Testing the Prognostic Accuracy of the Updated Pediatric Sepsis Biomarker Risk Model

Background

We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort.

Objective

To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort.

Methods

Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system.

Results

Mortality in the test cohort was 13.2%. Using a risk cut-off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62–95), specificity was 75% (68–82), positive predictive value was 34% (22–47), and negative predictive value was 97% (91–99). The area under the receiver operating characteristic curve was 0.81 (0.70–0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47–1.35; p<0.001).

Conclusions

The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system.     

The effect of seasonal drying on sulphate dynamics in streams across southeastern Canada and the northeastern USA

Within the southeast Canada and northeast USA region, a peak in sulphate (SO₄ ^2?) concentration has been reported for some streams following periods of substantial catchment drying during the summer months (ON, Canada; VT, NH and NY, USA). However, it is currently unclear if a SO₄ ^2? response to seasonal drying is widespread across the broader region, or to what extent the level of response varies among catchments. In our study, SO₄ ^2? response to seasonal drying was compared in 20 catchments from 11 locations across southeastern Canada (ON, QC and NS) and northeastern USA (NH, NY, VT, WV and ME). Using long-term monitoring data of stream discharge and chemistry, the number of days for each month of the dry season (# d) when discharge (Q) was below a threshold level (25th percentile; Q₂₅) was calculated for each catchment to give a measure of ‘seasonal dryness’ (# d Q < Q₂₅). A SO₄ ^2? response score (rs) was then calculated for each catchment based on linear regression analysis of # d Q < Q₂₅ versus either the annual SO₄ ^2? concentration, or the residual of annual SO₄ ^2? concentration as a function of time (year). The final rs values for each catchment provided an estimate of the proportion of variation in annual SO₄ ^2? concentration which could be explained by seasonal drying (possible rs range = 0–1). Of the 20 catchments, 13 exhibited some level of a SO₄ ^2? response to seasonal drying (rs = 0.04–0.72) with an additional two catchments exhibiting a SO₄ ^2? response for one or more seasons. SO₄ ^2? response scores were positively related to percent wetland area (w) (rs = 1.000 ? 0.978e^{?0.054* w} , r ² = 0.44) and percent saturated area (sat) (rs = 0.481 ? 0.488e^{?0.101* sat}, r ² = 0.54) indicating that wetlands/saturated areas were an important driver of regional variation in the SO₄ ^2? response to seasonal drying. Our results suggest that any shift towards drier summers as a result of climate change could impact SO₄ ^2? dynamics in a large number of catchments throughout the region.     

Modeled ecohydrological responses to climate change at seven small watersheds in the northeastern United States

A cross‐site analysis was conducted on seven diverse, forested watersheds in the northeastern United States to evaluate hydrological responses (evapotranspiration, soil moisture, seasonal and annual streamflow, and water stress) to projections of future climate. We used output from four atmosphere–ocean general circulation models (AOGCMs; CCSM4, HadGEM2‐CC, MIROC5, and MRI‐CGCM3) included in Phase 5 of the Coupled Model Intercomparison Project, coupled with two Representative Concentration Pathways (RCP 8.5 and 4.5). The coarse resolution AOGCMs outputs were statistically downscaled using an asynchronous regional regression model to provide finer resolution future climate projections as inputs to the deterministic dynamic ecosystem model PnET‐BGC. Simulation results indicated that projected warmer temperatures and longer growing seasons in the northeastern United States are anticipated to increase evapotranspiration across all sites, although invoking CO₂ effects on vegetation (growth enhancement and increases in water use efficiency (WUE)) diminish this response. The model showed enhanced evapotranspiration resulted in drier growing season conditions across all sites and all scenarios in the future. Spruce‐fir conifer forests have a lower optimum temperature for photosynthesis, making them more susceptible to temperature stress than more tolerant hardwood species, potentially giving hardwoods a competitive advantage in the future. However, some hardwood forests are projected to experience seasonal water stress, despite anticipated increases in precipitation, due to the higher temperatures, earlier loss of snow packs, longer growing seasons, and associated water deficits. Considering future CO₂ effects on WUE in the model alleviated water stress across all sites. Modeled streamflow responses were highly variable, with some sites showing significant increases in annual water yield, while others showed decreases. This variability in streamflow responses poses a challenge to water resource management in the northeastern United States. Our analyses suggest that dominant vegetation type and soil type are important attributes in determining future hydrological responses to climate change.     

The fitness of twin mothers: evidence from rural Gambia

We used a longitudinal database from a natural fertility population in rural Gambia to compare the overall fertility of mothers who had given birth to twins at some point in their reproductive history and mothers who had only ever given birth to singletons. We found that twin mothers had shorter birth intervals, higher age‐specific fertility and more surviving children than singleton mothers. This suggests that, despite the considerably higher mortality of twins found in this population, twin mothers have a fitness advantage over singleton mothers, even in the absence of modern medical care. We ran a simple simulation model to estimate the relative fitness of twin and singleton mothers, and found that the model also estimated higher fitness for twin mothers. Further, girls who went on to become twin mothers were of higher anthropometric status during their teenage years than those who became singleton mothers.     

Dissolved organic nitrogen budgets for upland, forested ecosystems in New England

Relatively high deposition ofnitrogen (N) in the northeastern United States hascaused concern because sites could become N saturated.In the past, mass-balance studies have been used tomonitor the N status of sites and to investigate theimpact of increased N deposition. Typically, theseefforts have focused on dissolved inorganic forms ofN (DIN = NH₄-N + NO₃-N) and have largelyignored dissolved organic nitrogen (DON) due todifficulties in its analysis. Recent advances in themeasurement of total dissolved nitrogen (TDN) havefacilitated measurement of DON as the residual of TDN– DIN. We calculated DON and DIN budgets using data onprecipitation and streamwater chemistry collected from9 forested watersheds at 4 sites in New England. TDNin precipitation was composed primarily of DIN. Netretention of TDN ranged from 62 to 89% (4.7 to 10 kgha^{minus 1} yr^{minus 1}) of annual inputs. DON made up themajority of TDN in stream exports, suggesting thatinclusion of DON is critical to assessing N dynamicseven in areas with large anthropogenic inputs of DIN.Despite the dominance of DON in streamwater,precipitation inputs of DON were approximately equalto outputs. DON concentrations in streamwater did notappear significantly influenced by seasonal biologicalcontrols, but did increase with discharge on somewatersheds. Streamwater NO₃-N was the onlyfraction of N that exhibited a seasonal pattern, withconcentrations increasing during the winter months andpeaking during snowmelt runoff. Concentrations ofNO₃-N varied considerably among watersheds andare related to DOC:DON ratios in streamwater. AnnualDIN exports were negatively correlated withstreamwater DOC:DON ratios, indicating that theseratios might be a useful index of N status of uplandforests.     

Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling

Unrepaired or inaccurately repaired DNA damage can lead to a range of cell fates, such as apoptosis, cellular senescence or cancer, depending on the efficiency and accuracy of DNA damage repair and on the downstream DNA damage signalling. DNA damage repair and signalling have been studied and modelled in detail separately, but it is not yet clear how they integrate with one another to control cell fate. In this study, we have created an integrated stochastic model of DNA damage repair by non-homologous end joining and of gamma irradiation-induced cellular senescence in human cells that are not apoptosis-prone. The integrated model successfully explains the changes that occur in the dynamics of DNA damage repair after irradiation. Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model. Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence. The integrated model is valuable for studying the processes of DNA damage induced cell fate and predicting the effectiveness of DNA damage related medical interventions at the cellular level.