bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of patient‐reported outcomes in oncology clinical trials using immune checkpoint inhibitors: A systematic review
Authors: Malone Eoghan , Barua Reeta , Meti Nicholas , Li Xuan , Fazelzad Rouhi , Hansen Aaron R.
Published: June 2021

Background

There are limited data regarding the quality of patient‐reported outcome (PRO) data in immune checkpoint inhibitor (ICI) clinical trial publications.

Methods

A systematic search of citations from various databases was conducted to identify prospective clinical trials involving ICI in advanced tumors from 2003 to 2020. A 30‐point score was adapted from the CONSORT PRO extension statement to assess adherence to CONSORT PRO reporting. Linear regression was used to identify factors associated with quality reporting.

Results

After the review of 8058 articles, 33 trials were included with ICIs as either monotherapy (91%) or part of a combination regimen (9%). The median score was 23.5 points (range 15–29). In the majority of cases (82%), PROs were reported in a separate publication from the original study. Most of the trials were conducted in the metastatic setting and predominantly in melanoma, lung, and renal cell carcinoma (RCC) (73%). Univariate analysis revealed that trials with greater than 250 patients were associated with a higher score. The score was more likely to be lower in disease sites other than melanoma, lung, and RCC and was higher in the KEYNOTE than in the CHECKMATE trial series. There was no significant correlation between the score and whether a trial met its primary end‐point or if the trial improved or worsened the quality of life. In the multivariate analysis, the number of patients enrolled to the trial, disease site, and trial series remained significant.

Conclusions

The quality of reporting of PROs in ICI phase II and III clinical trials is heterogeneous across various cancer sites. As PRO data are increasingly used to counsel patients and complement clinical decision making, innovative and collaborative efforts are required to improve the reporting of these essential data.
Comparing the frequency of CD33+ pSTAT3+ myeloid‐derived suppressor cells and IL‐17+ lymphocytes in patients with prostate cancer and benign prostatic hyperplasia
Authors: Sanaei Mohammad‐Javad , Taheri Fatemeh , Heshmati Masoud , Bashash Davood , Nazmabadi Roya , Mohammad‐Alibeigi Faramarz , Nahid‐Samiei Mahboobeh , Shirzad Hedayatollah , Bagheri Nader
Published: June 2021

Prostate cancer (PCa) is one of the most epidemic types of cancer in men. The tumor microenvironment (TME) of PCa is involved in the emergence of immunosuppressive factors such as myeloid‐derived suppressor cells (MDSC), which regulate the immune system by several mechanisms, including interleukin (IL)‐10 production. On the other hand, IL‐17+ helper T cells (Th17) induce MDSCs and chronic inflammation in TME by producing IL‐17. This study demonstrated that the frequency of CD33+ pSTAT3+ MDSC and IL‐17+ lymphocyte as well as IL‐10 messenger RNA (mRNA) expression were significantly higher in the PCa patients than in the benign prostatic hyperplasia (BPH) group. Moreover, there was no significant relationship between the frequency of CD33+ pSTAT3+ MDSC, and IL‐17+ lymphocyte with Gleason scores in the PCa group. We suggested that the higher frequency of CD33+ pSTAT3+ MDSC and IL‐17+ lymphocyte and the more frequent expression of IL‐10 mRNA in PCa patients may play roles in tumor progression from BPH to PCa.
Kinetics and catalytic distillation simulation for the heterogeneously catalytic synthesis of imine
Authors: Chen Jian , Zhu Mengjing , Xiang Fuwei , Li Junfeng , Yang Hongjun , Mao Zhipeng , Chang Ganggang , Li Shaoping
Published: June 2021

(2‐methyl‐6‐ethylphenyl)‐1‐methoxypropyl‐2‐imine (MEMI) is an important intermediate for the synthesis of commercial pesticide S‐metolachlor. However, the research on heterogeneously catalytic kinetics of MEMI, and further the catalytic distillation simulation aiming at continuous operation, have never been reported. Herein, the catalytic kinetics for the synthesis of MEMI by HPW/Al‐MCM‐41 have been systematically investigated, and further fitted by using a pseudo‐homogeneous kinetic model, based on which, the reaction equilibrium constant, activation energy, and rate constant are obtained. Furthermore, simulation of the continuous process of MEMI synthesis was carried out using the software Aspen Plus V10. Sensitivity analysis of operating parameters such as feed stage, distillation rate, number of reactive theoretical stages, and the best operating conditions were also obtained. An excellent product purity (>98.9%) of MEMI could be achieved when operated at the optimum conditions. Compared with the batch method, catalytic distillation provided continuous synthesis of MEMI, and the reaction was more thorough, achieving process integration and optimization. Our results provide substantial theoretical and empirical supports for the industrial synthesis of MEMI.
Severity of arterial and/or arteriolar sclerosis in IgA nephropathy and the effects of renin–angiotensin system inhibitors on its prognosis
Authors: Sugiura Naoko , Moriyama Takahito , Miyabe Yoei , Karasawa Kazunori , Nitta Kosaku
Published: June 2021

IgA nephropathy (IgAN) patients often suffer from arterial and/or arteriolar sclerosis (AAS); however, it is unclear whether these features are associated with a poor prognosis. This retrospective cohort study aimed to analyse the prognosis of IgAN patients with AAS and assess whether treatment with renin–angiotensin system inhibitors (RASI) improved their survival. The study included 678 IgAN patients, who were grouped into AAS0 (n = 340; AAS absent) and AAS1 (n = 338; AAS present) groups. Each patient's clinical, laboratory, and histological backgrounds and 20‐year renal prognosis were analysed. In the AAS1 group, the impact of RASI initiated during the follow‐up period on the renal prognosis was also evaluated after adjustments for background characteristics. IgAN patients with AAS had significantly higher age, blood pressure, body mass index, total cholesterol, uric acid levels, and proteinuria than patients without AAS; they also had more severe histological findings, decreased renal function, and lower survival rates than those without AAS (64.0 versus 84.7%, p < 0.001). Multivariate Cox regression analysis incorporating clinical and histological findings and treatments revealed AAS as an independent factor for disease progression (hazard ratio: 2.23, p = 0.010). Participants in the AAS1 group treated with RASI during follow‐up had a significantly higher renal survival rate than those who were not (75.5 versus 44.3%, p = 0.013). In conclusion, AAS was found to be associated with serious clinical, laboratory, and histological findings and poor prognosis. RASI initiated during the follow‐up period was found to improve renal prognosis.
RhII‐Catalyzed De‐symmetrization of Ethane‐1,2‐dithiol and Propane‐1,3‐dithiol Yields Metallo‐β‐lactamase Inhibitors
Authors: Krasavin Mikhail , Zhukovsky Daniil , Solovyev Igor , Barkhatova Darina , Dar'in Dmitry , Frank Denia , Martinelli Giada , Weizel Lilia , Proschak Anna , Rotter Marco , Kramer Jan S. , Brunst Steffen , Wichelhaus Thomas A. , Proschak Ewgenij
Published: June 2021

Diversity‐oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS‐compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)‐catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo‐β‐lactamases (MBLs) NDM‐1 and VIM‐1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.
Children and adolescents with hematologic cancers deserve better end‐of‐life care
Authors: Rapoport Adam , Gupta Sumit
Published: June 2021

Children and adolescents with hematologic malignancies consistently experience higher rates of aggressive care at the end of life. Clinicians and researchers must now turn their attention to reducing this disparity.
Sociodemographic and hospital‐based predictors of intense end‐of‐life care among children, adolescents, and young adults with hematologic malignancies
Authors: Mun Sophia , Wang Rong , Ma Xiaomei , Ananth Prasanna
Published: June 2021

Background

Children, adolescents, and young adults with hematologic malignancies tend to receive high‐intensity end‐of‐life care (HI‐EOLC), but sociodemographic and hospital‐based predictors of HI‐EOLC remain unclear.

Methods

The authors conducted a population‐based, retrospective cohort study with the Premier Healthcare Database. They identified individuals with hematologic malignancies who were 0 to 39 years old at death and died between 2010 and 2017. HI‐EOLC was defined as experiencing 2 or more of the following: cardiopulmonary resuscitation, intravenous chemotherapy, hemodialysis, mechanical ventilation, tracheostomy placement, or an emergency department visit within the last 30 days of life and death in the intensive care unit. Multivariable logistic regression models were constructed to identify patient sociodemographic and hospital characteristics associated with HI‐EOLC.

Results

Among 1454 decedents, more than half (55%) experienced HI‐EOLC. In multivariable models, patients treated in medium (adjusted odds ratio [aOR], 1.63; 95% confidence interval [CI], 1.07‐2.50) or large hospitals (aOR, 2.21; 95% CI, 1.45‐3.39), insured by Medicaid (aOR, 1.40 ; 95% CI, 1.09‐2.06), or receiving cancer‐directed treatment in the Northeast (aOR, 1.50; 95% CI, 1.05‐2.15) were more likely to receive HI‐EOLC.

Conclusions

A majority of children, adolescents, and young adults with hematologic malignancies experienced HI‐EOLC, and the likelihood of HI‐EOLC was influenced by the hospital size, type of insurance, and geographic region. Further research is needed to determine how to mitigate these risks.
Antibacterial and antioxidant effect of ethanol extracts of Terminalia chebula on Streptococcus mutans
Authors: Nam Yea Ji , Hwang Young Sun
Published: June 2021

Objective

Dental caries is a high prevalent chronic bacterial infectious disease caused by plaque, a bacterial colony deposited on tooth surfaces and gum tissues. Streptococcus mutans is a primary cariogenic bacterium commonly found in the human oral cavity. Oral hygiene products containing antibacterial ingredients can be helpful in caries management. In this study, we investigated the anticaries mechanism of the ethanol extract of Terminalia chebula (EETC) on S. mutans and suggest its possible application as a functional ingredients for oral hygiene products.

Materials and methods

The EETC was prepared from the Terminalia chebula fruit. Disk diffusion, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and colony forming unit (CFU) were analyzed to observe the antibacterial activity of EETC. The glucan formation was measured using the filtrate of bacterial culture medium and sucrose. Gene expression was analyzed using RT‐PCR. Cytotoxicity was analyzed using the MTT assay. The radical‐scavenging activities of DPPH and ABTS were also tested to verify the antioxidant activity of EETC.

Results

The antibacterial activity of the EETC was explored through a disc diffusion analysis and CFU measurement. EETC treatment decreased insoluble glucan formation and gene expression of glycosyltransferase B (gtf B), glycosyltransferase C (gtf C), glycosyltransferase D (gtf D), and fructosyltransferase (ftf). The MIC and MBC of EETC on S. mutans were not cytotoxic to gingival fibroblasts. In addition, we observed DPPH and ABTS‐radical scavenging activities of EETC.

Conclusions

These results indicate that the antibacterial and antioxidant effects of EETC may contribute to oral hygiene products for dental caries management.
Light‐Driven Waste‐To‐Value Upcycling: Bio‐Based Polyols and Polyurethanes from the Photo‐Oxygenation of Cardanols
Authors: Stuhr Robin , Bayer Patrick , Stark Christian B. W. , Jacobi von Wangelin Axel
Published: June 2021

The upcycling of waste biomass into valuable materials by resource‐efficient chemical transformations is a prime objective for sustainable chemistry. This approach is demonstrated in a straightforward light‐driven synthesis of polyols and polyurethane foams from the multi‐ton waste products of cashew nut processing. The photo‐oxygenation of cardanol from nutshell oil results in the formation of synthetically versatile hydroperoxides. The choice of the workup method (i. e., reduction, hydrogenation, epoxidation) enables access to a diverse range of alcohols with tunable alkene and OH functions. Condensation with isocyanates to give rigid polyurethane foams provides a resource‐efficient waste‐to‐value chain that benefits from the availability of cardanol and installation of OH groups from aerial O2.
Coldwater fish in a warm water world: Implications for predation of salmon smolts during estuary transit
Authors: Nobriga Matthew L. , Michel Cyril J. , Johnson Rachel C. , Wikert John D.
Published: June 2021

Predator–prey systems face intensifying pressure from human exploitation and a warming climate with implications for where and how natural resource management can successfully intervene. We hypothesized young salmon migrating to the Pacific Ocean face a seasonally intensifying predator gauntlet when warming water temperature intensifies a multiple predator effect (MPE) from Striped Bass Morone saxatilis and Largemouth Bass Micropterus salmoides. We evaluated this hypothesis using data synthesis and simulation modeling.

Contemporary studies based on acoustically tagged fish reaffirmed older observations that Chinook Salmon smolts must transit the Delta before water temperature reaches 20°C or mortality will be nearly 100%. Striped Bass attack rates on tethered smolts were insensitive to distance from shore and water temperature, whereas Largemouth Bass attack rates were highest near shorelines in warm water, supporting the temporal aspect of the hypothesis. Whether the combined effects of the two predators produce an MPE remains unconfirmed due to limitations on quantifying salmon behavior.

We used multiple simulation models to try to reconstruct the empirical relationship between smolt survival and water temperature. Simulations reinforced attack rate results, but could not recreate the temperature dependence in smolt survival except at higher than observed temperatures. We propose three hypotheses for why and recommend discerning among them should be a focus of research.

We found significant linear relationships between monthly mean inflow to the Delta from each of its two largest tributaries and monthly mean water temperatures along associated salmon migration routes, but these relationships can be nonlinear, with most of the correlation occurring at low inflows when water temperature is largely controlled by air temperature and day length. As the global climate warms, changed circumstances in predator–prey relationships may present important challenges when managing species vulnerable to extinction in addition to presently more abundant species.
Three tips for creating an online course for nontraditional student populations
Authors: Forman M. Rebecca , Chapman John A.
Published: June 2021

In spring 2020, the University of Minnesota Erosion and Stormwater Management Certification Program temporarily ceased in‐person workshops due to the spread of COVID‐19. Twenty workshops were canceled, and the 1,233 attendees (all adult learners) were moved into asynchronous online course sections. These online workshops were the first remote courses that many of the attendees had ever attempted. Here, we provide tips for successfully creating online classes for nontraditional student populations.
A non‐Newtonian fluidic cellulose‐modified glass microfiber separator for flexible lithium‐ion batteries
Authors: Zhu Ying , Cao Kaiyue , Cheng Wanke , Zeng Suqing , Dou Shuo , Chen Wenshuai , Zhao Dawei , Yu Haipeng
Published: June 2021

The separator is of great importance for regulating ion transmission, maintaining electrode stability, and device safety in lithium‐ion batteries. Despite their many advantages, glass microfiber separators have shortcomings that often give rise to poor cycle performance and fatal short‐circuit risk when used in flexible batteries. Here, we propose the use of a scalable non‐Newtonian fluidic cellulose permeation‐diffusion strategy to develop a cellulose/glass microfiber composite film with an hourglass‐gradient structure. Due to the unique gradient morphology resulting from the presence of cellulose macromolecules, the as‐prepared composite film showed an improved surface mass density, adjustable pore structure, controllable ion transport, ideal mechanical flexibility, and robustness. When used as the separator in an assembled lithium‐ion battery, the composite film exhibited rapid ion diffusion and Li dendrite inhibition, which endowed the battery with excellent cycle stability (specific capacity of 108.5 mAh g−1 after 1000 cycles) and good rate performance. This composite film shows great potential application in flexible lithium‐ion batteries including but not limited to pouch cells.

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Identifying genetic risk variants associated with brain volumetric phenotypes via K‐sample Ball Divergence method
Authors: Hu Yue , Tan Haizhu , Li Cai , Zhang Heping
Published: June 2021

Regional human brain volumes including total area, average thickness, and total volume are heritable and associated with neurological disorders. However, the genetic architecture of brain structure and function is still largely unknown and worthy of exploring. The Pediatric Imaging, Neurocognition, and Genetics (PING) data set provides an excellent resource with genome‐wide genetic data and related neuroimaging data. In this study, we perform genome‐wide association studies (GWAS) of 315 brain volumetric phenotypes from the PING data set including 1036 samples with 539,865 single‐nucleotide polymorphisms (SNPs). We introduce a nonparametric test based on K‐sample Ball Divergence (KBD) to identify genetic risk variants that influence regional brain volumes. We carry out simulations to demonstrate that KBD is a powerful test for identifying significant SNPs associated with multivariate phenotypes although controlling the type I error rate. We successfully identify nine SNPs below a significance level of 5 × 10−5 for the PING data. Among the nine identified genetic variants, two SNPs rs486179 and rs562110 are located in the ADRA1A gene that is a well‐known risk factor of mental illness, such as schizophrenia and attention deficit hyperactivity disorder. Our study suggests that the nonparametric test KBD is an effective method for identifying genetic variants associated with complex diseases in large‐scale GWAS of multiple phenotypes.
R2* and quantitative susceptibility mapping in deep gray matter of 498 healthy controls from 5 to 90 years
Authors: Treit Sarah , Naji Nashwan , Seres Peter , Rickard Julia , Stolz Emily , Wilman Alan H. , Beaulieu Christian
Published: June 2021

Putative MRI markers of iron in deep gray matter have demonstrated age related changes during discrete periods of healthy childhood or adulthood, but few studies have included subjects across the lifespan. This study reports both transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) of four primary deep gray matter regions (thalamus, putamen, caudate, and globus pallidus) in 498 healthy individuals aged 5–90 years. In the caudate, putamen, and globus pallidus, increases of QSM and R2* were steepest during childhood continuing gradually throughout adulthood, except caudate susceptibility which reached a plateau in the late 30s. The thalamus had a unique profile with steeper changes of R2* (reflecting additive effects of myelin and iron) than QSM during childhood, both reaching a plateau in the mid‐30s to early 40s and decreasing thereafter. There were no hemispheric or sex differences for any region. Notably, both R2* and QSM values showed more inter‐subject variability with increasing age from 5 to 90 years, potentially reflecting a common starting point in iron/myelination during childhood that diverges as a result of lifestyle and genetic factors that accumulate with age.
Squeezing flow of Casson hybrid nanofluid between parallel plates with a heat source or sink and thermophoretic particle deposition
Authors: Jyothi A. M. , Varun Kumar R. S. , Madhukesh J. K. , Prasannakumara B. C. , Ramesh G. K.
Published: June 2021

The investigations on the flow of non‐Newtonian fluids are becoming one of the major topics in the research field. These liquids have substantial applications in industrial and engineering fields such as drilling rigs, food processing, paint and adhesives, nuclear reactors and cooling systems. On the other hand, hybrid nanofluids play a major role in the heat transfer process. Keeping this in mind, the motion of Casson hybrid nanofluid squeezing flow between two parallel plates with the effect of heat source and thermophoretic particle deposition is examined here. The partial differential equations that govern fluid flow are converted into ordinary differential equations using appropriate similarity variables and those equations are numerically solved using the Runge–Kutta–Fehlberg fourth–fifth‐order method by implementing the shooting scheme. The graphs depict the effects of a number of key parameters on fluid profiles in the absence and presence of the Casson parameter. These graphs show that fluid velocity enhances with the augmentation of the local porosity parameter. Thermal dispersal upsurges for enhancement of heat source/sink parameter and the concentration profile escalates for an upsurge of the thermophoretic parameter. Skin friction enhances with enhancement in the local porosity parameter.
Maternal Socs3 knockdown attenuates postnatal obesity caused by an early life environment of maternal obesity and intrauterine overnutrition in progeny mice
Authors: Zhu Feng , Zhang Dawei , Shen Fangfang , Xu Ke , Huang Xin , Liu Jue , Zhang Jin , Teng Yiqun
Published: June 2021

Pathological states in the early life environment of mammalian offspring, including maternal obesity and intrauterine overnutrition, can induce obesity and metabolic disorder later in life. Leptin resistance caused by upregulation of Socs3 in the hypothalamus of offspring was believed to be the main mechanism of this effect. In this study, obese mother (OM) and lean mother (LM) models were generated by feeding C57BL/6N female mice a high‐fat diet or standard lean diet, respectively. Additionally, an obese mother with intervention (OMI) model was generated by injecting the high‐fat diet group with Socs3‐shRNA lentivirus during early pregnancy. The offspring of the groups was correspondingly named OM‐F1, LM‐F1, and OMI‐F1, representing progeny mouse models of different early life environments. The offspring were fed a high‐fat diet to test their propensity for obesity. The body weight, food intake and fat accumulation were higher, while glucose intolerance and insulin resistance were worse in the OM‐F1 group than LM‐F1 group. By contrast, the obesity phenotype, hyperphagia and metabolic disorder were alleviated in the OMI‐F1 group compared with the OM‐F1 group. The mechanism was identified that downregulation of hypothalamic SOCS3 resulted in an increased level of p‐STAT3 and p‐JAK2, which ameliorated the leptin resistance and restored the lean expression of appetite regulatory genes (Pomc and Agrp) in hypothalamus of OMI‐F1 group. Taken together, these results indicate that reducing maternal Socs3 expression during pregnancy can attenuate obesity caused by the early life environment in mice, which may inspire therapies that enable obese mothers to bear metabolically healthy children.
Association of Sleep Traits and Heel Bone Mineral Density: Observational and Mendelian Randomization Studies
Authors: Chen Jie , Zhang Jihui , So Hon Cheong , Ai Sizhi , Wang Ningjian , Tan Xiao , Wing Yun Kwok
Published: June 2021

Observational studies have suggested that sleep and circadian disturbances are potentially modifiable risk factors for low bone mineral density (BMD), but the causal relationship is unclear. This study aimed to (i) replicate the findings by examining observational association of sleep traits with low estimated BMD); (ii) examine whether these associations were causal by using Mendelian randomization (MR) analyses; and (iii) investigate potential modulation effects of sex and menopause. A total of 398,137 White British subjects (aged 39 to 73 years) with valid BMD estimated by quantitative ultrasound of the heel (eBMD) at baseline were included. Linear regression analyses and inverse-variance weighted method were used as main methods for observational and one-sample MR analyses, respectively, to investigate the associations between self-reported sleep traits (sleep duration, chronotype, daytime sleepiness, and insomnia) and low eBMD. Furthermore, sensitivity analyses were performed in subgroups based on sex and menopause in both observational and MR analyses. In observational analyses, short/long sleep, insomnia, and definite eveningness were associated with low eBMD (short sleep: β = −0.045, effect in standard deviation change of rank-based inverse normally transformed eBMD; long sleep: β = −0.028; sometimes insomnia: β = −0.012; usually insomnia: β = −0.021; definite eveningness: β = −0.047), whereas definite morningness was associated with decreased risk of low eBMD (β = 0.011). Subgroup analyses suggested associations of short/long sleep and definite eveningness with low eBMD among men, short sleep with low eBMD among premenopausal women, and short sleep, eveningness, and daytime sleepiness among postmenopausal women. In bidirectional MR analyses, there was no causal relationship between sleep traits and eBMD in either overall sample or subgroup analyses. In summary, although observational analysis showed a robust association of low eBMD with sleep duration, chronotype, and insomnia, there was no evidence of causal relationship as suggested by MR analysis. © 2021 American Society for Bone and Mineral Research (ASBMR).
Spreadsheet‐Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients
Authors: Mahmood Iftekhar , Tegenge Million A.
Published: June 2021

There is a growing interest in the use of physiologically based pharmacokinetic (PBPK) models as clinical pharmacology drug development tools. In PBPK modeling, not every organ or physiological parameter is required, leading to the development of a minimal PBPK (mPBPK) model, which is simple and efficient. The objective of this study was to streamline mPBPK modeling approaches and enable straightforward prediction of clearance of protein‐based products in children. Four mPBPK models for scaling clearance from adult to children were developed and evaluated on Excel spreadsheets using (1) liver and kidneys; (2) liver, kidneys, and skin; (3) liver, kidneys, skin, and lymph; and (4) interstitial, lymph, and plasma volume. There were 35 therapeutic proteins with a total of 113 observations across different age groups (premature neonates to adolescents). For monoclonal and polyclonal antibodies, more than 90% of observations were within a 0.5‐ to 2‐fold prediction error for all 4 methods. For nonantibodies, 79% to 100% of observations were within the 0.5‐ to 2‐fold prediction error for the 4 different methods. Methods 1 and 4 provided the best results, >90% of the total observations were within the 0.5‐ to 2‐fold prediction error for all 3 classes of protein‐based products across a wide age range. The precision of clearance prediction was comparatively lower in children ≤2 years of age vs older children (>2 years of age) with methods 1 and 4 predicting 80% to 100% and 75% to 90% of observations within the 0.5‐ to 2‐fold prediction error, respectively. The results of the study indicated that mPBPK models can be developed on spreadsheets, with acceptable performance for prediction of clearance.
Model‐Informed Drug Development in Pediatric Dose Selection
Authors: Bi Youwei , Liu Jiang , Li Fang , Yu Jingyu , Bhattaram Atul , Bewernitz Michael , Li Ruo‐jing , Ahn Jihye , Earp Justin , Ma Lian , Zhuang Luning , Yang Yuching , Zhang Xinyuan , Zhu Hao , Wang Yaning
Published: June 2021

Model‐informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic‐based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age‐dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure‐response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit‐risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model‐based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.
Drug Safety in Labeling for Pediatric Drug Development and Dose Selection in Submissions to the US Food and Drug Administration
Authors: Kim Clara , Park Kyunghun , McMahon Ann W. , Green Francis G. , Green Dionna J. , Burckart Gilbert J.
Published: June 2021

Pediatric safety evaluations are an essential part of a pediatric drug development program. Communication of the results of these safety evaluations is primarily accomplished by labeling of the drug either during the initial pediatric drug development program, or during the postmarketing period after drug approval for pediatric patients. During drug development, the dose–adverse drug event (ADE) relationship is an important part of the evaluation, but a consideration for pediatric ADEs that are unrelated to drug dosage must be maintained. Examples of dose‐related and non–dose‐related ADEs are presented. The failure to label a product for pediatric use has been safety related for a number of development programs. The US Food and Drug Administration's Pediatric Advisory Committee is a primary source of the pediatric postmarketing safety review and has been associated with a number of labeling changes through its ongoing review process. Pediatric drug safety remains a critical part of the assessment of dose‐effect relationship in the pediatric patient population during the drug development and postmarketing surveillance process.
Applying the Noninferiority Paradigm to Assess Exposure‐Response Similarity and Dose Between Pediatric and Adult Patients
Authors: Zhang Qunshu , Travis James , Rothwell Rebecca , Jay Christopher E. , Jahidur Rashid , Zhang Yifei , Crentsil Victor , Altepeter Tara , Lee Jessica J. , Burckart Gilbert J. , Ganley Charles , Wang Jian
Published: June 2021

The use of extrapolation of efficacy in pediatric drug development programs is possible when disease progression and treatment response are similar in adult and pediatric populations. Historically, the exposure‐response (E‐R) similarity was assessed by visual inspection of 2 E‐R curves to support pediatric extrapolation. The aim of this study was to develop a quantitative framework to describe the E‐R relationship and the difference in E‐R between pediatric and adult patients based on accumulated experience in pediatric drug development programs. Using clinical data for 8 drugs with either a linear or nonlinear E‐R relationship, we adapted the methodology used in noninferiority testing to assess the E‐R similarity between adult and pediatric patients at the targeted drug exposure. We implemented bootstrap‐based and Bayesian‐based methodologies to estimate the probability of concluding noninferiority of the E‐R relationship. This approach provides objective criteria that can be applied to an assessment of E‐R noninferiority in 2 populations to support extrapolation of efficacy in drug development programs from adults to pediatric populations.
Sarcopenia and preserved bone mineral density in paediatric survivors of high‐risk neuroblastoma with growth failure
Authors: Guo Michelle , Zemel Babette S. , Hawkes Colin P. , Long Jin , Kelly Andrea , Leonard Mary B. , Jaramillo Diego , Mostoufi‐Moab Sogol
Published: June 2021

Background

Survival from paediatric high‐risk neuroblastoma (HR‐NBL) has increased, but cis‐retinoic acid (cis‐RA), the cornerstone of HR‐NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR‐NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR‐NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR‐NBL survivors compared with controls.

Methods

This prospective cross‐sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual‐energy X‐ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex‐specific standard deviation scores (Z‐scores) included aBMD (adjusted for height Z‐score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole‐body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength‐Z). Muscle‐specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR‐NBL survivors and controls using Student's t‐test or Mann–Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes.

Results

We enrolled 20 survivors of HR‐NBL treated with cis‐RA [13 male; mean age: 12.4 ± 1.6 years; median (range) age at therapy initiation: 2.6 (0.3–9.1) years] and 20 age‐, sex‐ and race‐matched controls. Height‐Z was significantly lower in HR‐NBL survivors compared with controls (−1.73 ± 1.38 vs. 0.34 ± 1.12, P < 0.001). Areal BMD‐Z, BMAD‐Z, FMI‐Z, visceral adipose tissue and subcutaneous adipose tissue were not significantly different in HR‐NBL survivors compared with controls. Compared with controls, HR‐NBL survivors had lower leg lean mass‐Z (−1.46 ± 1.35 vs. − 0.17 ± 0.84, P < 0.001) and strength‐Z (−1.13 ± 0.86 vs. − 0.15 ± 0.71, P < 0.001). Muscle‐specific force was lower in HR‐NBL survivors compared with controls (P < 0.05).

Conclusions

Bone mineral density and adiposity are not severely impacted in HR‐NBL survivors with growth failure, but significant sarcopenia persists years after treatment. Future studies are needed to determine if sarcopenia improves with muscle‐specific interventions in this population of cancer survivors.
Improved Brain MR Imaging from a Compact, Lightweight 3T Scanner with High‐Performance Gradients
Authors: Camerucci Emanuele , Campeau Norbert G. , Trzasko Joshua D. , Gray Erin M. , Bernstein Matt A. , Cogswell Petrice M. , Shu Yunhong , Foo Thomas K. , Huston John
Published: June 2021

Background

A low‐cryogen, compact  3T (C3T) MRI scanner with high‐performance gradients capable of simultaneously achieving 80 mT/m gradient amplitude and 700 T/m/second slew rate has been in use to study research patients since March 2016 but has not been implemented in the clinical practice.

Purpose

To compare head MRI examinations obtained with the C3T system and a conventional whole‐body  3T (WB3T) scanner in seven parameters across five commonly used brain imaging sequences.

Study Type

Prospective.

Subjects

Thirty patients with a clinically indicated head MRI.

Sequence

 3T; T1 FLAIR, T1 MP‐RAGE, 3D T2 FLAIR, T2 FSE, and DWI.

Assessment

All patients tolerated the scans well. Three board‐certified neuroradiologists scored the comparative quality of C3T and WB3T images in blinded fashion using a five‐point Likert scale in terms of: signal‐to‐noise ratio, lesion conspicuity, motion artifact, gray/white matter contrast, cerebellar folia, susceptibility artifact, and overall quality.

Statistical Test

Left‐sided, right‐sided, and two‐sided Wilcoxon signed rank test; Fisher's method. A P value <0.05 was considered statistically significant.

Results

The C3T system performed better than the WB3T in virtually all comparisons, except for motion artifacts for the T1 FLAIR and T1 MP‐RAGE sequences, where the WB3T system was deemed better. When combining all sequences together, the C3T system outperformed the WB3T system in all image quality parameters evaluated, except for motion artifact (P = 0.13).

Data Conclusion

The C3T scanner provided better overall image quality for all sequences, and performed better in all individual categories, except for motion artifact on the T1 FLAIR and T1 MP‐RAGE.

Level of Evidence

2

Technical Efficacy Stage

1
MRI‐Based Investigation of Association Between Cerebrovascular Structural Alteration and White Matter Hyperintensity Induced by High Blood Pressure
Authors: Zhang Boyu , Wang Yingzhe , Wang Bei , Chu Ying‐Hua , Jiang Yanfeng , Cui Mei , Wang He , Chen Xingdong
Published: June 2021

Background

High blood pressure (BP) is a common risk factor for cerebral small vessel disease including white matter hyperintensity (WMH). Whether increased BP exacerbates WMH by impacting cerebral vascular morphologies remains poorly studied.

Purpose

To determine the relationships among high BP, cerebrovascular morphologies, and WMH in elderly individuals.

Study Type

Cohort.

Subjects

Eight hundred sixty‐three participants (54.2% female) from the Taizhou Imaging Study without clinical evidence of neurologic disorders were included in the analyses.

Field Strength/Sequence

3.0 T; time‐of‐flight magnetic resonance angiography (TOF MRA); T2 fluid‐attenuated inversion recovery (FLAIR); T1 magnetization‐prepared rapid gradient‐echo; gradient echo T2*‐weighted; diffusion tensor imaging; pulsed arterial spin labeling.

Assessment

Cerebrovascular morphologic measurements were quantified based on the TOF MRA images, including vessel density, radius, tortuosity, and branch number. WMH lesion volumes (WMHV) and WMH lesion counts (WMHC) were calculated automatically based on the T2 FLAIR images.

Statistical Tests

Multivariable linear regression analysis and path analysis with a linear single‐mediator model were employed. A P value <0.05 was considered statistically significant.

Results

Higher BP, especially diastolic BP, was significantly correlated with lower cerebrovascular density (β = −104) and lower branch numbers (β = −0.02). Although decreased tortuosity (β = −1.25) and increased radius (β = 93.8) were correlated with BP, no significant relationship of tortuosity (β = −4.6 × 10−4, P = 0.58) or radius (β = 0.03, P = 0.08) with BP in small vessels was found. The proportion of small vessels decreased as BP increased (SBP: β = −6.6 × 10−4; DBP: β = −9.0 × 10−4). Similarly, increased WMHV and WMHC were associated with decreased vessel density (volumes: β = −24, counts: β = −127), decreased tortuosity (volumes: β = −0.08, counts: β = −0.53), and increased radius (volumes: β = 12.6, counts: β = 86.6). Path analyses suggested an association between high BP and WMHs that were mediated by cerebrovascular morphologic changes.

Data Conclusion

Structural alterations of cerebral vessels induced by high BP are correlated with WMH. This result suggested that elevated BP might be one of the pathophysiological mechanisms involving in the co‐occurrence of cerebrovascular alteration and small vessel disease.

Level of Evidence: 1

Technical Efficacy Stage: 1
Deficits in or preservation of basic number processing in Parkinson’s disease? A registered report
Authors: Loenneker Hannah D. , Artemenko Christina , Willmes Klaus , Liepelt‐Scarfone Inga , Nuerk Hans‐Christoph
Published: June 2021

Neurodegenerative diseases such as Parkinson's disease (PD) have a huge impact on patients, caregivers, and the health‐care system. To date, the diagnosis of mild cognitive impairments in PD has been established based on domain‐general functions such as executive functions, attention, or working memory. However, specific numerical deficits observed in clinical practice have not yet been systematically investigated. PD‐immanent deterioration of domain‐general functions and domain‐specific numerical areas suggests the mechanisms of both primary and secondary dyscalculia. The current study will systematically investigate basic number processing performance in PD patients for the first time, targeting domain‐specific cognitive representations of numerosity and the influence of domain‐general factors. The overall sample consists of patients with a diagnosis of PD, according to consensus guidelines, and healthy controls. PD patients will be stratified into patients with normal cognition or mild cognitive impairment (level I‐PD‐MCI based on cognitive screening). Basic number processing will be assessed using transcoding, number line estimation, and (non)symbolic number magnitude comparison tasks. Discriminant analysis will be employed to assess whether basic number processing tasks can differentiate between a healthy control group and both PD groups. All participants will be subjected to a comprehensive numerical and a neuropsychological test battery, as well as sociodemographic and clinical measures. Study results will give the first broad insight into the extent of basic numerical deficits in different PD patient groups and will help us to understand the underlying mechanisms of the numerical deficits faced by PD patients in daily life.
Raman spectroscopy of holey nanographene C216
Authors: Maghsoumi Ali , Beser Uliana , Feng Xinliang , Narita Akimitsu , Müllen Klaus , Castiglioni Chiara , Tommasini Matteo
Published: June 2021

We report a detailed investigation by Raman spectroscopy of the holey nanographene C216, a hexagon‐shaped disk with armchair edges (1.4 nm long), from which the central aromatic ring is missing. Density functional theory (DFT) calculations allow to assign the main features of the Raman spectra that have been recorded with several excitation wavelengths. In the Raman spectra, we observe signatures of the hole in the structure, several G and D modes, as well as their overtones and combinations—up to third order.
Plasmon resonance, thermal, and optical contributions to anti‐Stokes‐to‐Stokes line strength ratios in continuous wave‐excited surface‐enhanced Raman scattering spectra of molecules at random Ag surface
Authors: Arzumanyan Grigory M. , Mamatkulov Kahramon Z. , Vorobyeva Mariya Y. , Orlov Sergey N. , Polivanov Yury N. , Fabelinsky Victor I. , Kozlov Dimitrii N. , Smirnov Valery V. , Bandarenka Hanna V. , Khinevich Nadzeya V. , Zavatski Siarhei A.
Published: June 2021

Surface‐enhanced Raman scattering (SERS) by biochemically relevant organic reporter molecules, spread out over a promising localized surface plasmon resonance (LSPR) structure of randomly arranged silver nanoscale particles (AgPs) of various dimensions and shape, was induced using tightly focused continuous wave (CW) 785‐nm laser radiation, and the spectra were registered simultaneously in the anti‐Stokes and Stokes spectral ranges. The spectra were recorded as a function of the excitation laser power density in the range of their profile reproducibility. The power density dependences of the line strength ratio for three respective pairs of vibrational lines of a thiolate of 2‐nitrobenzoic acid (TNB) in SERS spectra were derived. Using these data, we specify and quantify the contributions responsible for the discrepancy between this ratio and that defined by the thermal equilibrium populations of the upper and lower vibrational levels corresponding to the Raman‐active transitions. These contributions are the following: (i) the spectral profile of an LSPR contour, (ii) local heating of the reporter molecule/AgP conjugates by the 785‐nm radiation, and (iii) optical (Raman) pumping of the upper vibrational levels of the transitions involved. The extraction of the latter contribution enabled us to estimate the cross‐sections of the TNB/AgP conjugates Raman vibrational pumping by the radiation for each of the three vibrational modes.
Utility of the ACS‐NSQIP surgical risk calculator in predicting postoperative complications in patients undergoing oncologic proximal femoral replacement
Authors: Labott Joshua R. , Brinkmann Elyse J. , Hevesi Mario , Wyles Cody C. , Couch Cory G. , Rose Peter S. , Houdek Matthew T.
Published: June 2021

Introduction

Proximal femur replacement (PFR) in the setting of tumor resection is associated with a high rate of postoperative complication. The online American College of Surgeons‐National Surgical Quality Improvement Program (ACS‐NSQIP) surgical risk calculator is approved by the Center of Medicare and Medicaid services to estimate 30‐day postoperative complications. This study was to determine if the ACS‐NSQIP can predict postoperative complications following PFR.

Methods

We reviewed 103 (61 male and 42 female) patients undergoing PFR using the Current Procedural Terminology (CPT) codes available in the calculator: 27125 (hemiarthroplasty), 27130 (total hip), 27132 (conversion to total hip), 27134 (revision total hip), 27137 (revision acetabulum), 27138 (revision femur), and 27365 (excision tumor hip). The predicted rates of complications were compared with the observed rates.

Results

Complications occurred in 54 (52%) of patients, with the predicted risk based on CPT codes: 27125 (21.5%); 27130 (7.8%); 27132 (16.6%), 27134 (17.8%), 27137 (14.4%), 274138 (22.7%), and 27365 (16.2%). The calculator was a poor predictor of complications (27125, area under the curve [AUC] 0.576); (27130, AUC 0.489); (27132, AUC 0.490); (27134, AUC 00.489); (27137, AUC 0.489); (27138, AUC 0.471); and (27365, AUC 0.538).

Conclusion

Oncologic PFR is known for complications. The ACS‐NSQIP does not adequately predict the incidence of complications, and therefore cannot reliably be used in their shared decision‐making process preoperative.