bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-parametric inference of impurity transport coefficients in the ASDEX Upgrade tokamak
Authors: Nishizawa T. , Dux R. , McDermott R.M. , Sciortino F. , Cavedon M. , Schuster C. , Wolfrum E. , von Toussaint U. , Van Vuuren A.Jansen , Cruz-Zabala D.J. , Cano-Megias P. , Moon C. , the ASDEX Upgrade Team
Published: March 2022

We present a non-parametric inference of impurity transport coefficients by using charge exchange recombination spectroscopy measurements of Ne X, Ne VIII, O VIII, and C VI lines. Due to their close atomic numbers, neon, oxygen and carbon impurity ions are assumed to have the same diffusion coefficient D and convection velocity v. Unlike conventional techniques that modulate or perturb the impurity contents, we employ a quasi-stationary plasma with static impurity profiles. Since the ratio of v to D only describes the equilibrated profile of the sum of all impurity charge states, steady-state measurements can still decouple D and v if different charge states are simultaneously observed. We have formulated a non-parametric analysis framework based on the Bayesian probability theory and conducted transport coefficient measurements for a Type III ELMy H-mode plasma at ASDEX Upgrade. The charge exchange reactions with the background neutrals, which are known to affect the impurity charge state balance, are taken into account by introducing additional free parameters. While D at the pedestal is close to the neoclassical level (

<

1 m s−2), a large diffusion coefficient and a strong outward convection are inferred right inside the pedestal top.
The lpGBT production testing system
Authors: Guettouche N. , Baron S. , Biereigel S. , Hernandez Montesinos D. , Kulis S. , Vicente Leitao P. , Mendez J. , Moreira P. , Porret D. , Wyllie K.
Published: March 2022

The Low Power GigaBit Transceiver (lpGBT) is a radiation-tolerant Application-Specific Integrated Circuit (ASIC) designed to implement versatile high-speed bi-directional serial links in the experiments and environment of the Large Hadron Collider. With 336 programmable registers and 11 configuration pins, this ASIC is highly configurable. The current version of the chip, the lpGBTv1, is now under test. The project will then produce chips to equip the phase-2 experiment upgrades starting in 2025. More than 180000 components will be produced, tested and distributed to the users. The test involves validation of a wide variety of features and will be achieved at three different supply voltages, at −30 °C and at room temperature. Given the number of components and the complexity of the test, one of the biggest challenges was to minimize the execution time while maximizing coverage. This paper presents the new lpGBTv1 production test system, its development stages and some of the challenges which were met during its implementation.
Record-breaking rain falls at Greenland summit controlled by warm moist-air intrusion
Authors: Xu Min , Yang Qinghua , Hu Xiaoming , Liang Kaixin , Vihma Timo
Published: March 2022

On 14 August 2021, rain fell on the peak of Greenland for the first time on record. The atmospheric circulation and water vapour transport responsible for the rain were investigated. A high-pressure ridge favoured southwesterly advection of warm and moist air, the intrusion of which contributed to the rainfall. At the same time, Summit station observed above-freezing temperatures, which was the third time in a decade, after summers 2012 and 2019. The previous two warm events also included influxes of moisture, but no rainfall. Comparison between them and the 2021 event show different atmospheric pressure fields and water vapour transports. In 2021, the moisture from the southwest ascended the sloping ice sheet, whereas in the prior events moisture was transported from the southeast in smaller amounts. The sufficient supply of warm and moist air was the key factor in the 2021 rain event.
Exploring pathways to deep de-carbonization and the associated environmental impact in China’s ammonia industry
Authors: Zhao Fu , Fan Ying , Zhang Shaohui , Eichhammer Wolfgang , Haendel Michael , Yu Songmin
Published: March 2022

China is the largest producer of synthetic ammonia, accounting for one-third of the world’s total production. Ammonia is mainly used to produce fertilizer and is also considered as a potential fuel and new energy carrier for the future. Concomitantly, the ammonia industry is the largest energy consumer and CO2 emitter in China’s chemical industry. In this study, we developed the MESSAGEix-ammonia model with detailed process descriptions to evaluate the energy-saving and emission reduction potential that can be generated by energy efficiency (EE) improvement, as well as the transition path and emission characteristics in the context of deep emission reduction. Results show that the cost-effective EE measures implemented under the EE scenario could reduce fresh water, fuel coal, and electricity consumptions by 7%, 25%, and 16%, as well as reduce CO2, PM2.5, SO2, and NOx emissions by 33%, 24%, 24%, and 24%, respectively, by 2060. Regarding the exploration of the deep de-carbonization path, carbon capture and storage technology (CCS) increases the CO2 reduction potential to 62%, but it requires additional electricity. Meanwhile, electrolysis technology not only saves additional fresh water and fuel coal, but also reduces CO2, PM2.5, SO2, and NOx by 80%, 84%, 86%, and 84%, respectively. Furthermore, the integration of electrolysis technology and CCS can bring 98% carbon emission reduction, which is close to net-zero emission status. With the development of renewable electricity, sufficient, clean, and affordable electricity can be provided for electrolysis devices. Our recommendation to policy makers is that electrolysis of water to produce ammonia using renewable electricity is a feasible deep de-carbonization pathway.
Testis on a chip—a microfluidic three-dimensional culture system for the development of spermatogenesis in-vitro
Authors: AbuMadighem Ali , Shuchat Sholom , Lunenfeld Eitan , Yossifon Gilad , Huleihel Mahmoud
Published: March 2022

This research presents a novel testis-on-a-chip (ToC) platform. Testicular cells are enzymatically isolated from the seminiferous tubules of sexually immature mice, seeded in a methylcellulose gel and cultured in a microfluidic chip. The unique design sandwiches the soft methylcellulose between stiffer agar support gels. The cells develop into spheroids continuing to proliferate and differentiate. After seven weeks of culture the cells have over 95% viability. Confocal microscopy of the developed spheroids reveals a structure containing the various stages of spermatogenesis up to and including meiosis II: premeiotic, meiotic and post-meiotic germ cells. The spheroid structure also contains the supporting Sertoli and peritubular cells. The responsiveness of the system to the addition of testosterone and retinoic acid to the culture medium during the experiment was also investigated. As a benchmark, the ToC is compared to a conventional three-dimensional methylcellulose cell culture system in a well plate. Analysis via fluorescence-activated cell sorting shows more haploid cells in the chip as compared to the plates. Immunofluorescence staining after seven weeks of culture shows more differentiated cells in the chip as compared to the well plate. This demonstrates the feasibility of our platform as well as its advantages. This research opens new horizons for the study and realization of spermatogenesis in-vitro. It can also enable the implementation of microfluidic technologies in future therapeutic strategies for pre-pubertal male fertility preservation and adults with maturation arrest. Lastly, it can serve as a platform for drug and toxin testing.
In vitro breast cancer model with patient-specific morphological features for personalized medicine
Authors: Han Jonghyeuk , Jeon Seunggyu , Kim Min Kyeong , Jeong Wonwoo , Yoo James J , Kang Hyun-Wook
Published: March 2022

In vitro cancer models that can simulate patient-specific drug responses for personalized medicine have attracted significant attention. However, the technologies used to produce such models can only recapitulate the morphological heterogeneity of human cancer tissue. Here, we developed a novel 3D technique to bioprint an in vitro breast cancer model with patient-specific morphological features. This model can precisely mimic the cellular microstructures of heterogeneous cancer tissues and produce drug responses similar to those of human cancers. We established a bioprinting process for generating cancer cell aggregates with ductal and solid tissue microstructures that reflected the morphology of breast cancer tissues, and applied it to develop breast cancer models. The genotypic and phenotypic characteristics of the ductal and solid cancer aggregates bioprinted with human breast cancer cells (MCF7, SKBR3, MDA-MB-231) were respectively similar to those of early and advanced cancers. The bioprinted solid cancer cell aggregates showed significantly higher hypoxia (>8 times) and mesenchymal (>2–4 times) marker expressions, invasion activity (>15 times), and drug resistance than the bioprinted ductal aggregates. Co-printing the ductal and solid aggregates produced heterogeneous breast cancer tissue models that recapitulated three different stages of breast cancer tissue morphology. The bioprinted cancer tissue models representing advanced cancer were more and less resistant, respectively, to the anthracycline antibiotic doxorubicin and the hypoxia-activated prodrug tirapazamine; these were analogous to the results in human cancer. The present findings showed that cancer cell aggregates can mimic the pathological micromorphology of human breast cancer tissue and they can be bioprinted to produce breast cancer tissue in vitro that can morphologically represent the clinical stage of cancer in individual patients.
Sensitive electrochemical sensor based on gold nanoparticles assembled ferrocene-functionalised graphene oxide modified glassy carbon electrode for simultaneous determination of dopamine and acetaminophen
Authors: Changsan Nirankan , Chairam Sanoe , Jarujamrus Purim , Amatatongchai Maliwan
Published: March 2022

In this article, a novel electron transfer mediator based on the ferrocene-functionalised graphene oxide (Fc-GO) was successfully synthesised by the amide linkage between amino (–NH2) in m-ferrocenylaniline (FcAni) and carboxylic (–COOH) in GO sheet through coupling reagents. This novel electroactive Fc-GO can effectively prevent the ferrocene mediator leaking from the electrode surface. Then, gold nanoparticles assembled ferrocene-functionalised graphene oxide (AuNPs@Fc-GO) was prepared and further confirmed by transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM) with energy dispersive X-ray spectroscopy (EDS), Fourier transform-infrared spectroscopy (FTIR) and X-ray powder diffractometer (XRD). The AuNPs@Fc-GO was modified on the surface of glassy carbon electrode (GCE) to construct an electrochemical sensor for sensitively simultaneous determination of dopamine (DA) and acetaminophen (AC). The characteristics toward DA and AC were investigated by the cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. Simultaneous determination of both analytes was accomplished under the optimum condition. The oxidation peak potential of DA and AC was 0.20 and 0.43 V, respectively. The linear current response was obtained in the concentration range of 2–200 μM with the detection limit (S/N = 3) of 0.32 μM for DA and 2–200 μM with the detection limit of 0.21 μM for AC, respectively. Finally, the AuNPs@Fc-GO modified GCE was applied for the determination of DA and AC in human urine samples with satisfactory results. Therefore, the AuNPs@Fc-GO was a novel promising candidate for fabricating an electrochemical sensor for the determination of DA and AC in real biological samples.
On the symplectic type of isomorphisms of the 𝑝-torsion of elliptic curves
Authors: Freitas Nuno , Kraus Alain
Published: March 2022

Let

p
≥
3

p \geq 3

be a prime. Let

E

/

Q

E/\mathbb {Q}

and

E
′

/

Q

E’/\mathbb {Q}

be elliptic curves with isomorphic

p
p

-torsion modules

E
[
p
]

E[p]

and

E
′

[
p
]

E’[p]

. Assume further that either (i) every

G

Q

G_\mathbb {Q}

-modules isomorphism

ϕ
:
E
[
p
]
→

E
′

[
p
]

\phi : E[p] \to E’[p]

admits a multiple

λ
⋅
ϕ

\lambda \cdot \phi

with

λ
∈

F

p
×

\lambda \in \mathbb {F}_p^\times

preserving the Weil pairing; or (ii) no

G

Q

G_\mathbb {Q}

-isomorphism

ϕ
:
E
[
p
]
→

E
′

[
p
]

\phi : E[p] \to E’[p]

preserves the Weil pairing. This paper considers the problem of deciding if we are in case (i) or (ii).

Our approach is to consider the problem locally at a prime

ℓ
≠
p

\ell \neq p

. Firstly, we determine the primes

ℓ
\ell

for which the local curves

E

/

Q

ℓ

E/\mathbb {Q}_\ell

and

E
′

/

Q

ℓ

E’/\mathbb {Q}_\ell

contain enough information to decide between (i) or (ii). Secondly, we establish a collection of criteria, in terms of the standard invariants associated to minimal Weierstrass models of

E

/

Q

ℓ

E/\mathbb {Q}_\ell

and

E
′

/

Q

ℓ

E’/\mathbb {Q}_\ell

, to decide between (i) and (ii). We show that our results give a complete solution to the problem by local methods away from 

p
p

.

We apply our methods to show the non-existence of rational points on certain hyperelliptic curves of the form

y
2

=

x
p

−
ℓ

y^2 = x^p - \ell

and

y
2

=

x
p

−
2
ℓ

y^2 = x^p - 2\ell

where

ℓ
\ell

is a prime; we also give incremental results on the Fermat equation

x
2

+

y
3

=

z
p

x^2 + y^3 = z^p

. As a different application, we discuss variants of a question raised by Mazur concerning the existence of symplectic isomorphisms between the

p
p

-torsion of two non-isogenous elliptic curves defined over

Q

\mathbb {Q}

.
Counting fluorescently labeled proteins in tissues in the spinning–disk microscope using single–molecule calibrations
Authors: Liao Maijia , Kuo Yin–Wei , Howard Jonathon
Published: March 2022

Counting molecules in living cells is important for understanding biological phenomena. We used single–step bleaching to estimate the single–fluorophore intensity in a spinning–disk confocal microscope and quantify the amount of EB1–eGFPs in the neurons of fly larvae, allowing us to estimate their binding constant and the GTP–cap size of microtubules.
Revisiting the Wald Test in Small Case-Control Studies With a Skewed Covariate
Authors: Gnona Komla M , Stewart William C L
Published: March 2022

The Wald test is routinely used in case-control studies to test for association between a covariate and disease. However, when the evidence for association is high, the Wald test tends to inflate small P values as a result of the Hauck-Donner effect (HDE). Here, we investigate the HDE in the context of genetic burden, both with and without additional covariates. First, we examine the burden-based P values in the absence of association using whole-exome sequence data from 1000 Genomes Project reference samples (n = 54) and selected preterm infants with neonatal complications (n = 74). Our careful analysis of the burden-based P values shows that the HDE is present and that the cause of the HDE in this setting is likely a natural extension of the well-known cause of the HDE in 2 × 2 contingency tables. Second, in a reanalysis of real data, we find that the permutation test provides increased power over the Wald, Firth, and likelihood ratio tests, which agrees with our intuition since the permutation test is valid for any sample size and since it does not suffer from the HDE. Therefore, we propose a powerful and computationally efficient permutation-based approach for the analysis and reanalysis of small case-control association studies.
Higher Pulse Pressure Is Associated With Increased Risk of Cardio-cerebrovascular Disease and All-Cause Mortality: A Korean National Cohort Study
Authors: Lee Jae-woo , Shin Sang-Jun , Kim Joungyoun , Kang Hee-Taik
Published: March 2022

BACKGROUND

This study aimed to investigate the association of pulse pressure (PP) with the cardio-cerebrovascular disease (CCVD) risk and all-cause mortality according to blood pressure level using Korean national cohort data.

METHODS

This study was retrospectively designed and based on the Korean National Health Insurance Service-National Health Screening Cohort. Participants aged 40–69 years at baseline were categorized into normal, elevated, stage 1, and stage 2 groups according to blood pressure. Each group was further classified into 5 groups separated by 10-mm Hg increments in PP. The primary composite outcome was defined as CCVDs and all-cause mortality. Cox proportional hazards regression models were adopted after stepwise adjustment for confounders to investigate the composite outcome.

RESULTS

During the follow-up period (median follow-up period, 12.0 years), the primary composite outcome occurred in 18,444 (15.0%) of 122,783 men and 10,096 (11.4%) of 88,550 women. After complete adjustment for confounders, in the stage 1 hypertensive men, the hazard ratio (95% confidence intervals [CIs]) of the 31–40, 41–50, 51–60, and >60 mm Hg PP groups was 1.112 (1.013–1.221), 1.035 (0.942–1.137), 1.009 (0.907–1.123), and 1.324 (1.130–1.551) in comparison with the ≤30 mm Hg PP group. In the stage 2 hypertensive men, the HRs (95% CIs) were 1.069 (0.949–1.204), 1.059 (0.940–1.192), 1.123 (0.999–1.263), and 1.202 (1.061–1.358) compared to the ≤30 mm Hg PP group. However, these associations were not significant in women.

CONCLUSIONS

Hypertensive men with an increased PP have an increased risk of CCVDs and all-cause mortality.
New and emerging pharmacotherapies for the management of multiple myeloma
Authors: Moore Donald C , Oxencis Carolyn J , Shank Brandon R
Published: March 2022

Purpose

The pharmacology, efficacy, safety, and dosing/administration of new and emerging therapies for the treatment of multiple myeloma are summarized.

There have been significant advancements in the treatment of multiple myeloma in recent years, with an expansion of available drug therapies. Newer therapies for multiple myeloma include the anti-CD38 monoclonal antibodies daratumumab and isatuximab, the exportin 1 inhibitor selinexor, the anti–B-cell maturation antigen (BCMA) antibody-drug conjugate belantamab mafodotin, and the chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel. These agents have unique toxicity profiles, specific monitoring parameters, and operational considerations that clinicians treating multiple myeloma should be aware of. There is likely to be continued rapid expansion of new agents for patients with multiple myeloma, as there are many novel investigational agents in the drug development pipeline, such as bispecific antibodies and additional CAR T-cell therapies.

Conclusion

Several therapeutic agents have been recently approved by the Food and Drug Administration for the treatment of multiple myeloma. There are many novel agents in the pipeline, including bispecific antibodies and CAR T-cell therapies that have the potential to continue to change the treatment landscape of multiple myeloma.
Benchmarking differential expression, imputation and quantification methods for proteomics data
Authors: Lin Miao-Hsia , Wu Pei-Shan , Wong Tzu-Hsuan , Lin I-Ying , Lin Johnathan , Cox Jürgen , Yu Sung-Huan
Published: March 2022

Data analysis is a critical part of quantitative proteomics studies in interpreting biological questions. Numerous computational tools for protein quantification, imputation and differential expression (DE) analysis were generated in the past decade and the search for optimal tools is still going on. Moreover, due to the rapid development of RNA sequencing (RNA-seq) technology, a vast number of DE analysis methods were created for that purpose. The applicability of these newly developed RNA-seq-oriented tools to proteomics data remains in doubt. In order to benchmark these analysis methods, a proteomics dataset consisting of proteins derived from humans, yeast and drosophila, in defined ratios, was generated in this study. Based on this dataset, DE analysis tools, including microarray- and RNA-seq-based ones, imputation algorithms and protein quantification methods were compared and benchmarked. Furthermore, applying these approaches to two public datasets showed that RNA-seq-based DE tools achieved higher accuracy (ACC) in identifying DEPs. This study provides useful guidelines for analyzing quantitative proteomics datasets. All the methods used in this study were integrated into the Perseus software, version 2.0.3.0, which is available at https://www.maxquant.org/perseus.
Coaptation length predicts early- and intermediate-term durability following degenerative mitral repair
Authors: Hage Fadi , Hage Ali , Malik Mohsyn I , Tzemos Nikolaos , Chu Michael W A
Published: March 2022

OBJECTIVES

The impact of coaptation length on recurrent mitral regurgitation following degenerative mitral repair is not fully understood.

METHODS

Between May 2008 and February 2021, 386 consecutive patients underwent mitral repair for degenerative mitral regurgitation at a single centre. We compared patients with a post-repair coaptation length >11 mm (long-coaptation group, n = 230) and ≤11 mm (short-coaptation group, n = 156). The coaptation length cutoff was selected based on published postoperative transesophageal echocardiographic measurement of mitral repair patients and healthy controls. Propensity score with inverse probability of treatment weighting (IPTW) analyses were performed. The median duration of clinical follow-up was 41 months and follow-up was complete in the entire cohort.

RESULTS

The long-coaptation patients underwent more neochord implantation (89% vs 65%, P < 0.001) and less leaflet resection (11% vs 29%, P < 0.001). Overall in-hospital/30-day mortality and mitral reintervention occurred in 3 (1%) and 4 (1%) patients, respectively, and freedom from recurrent mitral regurgitation was 98% at 1 year and 94% at 5 years. Freedom from recurrent mitral regurgitation moderate or greater was significantly higher in the long-coaptation patients (IPTW-adjusted difference in average time to recurrent mitral regurgitation: 31 months, 95% confidence interval 9–53, P = 0.006). However, there was no difference in intermediate-term survival between both groups (IPTW-adjusted difference in average time to death: 9.5 months, 95% confidence interval −27 to 46, P = 0.61). Stratified analysis and pairwise comparison of different coaptation intervals also appeared to support the protective effect of longer coaptation on repair durability.

CONCLUSIONS

Longer coaptation length appears to be associated with improved intermediate-term durability after mitral repair.
Thoracoabdominal aortic aneurysm repair based on pre- and postoperative evaluation of the artery of Adamkiewicz
Authors: Imamura Yuki , Kin Hajime , Yoshioka Kunihiro , Tabayashi Azuma , Saitoh Daiki
Published: March 2022

OBJECTIVES

The aim of this study was to evaluate our experience with thoraco-abdominal aortic aneurysm repair based on the pre- and postoperative evaluation of the artery of Adamkiewicz (AKA).

METHODS

Between April 2017 and May 2021, 32 patients who underwent thoracoabdominal aortic repair underwent pre- and postoperative multidetector row computed tomography (MDCT) for AKA evaluation. Based on the identification of the AKA on preoperative MDCT, only 1 critical segmental artery was reattached to the AKA (CSA-AKA). Postoperative MDCT was used to evaluate the patency of the reattached CSA-AKA.

RESULTS

Pre- and postoperative MDCT helped identify and visualize the AKA in all patients (100%). In 8 patients, alternative continuity to the AKA developed through collateral circulation. The total number of CSA-AKA with collateral circulation was 48 among the 32 cases; the number of reattached segmental arteries per case was 1.3 ± 0.9 (range, 0–4). The overall rate of patency of the reattached CSA-AKA was 53% (23/43). Three patients exhibited spinal cord injuries (paraplegia, 2; paraparesis, 1). In the 2 paraplegia cases exhibiting partial or complete occlusion of the reattached CSA-AKA, the development of collateral circulation was not visualized via postoperative MDCT. In the paraparesis case, postoperative MDCT helped visualize the development of collateral circulation to the CSA-AKA, resulting in full recovery at discharge.

CONCLUSIONS

The study findings suggest that spinal cord injuries do not occur in the presence of a patent preoperatively identified CSA-AKA or the development of collateral circulation. Pre- and postoperative identification of collateral pathways to the AKA may help reveal paraplegia risk factors.
The genome of Hibiscus hamabo reveals its adaptation to saline and waterlogged habitat
Authors: Wang Zhiquan , Xue Jia-Yu , Hu Shuai-Ya , Zhang Fengjiao , Yu Ranran , Chen Dijun , Van de Peer Yves , Jiang Jiafu , Song Aiping , Ni Longjie , Hua Jianfeng , Lu Zhiguo , Yu Chaoguang , Yin Yunlong , Gu Chunsun
Published: March 2022

Hibiscus hamabo is a semi-mangrove species with strong tolerance to salt and waterlogging stress. However, the molecular basis and mechanisms that underlie this strong adaptability to harsh environments remain poorly understood. Here, we assembled a high-quality, chromosome-level genome of this semi-mangrove plant and analyzed its transcriptome under different stress treatments to reveal regulatory responses and mechanisms. Our analyses suggested that H. hamabo has undergone two recent successive polyploidy events, a whole-genome duplication followed by a whole-genome triplication, resulting in an unusually large gene number (107 309 genes). Comparison of the H. hamabo genome with that of its close relative Hibiscus cannabinus, which has not experienced a recent WGT, indicated that genes associated with high stress resistance have been preferentially preserved in the H. hamabo genome, suggesting an underlying association between polyploidy and stronger stress resistance. Transcriptomic data indicated that genes in the roots and leaves responded differently to stress. In roots, genes that regulate ion channels involved in biosynthetic and metabolic processes responded quickly to adjust the ion concentration and provide metabolic products to protect root cells, whereas no such rapid response was observed from genes in leaves. Using co-expression networks, potential stress resistance genes were identified for use in future functional investigations. The genome sequence, along with several transcriptome datasets, provide insights into genome evolution and the mechanism of salt and waterlogging tolerance in H. hamabo, suggesting the importance of polyploidization for environmental adaptation.
Animal Study Translation: The Other Reproducibility Challenge
Authors: Berridge Brian R
Published: March 2022

Animal research is currently an irreplaceable contributor to our efforts to protect and improve public health. Its relevance, importance, and contributions are represented in historical precedent, regulatory expectations, evidence of our rapidly developing understanding of human health and disease, as well as success in the development of novel therapeutics that are improving quality of life and extending human and animal life expectancy. The rapid and evolving success in responding to the current COVID pandemic significantly supported by animal studies is a clear example of the importance of animal research. But there is growing interest in reducing our dependence on animals and challenges to the effective translation of current animal studies to human applications. There are several potential contributors to gaps in the translatability of animal research to humans, including our approaches to choosing or rationalizing the relevance of a particular animal model, our understanding of their biological variability and how that applies to outcomes, the data we collect from animal studies, and even how we manage the animals. These important contributors to the success of animal research are explored in this issue of the ILAR Journal.
Development of a Liquid Chromatography–Tandem Mass Spectrometry Method for the Simultaneous Determination of 40 Drugs of Abuse in Human Urine: Application to Real Cases
Authors: Pascual-Caro Sergi , Borrull Francesc , Aguilar Carme , Calull Marta
Published: March 2022

Drugs of abuse are constantly evolving, while new synthetized substances are constantly emerging to avoid regulations. However, traditional drugs such as cocaine and amphetamine are still two of the most consumed drugs in the world. It is important, therefore, to provide suitable multiresidue methods for determining a wide range of drugs for use in toxicological and forensic analyses. The aim of this study is to develop a method for determining several families of drugs of abuse, including classic drugs, new psychoactive substances and some of their metabolites, in urine by liquid chromatography–tandem mass spectrometry. Urine is one of the most common biological matrices used in drug analysis because of its easy collection and a wide window of detection. In this study, we used solid-phase extraction to remove interferences and extract analytes from urine. Four different mixed-mode cation-exchange commercial sorbents were evaluated. The best results, in terms of apparent recoveries, were achieved with one of the strong cationic sorbents, ExtraBond SCX. The method achieved detection limits from 0.003 to 0.500 ng/mL and quantification limits from 0.050 to 1.500 ng/mL, which are suitable for determining these compounds at the usual levels found in the urine of drug users. The applicability of this method was demonstrated by analyzing real urine specimens from women following a detoxification program. Our results showed that the drug most consumed was cocaine, since it was detected in most urine specimens together with its main metabolite, benzoylecgonine. The polyconsumption of drugs from different families was also observed in some urine samples analyzed.
T2 Global Hospital Infrastructure and Pediatric Burns
Authors: Puthumana Joseph S , Hultman Charles S , Redett Richard J
Published: March 2022

Introduction

Low income regions across the world carry the highest proportion and highest mortality burden of pediatric burns. In recent years, attention to remedy these inequities has shifted from isolated mission trips towards building infrastructure for lasting improvements in surgical care. This study aims to investigate disparities in pediatric burn care infrastructure and their relationship to mortality outcomes.

Methods

The multinational Global Burn Registry was queried for all burn cases between January 2018 and August 2021. Burn cases and mortality rates were compared across infrastructure factors by Pearson Chi-Square. Multinomial logistic regression was used to isolate independent modifiable risk factors for mortality controlling for total body surface area of burn (TBSA).

Results

There were a total of 8537 cases of which 3492 (40.9%) were pediatric. Significantly lower mortality rates were found in facilities with sophisticated nutritional supplementation (p < 0.001), permanent internet connectivity (p < 0.001), reliable critical care access (p < 0.001), reliable burn OR access (p=0.003), dedicated burn unit (p < 0.001), and advanced plastic and reconstructive skills available (p=0.003); there was no significant difference if specialist capabilities in supportive fields (e.g. nephrology, cardiology) were available (p=0.063). Significant disparities were found in the availability of these resources between high and low income countries, as well granular information within low income regions: though blood transfusion access was limited in the African (49.0%) and South-East (50.6%) regions compared to full access in the Americas and Europe (p < 0.001), 100% of cases in the South-East had access to a specialized burn unit compared to 8.1% of cases in Africa. In a multinomial logistic regression controlling for TBSA, the most significant risk factor for mortality was limited critical care availability (OR 15.18, p< 0.001). The most significant protective factor was sophisticated nutritional access (OR 0.40, p=0.024).

Conclusions

This is the first quantitative analysis of disparities in global burn infrastructure and their impact on pediatric mortality. The identification of nutritional support as an independent and significant protective factor suggests that low-cost interventions in hospital nutrition infrastructure merit further study and may realize significant gains in global burn care. Granular information in the variability of regional needs will begin to direct targeted infrastructure initiatives rather than a one-size-fits-all approach in developing nations.
5 Admission Frailty Is Associated with Acute Respiratory Failure and Mortality in Burn Patients > 50
Authors: Galet Colette , Lawrence Kevin , Skipton Romanowski Kathleen S , Skeete Dionne , Mashruwala Neil
Published: March 2022

Introduction

Pre-injury frailty has been shown to predict mortality of older burn patients. Herein, we assessed the utility of the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS) to predict burn-specific outcomes. We hypothesize that frail patients are at greater risk for complications such as graft loss, acute respiratory failure, and acute kidney injury and will require increased healthcare support at discharge.

Methods

This is a retrospective cohort study. Patients 50 years and older admitted to our Institution for burn injuries between July 2009 and June 2019 were included. Patients with inhalation injury only, no data on total burn surface area, or for whom medical history was incomplete were excluded. Demographics; comorbidities; pre-injury functional status; admission, injury, and hospitalization information; complications (graft loss, acute respiratory failure, and acute kidney disease (AKI)); mortality, and discharge disposition were collected. Patients were scored on the CSHA-CFS based on pre-admission health and functional status. The frail and non-frail groups were compared. Multivariate analyses were performed to assess the association between admission frailty and outcomes. P < 0.05 was considered significant.

Results

We included 851 patients, 697 were not frail and 154 were frail. Frail patients were significantly older (66.1 ± 10.8 vs. 63.5 ± 10.9, p = 0.002), more likely Caucasian (98.1% vs. 91%, p = 0.027) and to have suffered flame burn injuries (68.8% vs. 59.8%, p < 0.001). Frail patients had a lower %TBSA (4.4 ± 8.1% vs. 10.1 ± 13.1, p < 0.001) but were more likely to stay longer in hospital relative to %TBSA (3.6 ± 6.7 vs. 1.9 ± 3.1, p < 0.001). Frail patients were less likely to have had skin graft procedures (27.3% vs. 57.4, p < 0.001). On multivariate analysis, controlling for age, sex, race, mechanism of injury, %TBSA, 2nd degree and 3rd degree burn surface, inhalation injury, frailty was associated with acute respiratory failure (OR = 2.599 [1.460-4.628], p = 0.001). Frailty was also associated with mortality (OR = 6.915 [2.455-19.980]; p < 0.001) when controlling for the same variables as well as acute respiratory failure and AKI. Frailty was also associated with discharge to home with healthcare services (OR = 2.678 [1.491-4.809], p = 0.001), to SNF, rehabilitation, or long-term acute care facilities (OR = 3.572 [1.933-6.602], p < 0.001), and to hospice (OR = 5.759 [1.519-21.827], p = 0.010) when compared to home without healthcare services.

Conclusions

Frailty is associated with increased risk of acute respiratory failure, mortality, and requiring increased healthcare support post-discharge. Our data suggest frailty as a tool to predict morbidity and mortality as well as for goals of care discussions for the burn patient.
23 Chlorhexidine Delays Wound Healing in Human Skin
Authors: Gibson Angela , Liu Aiping , Tran Collin L , Hassan Sameeha E
Published: March 2022

Introduction

Chlorhexidine (CHG) is ubiquitous in surgical perioperative care. In vivo studies of CHG cytotoxicity on human skin are lacking. Given the use of CHG for daily wound cares and as a presurgical scrub, including donor site preparation, we sought to identify if CHG cytotoxicity would persist in a clinically relevant in vivo human skin xenograft model.

Methods

Human skin tissues were obtained from elective surgeries. Partial thickness wounds were created ex vivo in human skin using a 4 mm punch biopsy. 2% CHG (treatment) or PBS (control) was applied to the wounds for 30 minutes followed by rinsing the tissue +/- mechanical disruptive irrigation. Tissues were cultured at the air-liquid interface for 24 hours in culture media after treatment and tissue viability was performed using an MTT assay. For in vivo studies, athymic mice (n=4) were grafted on bilateral flanks with human skin. Eight weeks after engraftment and normalization of skin architecture, 4 mm partial thickness wounds were created on each xenograft (2 per mouse – treatment and control). 2% CHG was applied daily for 2 minutes followed by irrigation with PBS in the treatment wound. The control wound received PBS application and irrigation. The xenografts received treatment daily for 14 days to mimic daily wound cares, and digital images were obtained to document presence of infection and gross wound healing. On day 14, the xenografts were harvested and stained for lactate dehydrogenase and H&E to assess cell viability and wound re-epithelization, respectively.

Results

An MTT assay on ex vivo human skin wounds showed that CHG treated groups (irrigation or non-irrigation) had lower cell viability compared to the PBS treated group, however irrigation mitigates the cytotoxicity of CHG on human skin. In the in vivo xenograft study, no signs of infection were identified in either PBS or CHG treated wounds throughout the study. The wound size appeared larger on gross inspection in the CHG treated group compared to the PBS group as early as day 2.Microscopically, the PBS treated wounds were fully re-epithelialized (n=2) or had significantly more re-epithelialization (n=2) than the CHG treated wounds (n=4) after 14 days of treatment. The PBS-treated wounds were viable throughout the tissue, indicating the irrigation procedure was not harmful to the cells. In the CHG-treated wounds, nonviable cells were observed in the dermis beneath the wound that was directly in contact with CHG suggesting penetration of CHG contributes to cytotoxicity in acute wounds.

Conclusions

Daily CHG use is cytotoxic to human skin and impedes wound healing.
24 The CD34+ Adipose-derived Stem Cells from Fat Grafts Accelerates Keratinocyte Wound Closure
Authors: Balko Stefan , Raouf Afshin , Kerr Evan , Logsetty Sarvesh
Published: March 2022

Introduction

Adipose derived stem cells (ADSCs) possess high regenerative potential and therefore are postulated to enhance re-epithelialization via recruitment of keratinocytes into the wound bed, and thusly improve healing of severe burns. Although ADSC’s are enriched in the stromal vascular fraction (SVF) of fat grafts, the ADSC frequency in these samples is very low (1%) which has hindered their further characterization. So far, the CD34+ subset of SVF cells has shown to contain up to 75% of all the ADSCs present in SVF samples but their ADSC frequency remains low (2.5%). Unfortunately, while the ADSC frequency increases in passaged SVF cells, the expression of CD34 is lost in these cells. Therefore, there is a pressing need to identify new ADSC biomarkers to study ADSC mechanisms that accelerate wound closure. In this study, we aim to identify new ADSC biomarkers and to examine the impact of ADSC-enriched cells on skin wound closure.

Methods

Single cells from SVFs were obtained from disassociated fat tissue, collected from excess lipoaspirates used in patients undergoing mastectomies. Native cells (P0), and passaged cells (P3) were placed in cell cultures and the ADSC numbers were obtained using the colony forming unit-fibroblast assays. The expression of 244 cell surface receptors was examined in P0 (low ADSCs) and P3 (high ADSCs) SVF cells to obtain new ADSC biomarkers. In another experiment, the impact of ADSC-enriched CD34+ SVF cells on wound closure was assessed. Using transwell inserts containing adult human epidermal keratinocyte (HEKa) cells in the bottom and the bulk SVF or CD34+ SVF cells in the top chamber, a scratch was induced in the HEKa cell layer and the scratch area was examined at 0h and 12h.

Results

Our cell surface antibody array experiments revealed 10 potentially new ADSC biomarkers that will be used to examine their ability to enrich for ADSCs. Both the bulk SVF and the CD34+ SVF cells showed a 2-fold increase in would closure. It is noteworthy that ADSCs frequency in the CD34+ SVF cells is still very low, and these experiments need to be conducted using the new SVF subsets with potentially higher ADSC frequencies based on our cell surface array.

Conclusions

The ADSC-enriched CD34+ SVF enhance keratinocyte wound closure, a function that is important to healing of severe burns. Further studies are needed to validate our findings using more purified SVF subsets to identify ADSC-regulated keratinocyte wound closure mechanisms.
35 Using a New Quality Registry System to Improve Data Completeness for a National Burn Registry
Authors: Phillips Bart D , Bessey Palmer Q , Mandell Samuel P , Thompson Callie M , Phillips Matthew H , Hoarle Kimberly , Higginson Sara , Hsu Naiwei , Pardon Darryl A , Weber Joan M
Published: March 2022

Introduction

The burn care community has demonstrated a long-standing commitment to quality of care, improved outcomes, and research by collecting and sharing clinical data through burn registries. The key to optimizing the value creation from these registries is data quality. In 2019 a new registry platform incorporating the latest, standardized, data definitions and sophisticated audit controls was piloted with 12 burn centers. The following year it was introduced to the broader burn care community along with a robust registrar education and training program. We sought to evaluate the effect of this new system on quality of data collection.

Methods

We compared data from 27 centers that collected data on the new system against their data collected on prior registry systems. We analyzed 26 data elements, across four different variable categories (Admissions (n=6), Demographics (n=5), Injury (n=10), and Outcomes(n=5)) that have been consistently collected over time, for data completeness. A two-proportion z test was used to assess statistical significance of differences in data completeness rates.

Results

The 27-center cohort entered data on 4,524 inpatient burn admissions between January 1, 2020 and June 30th 2021 and 7,259 admissions between July 1st, 2019 and June 30th, 2020 in their legacy system. The data elements were harmonized to maximize longitudinal comparability.

When comparing data from the same centers but using different registry software (graphic 1) 16 of 26 variables profiled had a higher percentage of completeness in the new registry system (all statistically significant), 5 variables were statistically significantly lower, and 5 variables were not significantly different. Overall, this subset of data elements showed a 14% improvement in data completeness between the new and legacy systems (90% vs 75%).

Conclusions

The development of a clinical registry requires significant commitment and leadership from the healthcare association and broader clinical community. The resources and effort that the burn community has expended to improve data quality has produced important gains in data quality with the introduction of a new, high-quality registry. The burn care community should continue to emphasize education, innovation, and collaboration to collect the highest quality data at the lowest burden from all burn centers.
50 Rise of the (Learning) Machines: Artificial Intelligence for the Assessment of Adult Thermal Burns
Authors: Carter Jeffrey E , Phelan Herb A , Hickerson William L , DiMaio J Michael , Shupp Jeffrey W , Holmes James H
Published: March 2022

Introduction

Burn depth assessment (BDA) is an essential component of the physical exam used in the treatment and triage of burn injured patients. And while many specialties incorporate labs and imaging to determine diagnoses, burn professionals must rely on a physical exam that is accurate in only 70-80% of cases. Our goal was to assess the accuracy of a new imaging technology called Multispectral imaging (MSI) combined with a machine learning algorithm to aid in rapid BDA. We present the results of the first multi-center study using this technology in adult burn injuries.

Methods

In a multi-center IRB-approved study, an MSI device was used to image subjects >18 years of age with thermal burn injuries. The imaging device captured a set of images measuring the reflectance of visible and near-IR light. Subjects were enrolled and imaged within 72 hours of injury with serial imaging as permitted. The images were used to develop a type of machine learning algorithm called a convolutional neural network (CNN) that could identify the regions of non-healing burn within an image. Non-healing burn areas were determined by a panel of three burn surgeons using two standards: a) images confirming 21-day spontaneous healing; or b) pathology reports detailing histologic changes from multiple punch biopsies taken prior to burn excision. From this data, an ensemble of eight separate CNN algorithms was used to automatically identify non-healing burn tissue. Training and test accuracies of the ensemble CNN were calculated using cross-validation at the level of the subject.

Results

One hundred (100) adults were enrolled and imaged. The population had a mean age 45.6 ± 16.7; mean TBSA 13.0 ± 9.3; and was 31% female. From these adults, 210 burn regions were serially imaged. The estimated performance result from the ensemble CNN for identification of non-healing burn regions was AUC of 0.96. Based on the ROC curve, an ideal threshold showed an accuracy of 92.0%, sensitivity 91.9%, and specificity 92.0%.

Conclusions

Our study demonstrates a non-invasive technology that rapidly determines an accurate DBA relative to traditional bedside exam. More accurate burn wound assessment could lead to avoiding unnecessary surgeries or delays in treatment and dramatic cost savings. Use of such a device in a disaster has additional value to better align a patient’s burn care needs and available resources.