bluuebunny/crossref_metadata_2025_split huggingface dataset:
Avelumab in patients with gestational trophoblastic tumors resistant to monochemotherapy: Final outcomes of TROPHIMMUN phase II trial, cohort A.
Authors: You Benoit , Bolze Pierre-Adrien , Lotz Jean-Pierre , Massardier Jerome , Gladieff Laurence , Joly Florence , Hajri Touria , Maucort-Boulch Delphine , Bin Sylvie , Rousset Pascal , Villeneuve Laurent , Roux Adeline , Alves-Ferreira Marine , Grazziotin Daniele , Mercier Catherine , Freyer Gilles , Golfier Francois 
Published: June 2020

LBA6008 Background: Patients with gestational trophoblastic tumors (GTT) resistant to monochemotherapy are treated with historic chemotherapy regimens known to be effective, but toxic. PD-L1 is constitutively expressed in all GTT subtypes (Bolze et al. Int J Gynecol Cancer 2017). HLA-G and natural killer (NK) cells are involved in GTT immune-surveillance. The anti-PD-L1 monoclonal antibody avelumab (Pfizer & Merck KGaA) triggers cytotoxicity through NK cells. The objective of TROPHIMMUN trial was to assess the efficacy of avelumab in patients with chemoresistant GTT. Methods: In the cohort A of this academic multicenter trial (NCT03135769), avelumab was given at 10 mg/kg Q2W in patients with GTT resistant to monochemotherapy. Avelumab was prescribed until hCG normalization, and then for 3 consolidation cycles. The primary objective was the rate of patients with hCG normalization, with a 2 step Simon design. Results: 15 patients (median 34 y old) followed by the French Gestational Trophoblastic Center were treated from Dec 2016 to Sept 2019 (stage I/III: 53%/47%; FIGO score 0-4: 33%; score 5-6: 47%; score >6: 20%). They all had progressed with previous methotrexate, and 1 patient with actinomycin-D. They received median 8 avelumab cycles (range: 2-11). The tolerability was favorable. 93 % of patients developed drug-related grade 1-2 toxicities (86% grade 1), mainly including fatigue (33% patients); nausea-vomiting (33%); infusion-related reactions (27%); thyroid disorder (20%); dry eyes (20%) & diarrhea (20%). A grade 3 uterus bleeding (treatment unrelated) was observed in 1 patient. Median follow-up was 30 months. Successful hCG normalizations were obtained in 8 patients (53%, median 9 avelumab cycles), either during avelumab treatment in 7 patients, or after avelumab discontinuation in 1 patient. None presented relapse afterwards, and 1 patient had a subsequent healthy pregnancy. Avelumab resistances requiring switch to chemotherapy were observed in 7 patients (47%), who normalized hCG with subsequent actinomycin-D (42%), or surgery/polychemotherapy (57%). The likelihood of success with avelumab was not related to the FIGO score, or disease stages. Conclusions: TROPHIMMUN is the first trial of immunotherapy in GTT patients. The anti-PD-L1 monoclonal antibody avelumab was effective, with a favorable safety profile compared to chemotherapy, in patients with resistance to mono-chemotherapy. About 50 % patients could be cured of their chemoresistant diseases. Avelumab may be a new therapeutic option. Clinical trial information: NCT03135769 .
Comparison of atomic force microscopy and zeta potential derived surface charge density
Authors: Herzberg M. , Dobberschütz S. , Okhrimenko D. , Bovet N. E. , Andersson M. P. , Stipp S. L. S. , Hassenkam T. 
Published: June 2020

AbstractSurface charge density can be derived from atomic force microscopy (AFM) by using Derjaguin, Landau, Vervey and Overbeek (DLVO) theory. The sub-micrometer data allows observation of local differences in charge density and changes with time or solution composition, which has interesting applications in crystal growth and inhibition, bone formation and colloid behavior. To calibrate this type of AFM data and verify DLVO assumptions, it has to be correlated with an established technique. We successfully matched AFM derived surface charge densities with zeta potential measurements on a mica surface within one order of magnitude. A reproducible difference between surface charge of the mica substrate exposed to solutions cations with monovalent and divalent charge was also observed. The results provide confidence that the AFM method is valid for obtaining local surface charge information.
Near-Adult Height After Growth Hormone Treatment in Children Born Prematurely—Data From KIGS
Authors: Boguszewski Margaret C S , Carlsson Martin , Lindberg Anders , Dahlgren Jovanna , Aydin Ferah , Camacho-Hübner Cecilia , Hokken-Koelega Anita C S 
Published: June 2020

Abstract

Context
Children born prematurely have been treated with growth hormone (GH), and a significant improvement in height during the first years of treatment has been described.

Objective
To evaluate the influence of prematurity on near-adult height (NAH) after GH treatment.

Design
KIGS (Pfizer International Growth Database) was queried for children born preterm treated with GH.

Setting
KIGS database.

Patients
A total of 586 children short in stature born preterm with various GH status and with available gestational age (GA), birth weight, and NAH, all treated with GH.

Intervention
GH treatment.

Main Outcome Measure
NAH.

Results
Values were expressed as median. From the 586 children included, 482 born appropriate for GA (AGA; median age 8.26 years) and 104 born small for gestational age (SGA) (median age 8.54 years); 66.6% of preterm AGA had GH peak &lt; 7 µg/L during a provocation test, whereas only 8.6% of preterm SGA. Change in height standard deviation scores (SDS) from GH start to NAH after 8.04 years of GH treatment was 1.82 in preterm AGA. Respective values were 7.08 years and 1.08 SDS for preterm SGA (P &lt; 0.001); 57% of the variability of the growth response to NAH could be explained, and the distance to parental height was the strongest predictor. No significant changes in height SDS were observed from puberty start to NAH. No correlation was found with GA. GH treatment was well tolerated.

Conclusion
GH treatment resulted in significant improvement in height in children born preterm, particularly during prepubertal years and for those with GH deficiency. The degree of prematurity did not influence the growth response.
Metformin Biodistribution: A Key to Mechanisms of Action?
Authors: Sundelin Elias , Jensen Jonas Brorson , Jakobsen Steen , Gormsen Lars C , Jessen Niels 
Published: June 2020

Abstract
Metformin has undisputed glucose-lowering effects in diabetes and an impressive safety record. It has also shown promising effects beyond diabetes, and several hundred clinical trials involving metformin are currently planned or active. Metformin targets intracellular effectors, but exactly which remain to be established, and in an era of precision medicine, an incomplete understanding of mechanisms of action may limit the use of metformin. Distribution of metformin depends on specific organic cation transporter proteins that are organ- and species-specific. Therefore, target tissues of metformin can be identified by cellular uptake of the drug, and exploring the biodistribution of the drug in humans becomes an attractive strategy to assist the many investigations into the mechanisms of action of metformin performed in animals. In this review, we combine the emerging evidence from the use of 11C-labeled metformin in humans to discuss metformin action in liver, intestines, and kidney, which are the organs with the most avid uptake of the drug.
Estradiol and Progesterone Levels are Related to Redox Status in the Follicular Fluid During In Vitro Fertilization
Authors: Pizarro Bartira Marques , Cordeiro Aline , Reginatto Mila Weydtt , Campos Samir P C , Mancebo Ana Cristina A , Areas Patricia C F , Antunes Roberto Azevedo , Souza Maria do Carmo Borges , Oliveira Karen Jesus , Bloise Flavia Fonseca , Bloise Enrrico , Fortunato Rodrigo Soares , Ortiga-Carvalho Tania Maria 
Published: June 2020

Abstract
Studies have reported a possible association between the levels of oxidative stress biomarkers in follicular fluid (FF) and infertility treatment outcomes. FF analysis can provide important information about oocyte quality. This study aimed to evaluate the possible correlation between oxidative stress biomarker and intrafollicular hormone levels and clinical and laboratory parameters in women during controlled ovarian stimulation. These women were undergoing in vitro fertilization with intracytoplasmic sperm injection (ICSI).The FF samples were acquired from September 2012 to February 2014 from women undergoing private fertility treatment in Rio de Janeiro, Brazil. A total of 196 women who were undergoing ICSI and had different infertility diagnoses were recruited. The FF from each patient (average patient age of 36.3 ± 4.3 years) was collected following puncture of just one follicle with the largest diameter. After ruling out blood contamination by spectrophotometry, 163 patient samples were utilized in the study. In the FF, the progesterone levels were negatively correlated with (a) hydrogen peroxide scavenging capacity (HPSC) (r = −0.294, P &lt; 0.0001), (b) total number of follicles (r = −0.246, P &lt; 0.001) and (c) total number of oocytes punctured (r = −0.268, P = 0.0001). The concentration of serum estradiol exhibited a positive correlation with intrafollicular HPSC (r = 0.165, P = 0.037). Our data indicate that the FF levels of estradiol and progesterone are related to the FF redox status, which is closely associated with the number of oocytes obtained during ICSI procedures.
Drugs of Abuse and the Nervous System
Authors: Stitt Derek , Kumar Neeraj 
Published: June 2020

ABSTRACTPURPOSE OF REVIEWThis article discusses the neurologic complications of traditional, nontraditional, and emerging drugs of abuse.RECENT FINDINGSThe manufacture, distribution, and use of so-called designer drugs are increasing. These agents can induce dramatic neurologic manifestations and can evade identification on conventional drug-screening assays. Additionally, gabapentinoids, drug agents that are very familiar to neurologists, are being abused in the general population at increasing rates to achieve euphoric highs and potentiate the effects of opiates. Furthermore, even well-known illicit narcotics such as heroin are posing dangers above their baseline because of “lacing” with additives or substitutes such as fentanyl and related compounds. These clandestine agents increase the potency of what are thought to be typical dosages to lethal levels, thus leading to more unintentional overdose deaths.SUMMARYThe potential for short- and long-term nervous system injury from drug abuse is well established. However, it is important for the practicing neurologist to possess awareness of the features and observed sequelae of the toxidromes of both traditional and nontraditional drugs of abuse. This is because the use of both is widespread in our society and conventional drug screening can miss detection of some powerful agents, thus forcing us to maintain a high index of suspicion based on recognition of the clinical features.
The Performance of an Artificial Neural Network Model in Predicting the Early Distribution Kinetics of Propofol in Morbidly Obese and Lean Subjects
Authors: Ingrande Jerry , Gabriel Rodney A. , McAuley Julian , Krasinska Karolina , Chien Allis , Lemmens Hendrikus J. M. 
Published: June 2020

BACKGROUND:
Induction of anesthesia is a phase characterized by rapid changes in both drug concentration and drug effect. Conventional mammillary compartmental models are limited in their ability to accurately describe the early drug distribution kinetics. Recirculatory models have been used to account for intravascular mixing after drug administration. However, these models themselves may be prone to misspecification. Artificial neural networks offer an advantage in that they are flexible and not limited to a specific structure and, therefore, may be superior in modeling complex nonlinear systems. They have been used successfully in the past to model steady-state or near steady-state kinetics, but never have they been used to model induction-phase kinetics using a high-resolution pharmacokinetic dataset. This study is the first to use an artificial neural network to model early- and late-phase kinetics of a drug.

METHODS:
Twenty morbidly obese and 10 lean subjects were each administered propofol for induction of anesthesia at a rate of 100 mg/kg/h based on lean body weight and total body weight for obese and lean subjects, respectively. High-resolution plasma samples were collected during the induction phase of anesthesia, with the last sample taken at 16 hours after propofol administration for a total of 47 samples per subject. Traditional mammillary compartment models, recirculatory models, and a gated recurrent unit neural network were constructed to model the propofol pharmacokinetics. Model performance was compared.

RESULTS:
A 4-compartment model, a recirculatory model, and a gated recurrent unit neural network were assessed. The final recirculatory model (mean prediction error: 0.348; mean square error: 23.92) and gated recurrent unit neural network that incorporated ensemble learning (mean prediction error: 0.161; mean square error: 20.83) had similar performance. Each of these models overpredicted propofol concentrations during the induction and elimination phases. Both models had superior performance compared to the 4-compartment model (mean prediction error: 0.108; mean square error: 31.61), which suffered from overprediction bias during the first 5 minutes followed by under-prediction bias after 5 minutes.

CONCLUSIONS:
A recirculatory model and gated recurrent unit artificial neural network that incorporated ensemble learning both had similar performance and were both superior to a compartmental model in describing our high-resolution pharmacokinetic data of propofol. The potential of neural networks in pharmacokinetic modeling is encouraging but may be limited by the amount of training data available for these models.
Integration of the Intrinsic Surgical Risk With Patient Comorbidities and Severity of Congenital Cardiac Disease Does Not Improve Risk Stratification in Children Undergoing Noncardiac Surgery
Authors: Faraoni David , Zou Xue , DiNardo James A. , Nasr Viviane G. 
Published: June 2020

BACKGROUND:
The objective of this study is to estimate the surgical risk of noncardiac procedures on the incidence of 30-day mortality in children with congenital heart disease.

METHODS:
Children with congenital heart disease undergoing noncardiac surgery from 2012 to 2016 and included in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Pediatric database were included in the derivation cohort, while the 2017 database was used as a validation cohort. Intrinsic surgical risk quartiles were built utilizing 30-day mortality rates for each Current Procedural Terminology code and relative value units to create 2 groups defined as low surgical risk (quartiles 1–3) and high surgical risk procedures (quartile 4). We used multivariable logistic regression to determine the predictors for 30-day mortality including patient comorbidities and intrinsic surgical risk. A partially external validation of the model was performed using the 2017 version of the database.

RESULTS:
We included 37,658 children with congenital heart disease undergoing noncardiac surgery with an incidence of overall 30-day mortality of 1.7% in the derivation cohort and 1.5% in the validation cohort (n = 13,129). Intrinsic surgical risk of procedures represented by Current Procedural Terminology procedural codes and relative value units risk quartiles was significantly associated with 30-day mortality (unadjusted P < .001). Predicted probability of 30-day mortality ranges from 0.2% (95% confidence interval [CI], 0.2–0.2) with no comorbidities to 39.6% (95% CI, 23.2–56.0) when all comorbidities were present among high surgical risk procedures and from 0.3% (95% CI, 0.3–0.3) to 54.8% (95% CI, 39.4–70.1) among low surgical risk procedures. An excellent discrimination was reported for the multivariable model with area under the curve (AUC) of 0.86 (95% CI, 0.85–0.88). High surgical risk was not associated with increased odds of 30-day mortality after adjustment for all other predictors (adjusted odds ratio [OR]: 0.75, 95% CI, 0.62–0.91). We also estimated the discriminative ability of a model that does not include the surgical risk (0.86 [95% CI, 0.84–0.88], with P value for the direct comparison of the AUC of the 2 models = 0.831). The multivariable model obtained from an external validation cohort reported an optimism corrected AUC of 0.88 (95% CI, 0.85–0.91).

CONCLUSIONS:
Our study demonstrates that integration of intrinsic surgical risk to comorbidities and severity of cardiac disease does not improve prediction of 30-day mortality in children undergoing noncardiac surgery. In children with congenital heart disease, patient comorbidities, and severity of the cardiac lesion are the predominant predictors of 30-day mortality.
Anticolonial Uprising and Communal Justice in Twentieth-Century Palestine
Authors: Winder Alex 
Published: June 2020

AbstractThis article examines the strategies, structures, and practices that allowed for the emergence of communities without police institutions during two Palestinian uprisings, the 1936–39 revolt and the 1987–91 intifada. For each period, the article identifies efforts to disengage from and disempower the state police, to establish alternative systems of anticolonial justice, and to employ disciplinary violence to serve the imperatives and enforce the decisions of Palestinian nationalist bodies. In particular, Palestinian systems of anticolonial justice drew on communal reconciliation (sulh) and other preexisting local iterations of communal justice. These local forms relied on discourses of egalitarianism and consensus, which produced stability in periods of upheaval but also obscured the inequalities they reproduced. Ultimately, the anticolonial structures that Palestinians established proved unable to withstand intense internal and external pressure, and some elements of the coercive forces that served them were absorbed into state police institutions.
A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage
Authors: Lupieri Adrien , Blaise Régis , Ghigo Alessandra , Smirnova Natalia , Sarthou Marie-Kerguelen , Malet Nicole , Limon Isabelle , Vincent Pierre , Hirsch Emilio , Gayral Stéphanie , Ramel Damien , Laffargue Muriel 
Published: June 2020

ABSTRACT
Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases.
Does anthropomorphic model design in ex vivo studies affect diagnostic accuracy for dental root fracture using CBCT?
Authors: Andraws Yalda Fedil , Clarkson Rosalyn J , Davies Jonathan , Rout Peter G J , Sengupta Anita , Horner Keith 
Published: June 2020

Objectives: The evidence for diagnostic accuracy using cone beam computed tomography (CBCT) for dental applications depends heavily on ex vivo research, but there is little knowledge of whether the model used affects the diagnostic accuracy results. The objective of this study was to determine the impact of different designs of anthropomorphic models on diagnostic accuracy for the specific task of dental root fracture detection. Methods: Horizontal or oblique root fracture was induced in 24 of 48 permanent maxillary incisors. The 48 teeth were scanned by CBCT using standard clinical exposure factors on five occasions, each with a different model design. Scans were viewed by five dental and maxillofacial radiologists, who each made a forced diagnosis of fracture or no fracture in each root and a judgment on root fracture using a five-point confidence scale. Sensitivity (Se), specificity (Sp) and areas under receiver operating characteristic (ROC) curve (Az) were calculated for each observer for each model. Results: There were no significant differences between the diagnostic accuracy measurements recorded using different models. There were, however, numerous significant differences between observers using the same anthropomorphic model. Conclusions: Despite the differences in X-ray attenuation between the five model designs, the results suggest that the anthropomorphic model does not affect the results of diagnostic accuracy studies on root fracture using this CBCT machine at standard clinical exposures. This provides some confidence in the previously published evidence. The interobserver diagnosis differences indicate that research using only two observers could provide misleading results.
Assessment of dental age estimation methods applied to Brazilian children: a systematic review and meta-analysis
Authors: Franco Ademir , de Oliveira Murilo Navarro , Campos Vidigal Maria Tereza , Blumenberg Cauane , Pinheiro Adriele Alves , Paranhos Luiz Renato 
Published: June 2020

Objectives: To review the scientific literature of studies on dental age estimation methods applied to Brazilian children. Methods: A systematic literature review was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in PROSPERO (CRD42020136170). Six scientific databases were used as primary search sources (PubMed, Scopus, LILACS, SciELO, Embase and Web of Science) and two databases (Open Grey and Open Thesis) were searched to partially select the “grey literature.” Only cross-sectional studies were included. The risk of bias was assessed by means of Joanna Briggs Institute Critical Appraisal Tools for Systematic Reviews. The standardized mean difference (SMD) between the estimated dental and chronological ages was meta-analysed via random effects model. Results: The search resulted in 2,527 studies, from which 13 met the eligibility criteria. Out of the eligible studies, 76.92% had low risk of bias and high methodological quality. Ten studies provided proper information to be included in the meta-analysis.The methods and their SMD between estimated and chronological ages were: Willems’=0.05, Lilequist and Lundberg’s = −0.11, Nolla’s = 0.22, Mornstad’s = 0.27, Cameriere’s = −0.31, Demirjian’s = 0.74 and Haavikko’s = −0.87. Conclusion: Although originally trained in populations worldwide, most of the international methods for radiographical dental age estimation had optimal performance in Brazilian children.