bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT
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

AbstractThere 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

AbstractModel‐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

AbstractPediatric 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

AbstractThe 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

AbstractBackgroundSurvival 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.MethodsThis 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.ResultsWe 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).ConclusionsBone 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

BackgroundA 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.PurposeTo 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 TypeProspective.SubjectsThirty patients with a clinically indicated head MRI.Sequence 3T; T1 FLAIR, T1 MP‐RAGE, 3D T2 FLAIR, T2 FSE, and DWI.AssessmentAll 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 TestLeft‐sided, right‐sided, and two‐sided Wilcoxon signed rank test; Fisher's method. A P value <0.05 was considered statistically significant.ResultsThe 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 ConclusionThe 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 Evidence2Technical Efficacy Stage1
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

BackgroundHigh 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.PurposeTo determine the relationships among high BP, cerebrovascular morphologies, and WMH in elderly individuals.Study TypeCohort.SubjectsEight 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/Sequence3.0 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.AssessmentCerebrovascular 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 TestsMultivariable linear regression analysis and path analysis with a linear single‐mediator model were employed. A P value <0.05 was considered statistically significant.ResultsHigher 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 ConclusionStructural 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: 1Technical 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

AbstractNeurodegenerative 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

AbstractWe 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

AbstractSurface‐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

AbstractIntroductionProximal 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.MethodsWe 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.ResultsComplications 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).ConclusionOncologic 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.