OBJECTIVES:Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We ...sought to determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock.
DESIGN:Retrospective observational study.
SETTING:PICU at an academic medical center.
PATIENTS:One hundred thirty patients treated for severe sepsis or septic shock.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure–free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74–277 min) and to first appropriate antimicrobial was 177 minutes (90–550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27–12.06) and 3.59 (95% CI, 1.09–11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45–16.2) and 4.92 (95% CI, 1.30–18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure–free days (16 interquartile range, 1–23 vs 20 interquartile range, 6–26; p = 0.04).
CONCLUSIONS:Delayed antimicrobial therapy was an independent risk factor for mortality and prolonged organ dysfunction in pediatric sepsis.
ABSTRACT We sort 4683 molecular clouds between 10° < < 65° from the Bolocam Galactic Plane Survey based on observational diagnostics of star formation activity: compact 70 m sources, mid-IR ...color-selected YSOs, H2O and CH3OH masers, and UCH ii regions. We also present a combined NH3-derived gas kinetic temperature and H2O maser catalog for 1788 clumps from our own GBT 100 m observations and from the literature. We identify a subsample of 2223 (47.5%) starless clump candidates (SCCs), the largest and most robust sample identified from a blind survey to date. Distributions of flux density, flux concentration, solid angle, kinetic temperature, column density, radius, and mass show strong (>1 dex) progressions when sorted by star formation indicator. The median SCC is marginally subvirial ( ∼ 0.7) with >75% of clumps with known distance being gravitationally bound ( < 2). These samples show a statistically significant increase in the median clump mass of ΔM ∼ 170-370 M from the starless candidates to clumps associated with protostars. This trend could be due to (i) mass growth of the clumps at M ˙ ∼ 200 - 440 M Myr−1 for an average freefall 0.8 Myr timescale, (ii) a systematic factor of two increase in dust opacity from starless to protostellar phases, and/or (iii) a variation in the ratio of starless to protostellar clump lifetime that scales as ∼M−0.4. By comparing to the observed number of CH3OH maser containing clumps, we estimate the phase lifetime of massive (M > 103 M ) starless clumps to be 0.37 0.08 Myr (M/103 M )−1; the majority (M < 450 M ) have phase lifetimes longer than their average freefall time.
Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic ...alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.
We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.
We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60years, gender ratio was 1:1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, and ALK=0%. In the entire cohort, median PFS was 2.8months, OS 13.3months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).
: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The type II polyproline helix (PPII) is a fundamental secondary structure of proteins, important in globular proteins, in intrinsically disordered proteins, and at protein‐protein interfaces. PPII is ...stabilized in part by n→π* interactions between consecutive carbonyls, via electron delocalization between an electron‐donor carbonyl lone pair (n) and an electron‐acceptor carbonyl (π*) on the subsequent residue. We previously demonstrated that changes to the electronic properties of the acyl donor can predictably modulate the strength of n→π* interactions, with data from model compounds, in solution in chloroform, in the solid state, and computationally. Herein, we examined whether the electronic properties of acyl capping groups could modulate the stability of PPII in peptides in water. In X−PPGY‐NH2 peptides (X=10 acyl capping groups), the effect of acyl group identity on PPII was quantified by circular dichroism and NMR spectroscopy. Electron‐rich acyl groups promoted PPII relative to the standard acetyl (Ac−) group, with the pivaloyl and iso‐butyryl groups most significantly increasing PPII. In contrast, acyl derivatives with electron‐withdrawing substituents and the formyl group relatively disfavored PPII. Similar results, though lesser in magnitude, were also observed in X−APPGY‐NH2 peptides, indicating that the capping group can impact PPII conformation at both proline and non‐proline residues. The pivaloyl group was particularly favorable in promoting PPII. The effects of acyl capping groups were further analyzed in X–DfpPGY‐NH2 and X−ADfpPGY‐NH2 peptides, Dfp=4,4‐difluoroproline. Data on these peptides indicated that acyl groups induced order Piv‐ > Ac‐ > For‐. These results suggest that greater consideration should be given to the identity of acyl capping groups in inducing structure in peptides.
The polyproline II helix (PPII) is stabilized by n→π* interactions. The ability to tune PPII structure in water via changes in the electronic properties of the acyl capping group is demonstrated herein. More electron‐rich acyl capping groups promote PPII, both at proline and non‐proline residues, via stronger n→π* interactions. In contrast, more electron‐poor groups exhibit lower PPII.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Surface Water and Ocean Topography (SWOT) satellite mission planned for launch in 2020 will map river elevations and inundated area globally for rivers >100 m wide. In advance of this launch, we ...here evaluated the possibility of estimating discharge in ungauged rivers using synthetic, daily “remote sensing” measurements derived from hydraulic models corrupted with minimal observational errors. Five discharge algorithms were evaluated, as well as the median of the five, for 19 rivers spanning a range of hydraulic and geomorphic conditions. Reliance upon a priori information, and thus applicability to truly ungauged reaches, varied among algorithms: one algorithm employed only global limits on velocity and depth, while the other algorithms relied on globally available prior estimates of discharge. We found at least one algorithm able to estimate instantaneous discharge to within 35% relative root‐mean‐squared error (RRMSE) on 14/16 nonbraided rivers despite out‐of‐bank flows, multichannel planforms, and backwater effects. Moreover, we found RRMSE was often dominated by bias; the median standard deviation of relative residuals across the 16 nonbraided rivers was only 12.5%. SWOT discharge algorithm progress is therefore encouraging, yet future efforts should consider incorporating ancillary data or multialgorithm synergy to improve results.
Key Points:
SWOT discharge algorithms were tested on synthetic observations for 19 rivers
Algorithms accurately characterized temporal dynamics of river discharge
At least one algorithm estimated discharge to <35% relative RMSE on 14/16 of nonbraided rivers
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated ...metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer.
Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity.
The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting.
The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal.
Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and ...glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock.
To develop and validate a real-time subclassification method for septic shock.
Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132).
The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval CI95 = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011).
We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
The detection of low-mass transiting exoplanets in multiple systems brings new constraints to planetary formation and evolution processes and challenges the current planet formation theories. ...Nevertheless, only a mere fraction of the small planets detected by Kepler and K2 have precise mass measurements, which are mandatory to constrain their composition. We aim to characterise the planets that orbit the relatively bright star K2-138. This system is dynamically particular as it presents the longest chain known to date of planets close to the 3:2 resonance. We obtained 215 HARPS spectra from which we derived the radial-velocity variations of K2-138. Via a joint Bayesian analysis of both the K2 photometry and HARPS radial-velocities (RVs), we constrained the parameters of the six planets in orbit. The masses of the four inner planets, from b to e, are 3.1, 6.3, 7.9, and 13.0 M⊕ with a precision of 34, 20, 18, and 15%, respectively. The bulk densities are 4.9, 2.8, 3.2, and 1.8 g cm−3, ranging from Earth to Neptune-like values. For planets f and g, we report upper limits. Finally, we predict transit timing variations of the order two to six minutes from the masses derived. Given its peculiar dynamics, K2-138 is an ideal target for transit timing variation (TTV) measurements from space with the upcoming CHaracterizing ExOPlanet Satellite (CHEOPS) to study this highly-packed system and compare TTV and RV masses.
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FMFMET, NUK, UL, UM, UPUK
IMPORTANCE: Emergency medical services (EMS) commonly perform endotracheal intubation (ETI) or insertion of supraglottic airways, such as the laryngeal tube (LT), on patients with out-of-hospital ...cardiac arrest (OHCA). The optimal method for OHCA advanced airway management is unknown. OBJECTIVE: To compare the effectiveness of a strategy of initial LT insertion vs initial ETI in adults with OHCA. DESIGN, SETTING, AND PARTICIPANTS: Multicenter pragmatic cluster-crossover clinical trial involving EMS agencies from the Resuscitation Outcomes Consortium. The trial included 3004 adults with OHCA and anticipated need for advanced airway management who were enrolled from December 1, 2015, to November 4, 2017. The final date of follow-up was November 10, 2017. INTERVENTIONS: Twenty-seven EMS agencies were randomized in 13 clusters to initial airway management strategy with LT (n = 1505 patients) or ETI (n = 1499 patients), with crossover to the alternate strategy at 3- to 5-month intervals. MAIN OUTCOMES AND MEASURES: The primary outcome was 72-hour survival. Secondary outcomes included return of spontaneous circulation, survival to hospital discharge, favorable neurological status at hospital discharge (Modified Rankin Scale score ≤3), and key adverse events. RESULTS: Among 3004 enrolled patients (median interquartile range age, 64 53-76 years, 1829 60.9% men), 3000 were included in the primary analysis. Rates of initial airway success were 90.3% with LT and 51.6% with ETI. Seventy-two hour survival was 18.3% in the LT group vs 15.4% in the ETI group (adjusted difference, 2.9% 95% CI, 0.2%-5.6%; P = .04). Secondary outcomes in the LT group vs ETI group were return of spontaneous circulation (27.9% vs 24.3%; adjusted difference, 3.6% 95% CI, 0.3%-6.8%; P = .03); hospital survival (10.8% vs 8.1%; adjusted difference, 2.7% 95% CI, 0.6%-4.8%; P = .01); and favorable neurological status at discharge (7.1% vs 5.0%; adjusted difference, 2.1% 95% CI, 0.3%-3.8%; P = .02). There were no significant differences in oropharyngeal or hypopharyngeal injury (0.2% vs 0.3%), airway swelling (1.1% vs 1.0%), or pneumonia or pneumonitis (26.1% vs 22.3%). CONCLUSIONS AND RELEVANCE: Among adults with OHCA, a strategy of initial LT insertion was associated with significantly greater 72-hour survival compared with a strategy of initial ETI. These findings suggest that LT insertion may be considered as an initial airway management strategy in patients with OHCA, but limitations of the pragmatic design, practice setting, and ETI performance characteristics suggest that further research is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02419573
IMPORTANCE: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. OBJECTIVE: To determine ...whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. INTERVENTIONS: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). MAIN OUTCOMES AND MEASURES: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 moderate disability or good recovery) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 no disability to 30 death), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. RESULTS: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 74% male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; 90% 1-sided confidence limit for benefit, −0.9%; P = .16; 97.5% 1-sided confidence limit for harm, 10.2%; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, −2.9% 95% CI, −7.9% to 2.1%; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, −0.9 95% CI, −2.5 to 0.7; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, −5.4% 95% CI, −12.8% to 2.1%; P = .16). CONCLUSIONS AND RELEVANCE: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01990768
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