Pediatric cardiopulmonary resuscitation (CPR) for >20 minutes has been considered futile after pediatric in-hospital cardiac arrests. This concept has recently been questioned, although the effect of ...CPR duration on outcomes has not recently been described. Our objective was to determine the relationship between CPR duration and outcomes after pediatric in-hospital cardiac arrests.
We examined the effect of CPR duration for pediatric in-hospital cardiac arrests from the Get With The Guidelines-Resuscitation prospective, multicenter registry of in-hospital cardiac arrests. We included 3419 children from 328 U.S. and Canadian Get With The Guidelines-Resuscitation sites with an in-hospital cardiac arrest between January 2000 and December 2009. Patients were stratified into 5 patient illness categories: surgical cardiac, medical cardiac, general medical, general surgical, and trauma. Survival to discharge was 27.9%, but only 19.0% of all cardiac arrest patients had favorable neurological outcomes. Between 1 and 15 minutes of CPR, survival decreased linearly by 2.1% per minute, and rates of favorable neurological outcome decreased by 1.2% per minute. Adjusted probability of survival was 41% for CPR duration of 1 to 15 minutes and 12% for >35 minutes. Among survivors, favorable neurological outcome occurred in 70% undergoing <15 minutes of CPR and 60% undergoing CPR >35 minutes. Compared with general medical patients, surgical cardiac patients had the highest adjusted odds ratios for survival and favorable neurological outcomes, 2.5 (95% confidence interval, 1.8-3.4) and 2.7 (95% confidence interval, 2.0-3.9), respectively.
CPR duration was independently associated with survival to hospital discharge and neurological outcome. Among survivors, neurological outcome was favorable for the majority of patients. Performing CPR for >20 minutes is not futile in some patient illness categories.
Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1–4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This ...first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors.
Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8–200 mg futibatinib three times a week (t.i.w.) or 4–24 mg once daily (q.d.).
A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure–response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2), and stable disease in 41 (48%).
Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D.
FOENIX-101 (ClinicalTrials.gov, NCT02052778).
•This is a first-in-human phase I dose-escalation trial of futibatinib, a highly selective, irreversible fibroblast growth factor receptor (FGFR)1–4 inhibitor.•Futibatinib showed tolerability and preliminary efficacy in patients with heavily pretreated advanced solid tumors.•A dose of 20 mg once-daily continuous futibatinib was selected as the phase II recommended dose.•Futibatinib is being investigated in ongoing phase II/III trials in patients with advanced cancers harboring FGFR aberrations.
Besides care for injured US military personnel, doctrine also requires life-, limb-, and eyesight-saving care to all injured casualties, including children. This study's objective was to evaluate the ...burden and epidemiology of pediatric medical care during the past decade of military operations in Iraq and Afghanistan.
Retrospective review of two military registries of all patients admitted to combat support hospitals and forward surgical teams from 2001 through 2011 was conducted. Pediatric (PED) patients were defined as younger than 18 years. Adult patients were divided into local civilian/noncoalition military (LOCAL) and coalition (COALITION) soldiers.
A total of 7,505 PED patients, 25,459 LOCAL adults, and 95,618 COALITION soldiers were analyzed in the primary registry. Children represented 5.8% of all admissions (11% bed days), LOCAL adults represented 20% (36% bed days), and COALITION soldiers represented 74% (53% bed days). PED median (interquartile range) length of stay was 3 days (1-7 days), longer than LOCAL with 2 days (1-6 days), and COALITION with 1 day (1-2 days) (p < 0.001). PED Injury Severity Score (ISS) was 9 (4-16), similar to LOCAL with 9 (4-16) but higher than COALITION with 5 (2-10) (p < 0.001). Mortality in trauma patients was highest in PED (8.5%) compared with LOCAL (7.1%) and COALITION (3%) (p < 0.01). Mechanisms of injury for PED trauma were blast (37%), penetrating (27%), blunt (23%), and burn (13%). Factors independently associated with PED mortality included ISS (odds ratio, 95% confidence interval) (1.08, 1.06-1.09), Glasgow Coma Scale (GCS) score (0.85, 0.82-0.88), base excess (0.87, 0.85-0.90), female sex (1.73, 1.18-2.52), age less than 8 years (1.43, 1.00-2.04), and burns (3.17, 1.89-5.32).
Deployed medical facilities not staffed or equipped to typical civilian standards have a high burden of pediatric casualties requiring care. The cause of increased mortality in pediatric versus adult populations despite similar severity of injury is potentially multifactorial. Military medical planners need to consider pediatric resources and training to improve outcomes for children injured during combat.
Epidemiologic study, level III.
The selection of a DNA aptamer through the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method involves multiple binding steps, in which a target and a library of randomized DNA ...sequences are mixed for selection of a single, nucleotide-specific molecule. Usually, 10 to 20 steps are required for SELEX to be completed. Throughout this process it is necessary to discriminate between true DNA aptamers and unspecified DNA-binding sequences. Thus, a novel machine learning-based approach was developed to support and simplify the early steps of the SELEX process, to help discriminate binding between DNA aptamers from those unspecified targets of DNA-binding sequences. An Artificial Intelligence (AI) approach to identify aptamers were implemented based on Natural Language Processing (NLP) and Machine Learning (ML). NLP method (CountVectorizer) was used to extract information from the nucleotide sequences. Four ML algorithms (Logistic Regression, Decision Tree, Gaussian Naïve Bayes, Support Vector Machines) were trained using data from the NLP method along with sequence information. The best performing model was Support Vector Machines because it had the best ability to discriminate between positive and negative classes. In our model, an Accuracy (A) of 0.995, the fraction of samples that the model correctly classified, and an Area Under the Receiving Operating Curve (AUROC) of 0.998, the degree by which a model is capable of distinguishing between classes, were observed. The developed AI approach is useful to identify potential DNA aptamers to reduce the amount of rounds in a SELEX selection. This new approach could be applied in the design of DNA libraries and result in a more efficient and faster process for DNA aptamers to be chosen during SELEX.
•Multiaxial models can be successfully adapted to estimate fretting fatigue life.•New data for Ti-6Al-4V cylinder/plane contact to evaluate wear-based life analysis.•Critical distance/plane method ...yields accurate estimates of fretting fatigue life.•Inclusion of wear in the modeling did not significantly improved the life estimates.•Elastic-plastic analysis of AA6201-T81 contacting wires improves life estimates.
The aim of this work is to show that multiaxial fatigue modeling can be successfully adapted to estimate crack initiation life of mechanical assemblies under fretting conditions. The paper is divided into two parts. In Part I, the focus is on the study of size and gradient effects but considering the influence of incorporating fretting wear on the life estimation procedure. New data for a Ti-6Al-4V cylindrical on plane contact configuration were produced to assess the analyses. It is shown that critical plane criteria, coupled with a critical distance which varies with life, are capable to provide accurate estimates of fretting fatigue life in the medium high cycle regime. The inclusion of wear in the modeling did not significantly improved the life estimates but increased a lot the computational cost. In Part II, the paper extended this life estimation approach to the contact of wires taken from overhead conductors. Fretting fatigue data of AA1350-H19 wires and new tests on the more resistant AA6201-T81 corroborated the successful use of the life methodology to other materials and applications.
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•Three major rice wastes were valorised through gasification assays.•Chars were characterised for chemical, textural and ecotoxic properties.•Chars and CAC were submitted to Cr(III) ...removal assays.•Chars adsorbed and precipitated more Cr(III) than CAC in the synthetic solution.•Chars precipitated more Cr(III) than CAC in the industrial wastewater.
Blends of rice waste streams were submitted to co-gasification assays. The resulting chars (G1C and G2C) were characterized and used in Cr(III) removal assays from a synthetic solution. A Commercial Activated Carbon (CAC) was used for comparison purposes. The chars were non-porous materials mainly composed by ashes (68.3–92.6% w/w). The influences of adsorbent loading (solid/liquid ratio – S/L) and initial pH in Cr(III) removal were tested. G2C at a S/L of 5 mg L−1 and an initial pH of 4.50 presented an uptake capacity significantly higher than CAC (7.29 and 2.59 mg g−1, respectively). G2C was used in Cr(III) removal assays from an industrial wastewater with Cr(III) concentrations of 50, 100 and 200 mg L−1. Cr(III) removal by precipitation (uptake capacity ranging from 11.1 to 14.9 mg g−1) was more effective in G2C, while adsorption (uptake capacity of 16.1 mg g−1) was the main removal mechanism in CAC.
Papillary thyroid cancer (PTC) is the most common thyroid carcinoma and exhibits an almost uniformly good prognosis, while anaplastic thyroid cancer (ATC) is less frequent and is one of the most ...aggressive cancers usually resistant to conventional treatment. Current hypothesis posits that ATC derives from PTC through the progressive acquisition of a discrete number of genomic alterations and implies that the mutational landscape of ATC resembles that of PTC. However, the clinical behaviour of ATC and PTC is radically different. We decided to address the disconnection between the clinical behaviour of ATC and PTC and the proposed model of the progressive development of ATC from PTC.
We carried out exome sequencing of DNA from 14 ATC specimens including three cases of concomitant ATC and PTC as well as their corresponding normal DNA from 14 patients. The sequencing results were validated using droplet digital PCR. We carried out immunohistochemistry and immunofluorescence studies of the concomitant ATC and PTC cases. In addition, we integrated our sequencing results with the existing TCGA data.
Most of the somatic mutations identified in the ATC component differed from the ones in PTC in the cases of concomitant ATC and PTC. The trunks of the phylogenetic trees representing the somatic mutations were short with long branches. In one case of concomitant PTC and ATC specimens, we observed an infiltration of PTC cells within the ATC component. Moreover, we integrated our results with data obtained from TCGA and observed that the most frequent mutations found in ATC presented high cancer cell fraction values and were significantly different from the PTC ones.
ATC diverge from PTC early in tumour development and both tumour types evolve independently. Our work allows the understanding of the relationship between ATC and PTC facilitating the clinical management of these malignancies.
The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in ...the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase I trials, such as dose–escalation methods or flat versus body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.
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