Population Pharmacokinetic Modelling of FE 999049, a Recombinant Human Follicle-Stimulating Hormone, in Healthy Women After Single Ascending Doses

OBJECTIVE: The purpose of this analysis was to develop a population pharmacokinetic model for a novel recombinant human follicle-stimulating hormone (FSH) (FE 999049) expressed from a human cell line of foetal retinal origin (PER.C6(®)) developed for controlled ovarian stimulation prior to assisted reproductive technologies.METHODS: Serum FSH levels were measured following a single subcutaneous FE 999049 injection of 37.5, 75, 150, 225 or 450 IU in 27 pituitary-suppressed healthy female subjects participating in this first-in-human single ascending dose trial. Data was analysed by nonlinear mixed effects population pharmacokinetic modelling in NONMEM 7.2.0.RESULTS: A one-compartment model with first-order absorption and elimination rates was found to best describe the data. A transit model was introduced to describe a delay in the absorption process. The apparent clearance (CL/F) and apparent volume of distribution (V/F) estimates were found to increase with body weight. Body weight was included as an allometrically scaled covariate with a power exponent of 0.75 for CL/F and 1 for V/F.CONCLUSIONS: The single-dose pharmacokinetics of FE 999049 were adequately described by a population pharmacokinetic model. The average drug concentration at steady state is expected to be reduced with increasing body weight

Greenland coastal air temperatures linked to Baffin Bay and Greenland Sea ice conditions during autumn through regional blocking patterns

Variations in sea ice freeze onset and regional sea surface temperatures (SST) in Baffin Bay and Greenland Sea are linked to autumn surface air temperatures (SAT) around coastal Greenland through 500 hPa blocking patterns, 1979-2014. We find strong, statistically significant correlations between Baffin Bay freeze onset and SSTs and SATs across the western and southernmost coastal areas, while weaker and fewer significant correlations are found between eastern SATs, SSTs, and freeze periods observed in the neighboring Greenland Sea. Autumn Greenland Blocking Index (GBI) values and the incidence of meridional circulation patterns have increased over the modern sea ice monitoring era. Increased anticyclonic blocking patterns promote poleward transport of warm air from lower latitudes and local warm air advection onshore from ocean-atmosphere sensible heat exchange through ice-free or thin ice-covered seas bordering the coastal stations. Temperature composites by years of extreme late freeze conditions, occurring since 2006 in Baffin Bay, reveal positive monthly SAT departures that often exceed one standard deviation from the 1981-2010 climate norma

Predicting general and cancer-related distress in women with newly diagnosed breast cancer

Background: Psychological distress can impact medical outcomes such as recovery from surgery and experience of side effects during treatment. Identifying the factors that explain variability in distress would guide future interventions aimed at decreasing distress. Two factors that have been implicated in distress are illness perceptions and coping, and are part of the Self-Regulatory Model of Illness Behaviour (SRM). The model suggests that coping mediates the relationship between illness perceptions and distress. Despite this; very little research has assessed this relationship with cancer-related distress, and none have examined women with screen-detected breast cancer. This study is the first to examine the relative contribution of illness perceptions and coping on general and cancer-related distress in women with screen-detected breast cancer. Methods: Women recently diagnosed with breast cancer (N = 94) who had yet to receive treatment completed measures of illness perceptions (Revised Illness Perception Questionnaire), cancer-specific coping (Mental Adjustment to Cancer Scale), general anxiety and depression (Hospital Anxiety and Depression scale), and cancer-related distress. Results: Hierarchical regression analyses revealed that medical variables, illness perceptions and coping predicted 50% of the variance in depression, 42% in general anxiety, and 40% in cancer-related distress. Believing in more emotional causes to breast cancer (beta = .22, p = .021), more illness identity (beta = .25, p = .004), greater anxious preoccupation (beta = .23, p = .030), and less fighting spirit (beta = -.31, p = .001) predicted greater depression. Greater illness coherence predicted less cancer-related distress (beta = -.20, p = .043). Greater anxious preoccupation also led to greater general anxiety (beta = .44, p < .001) and cancer-related distress (beta = .37, p = .001). Mediation analyses revealed that holding greater beliefs in a chronic timeline, more severe consequences, greater illness identity and less illness coherence increases cancer-specific distress (ps < .001) only if women were also more anxiously preoccupied with their diagnosis. Conclusions: Screening women for anxious preoccupation may help identify women with screen-detected breast cancer at risk of experiencing high levels of cancer-related distress; whilst illness perceptions and coping could be targeted for use in future interventions to reduce distress

Spatial and temporal structure of the Denmark Strait Overflow revealed by acoustic observations

In spite of the fundamental role the Atlantic Meridional Overturning Circulation (AMOC) plays for global climate stability, no direct current measurement of the Denmark Strait Overflow, which is the densest part of the AMOC, has been available until recently that resolve the cross-stream structure at the sill for long periods. Since 1999, an array of bottom-mounted acoustic instruments measuring current velocity and bottom-to-surface acoustic travel times was deployed at the sill. Here, the optimization of the array configuration based on a numerical overflow model is discussed. The simulation proves that more than 80% of the dense water transport variability is captured by two to three acoustic current profilers (ADCPs). The results are compared with time series from ADCPs and Inverted Echo Sounders deployed from 1999 to 2003, confirming that the dense overflow plume can be reliably measured by bottom-mounted instruments and that the overflow is largely geostrophically balanced at the sill

Observing and modelling the high water level from satellite radar altimetry during tropical cyclones

This paper investigates the capability of observing tropical cyclones using satellite radar altimetry. Two representative cyclones Yasi (February 2011) and Larry (March 2006) in the northeast Australian coastal area are selected based also on available tide gauge sea level measurements. It is shown that altimetry data can capture high water levels induced by Larry and Yasi through a careful re-processing and re-editing of the data. About 18 years of data from multi-satellite altimetry missions including TOPEX/Poseidon, Jason-1 and Jason-2, and seven tide gauges around the northern Australian coast are integrated using a multivariate regression approach. The results reveal that the multi-regression model can, in general, explain >60% of sea level variances in the study area. The model is then validated using independent data from tide gauge in Townsville. The comparison results indicate that the high sea levels predicted by the model taken into account of both altimetry and tide gauge data agree well with those observed at Townsville during cyclone Larry