbit model, on the other hand, has gained recognition as a useful model for studying anthrax infection and its pathophysiological effects. In this study, we assessed the hemodynamic effects of lethal toxin (LeTx) and edema toxin (EdTx) in the rabbit model using physiologically relevant amounts of the toxins. Moreover, we further examine the pathological effects of LeTx on cardiac tissue. We intravenously injected Dutch-belted rabbits with either low-dose and high-dose recombinant LeTx or a single dose of EdTx. The animals’ heart rate and mean arterial pressure were continuously monitored via telemetry until either 48 or 72 h post-challenge. Additional animals challenged with LeTx were used for cardiac troponin I (cTnI) quantitation, cardiac histopathology, and echocardiography. LeTx depressed heart rate at the lower dose and mean arterial pressure (MAP) at the higher dose. EdTx, on the other hand, temporarily intensified heart rate while lowering MAP. Both doses of LeTx caused cardiac pathology with the higher dose having a more profound effect. Lastly, left-ventricular dilation due to LeTx was not apparent at the given time-points. Our study demonstrates the hemodynamic effects of anthrax toxins, as well as the pathological effects of LeTx on the heart in the rabbit model, and it provides further evidence for the toxins’ direct impact on the heart

Managing for climate resilient fisheries: Applications to the Southern Ocean

Climate change is having profound effects on populations of fished species and the ecosystems on which they depend, lending to a growing body of work that advocates for climate resilience to be a priority in fishery management. Here, we provide a comprehensive analysis of the tools needed to manage for climate resiliency. The Antarctic region is among the most vulnerable to climate change, and thus, we then consider climate resilient management tools utilized by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR), the body responsible for the management of Antarctic marine living resources as part of the Antarctic Treaty System. We note progress, gaps, and opportunities for implementation. Across the literature, ecosystem-based management was cited as an appropriate tool for climate resilience of marine ecosystems, as was the use of climate model outputs (projections and simulations), marine protected areas (MPAs), and dynamic stock assessments. CCAMLR has a unique position where its Convention effectively mandates the principles of an ecosystem-based precautionary approach for managing fisheries, and many of its Member States have been advocating for climate initiatives within this approach. While CCAMLR has made limited overall progress towards ensuring climate resilience, it has advanced in some areas, such as MPA implementation, developing a risk assessment for krill, and including statements on climate change in fishery reports, although there is much work to be done. While climate change remains a worldwide issue that must be addressed on a global scale, CCAMLR holds the responsibility for adaptively managing Southern Ocean marine living resources for climate resilience

Longitudinal variability of time-location/activity patterns of population at different ages: a longitudinal study in California

<p>Abstract</p> <p>Background</p> <p>Longitudinal time-activity data are important for exposure modeling, since the extent to which short-term time-activity data represent long-term activity patterns is not well understood. This study was designed to evaluate longitudinal variations in human time-activity patterns.</p> <p>Method</p> <p>We report on 24-hour recall diaries and questionnaires collected via the internet from 151 parents of young children (mostly under age 55), and from 55 older adults of ages 55 and older, for both a weekday and a weekend day every three months over an 18-month period. Parents also provided data for their children. The self-administrated diary and questionnaire distinguished ~30 frequently visited microenvironments and ~20 activities which we selected to represent opportunities for exposure to toxic environmental compounds. Due to the non-normal distribution of time-location/activity data, we employed generalized linear mixed-distribution mixed-effect models to examine intra- and inter-individual variations. Here we describe variation in the likelihood of and time spent engaging in an activity or being in a microenvironment by age group, day-type (weekday/weekend), season (warm/cool), sex, employment status, and over the follow-up period.</p> <p>Results</p> <p>As expected, day-type and season influence time spent in many location and activity categories. Longitudinal changes were also observed, e.g., young children slept less with increasing follow-up, transit time increased, and time spent on working and shopping decreased during the study, possibly related to human physiological changes with age and changes in macro-economic factors such as gas prices and the economic recession.</p> <p>Conclusions</p> <p>This study provides valuable new information about time-activity assessed longitudinally in three major age groups and greatly expands our knowledge about intra- and inter-individual variations in time-location/activity patterns. Longitudinal variations beyond weekly and seasonal patterns should be taken into account in simulating long-term time-activity patterns in exposure modeling.</p

Key challenges in simulated patient programs: An international comparative case study

<p>Abstract</p> <p>Background</p> <p>The literature on simulated or standardized patient (SP) methodology is expanding. However, at the level of the program, there are several gaps in the literature. We seek to fill this gap through documenting experiences from four programs in Australia, Canada, Switzerland and the United Kingdom. We focused on challenges in SP methodology, faculty, organisational structure and quality assurance.</p> <p>Methods</p> <p>We used a multiple case study method with cross-case synthesis. Over eighteen months during a series of informal and formal interactions (focused meetings and conference presentations) we documented key characteristics of programs and drew on secondary document sources.</p> <p>Results</p> <p>Although programs shared challenges in SP methodology they also experienced differences. Key challenges common to programs included systematic quality assurance and the opportunity for research. There were differences in the terminology used to describe SPs, in their recruitment and training. Other differences reflected local conditions and demands in organisational structure, funding relationships with the host institution and national trends, especially in assessments.</p> <p>Conclusion</p> <p>This international case study reveals similarities and differences in SP methodology. Programs were highly contextualised and have emerged in response to local, institutional, profession/discipline and national conditions. Broader trends in healthcare education have also influenced development. Each of the programs experienced challenges in the same themes but the nature of the challenges often varied widely.</p

Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification

Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcγR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients