bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose‐Related Adverse Drug Events in Neonates: Recognition and Assessment
Authors: Allegaert Karel , van den Anker John 
Published: June 2021

AbstractThe efficacy and safety of a drug is dose or exposure related, and both are used to assess the benefit‐risk balance of a given drug and ultimately to decide on the specific drug license, including its dose and indication(s). Unfortunately, both efficacy and safety are much more difficult to establish in neonates, resulting in very few drugs licensed for use in this vulnerable population. This review will focus on dose‐related adverse events in neonates. Besides the regulatory classification on seriousness, adverse event assessment includes aspects related to signal detection, causality, and severity. Disentangling confounders from truly dose‐related adverse drug events remains a major challenge, as illustrated for drug‐induced renal impairment, drug‐induced liver injury, and neurodevelopmental outcome. Causality assessment, using either routine tools (Naranjo algorithm, World Health Organization's Uppsala Monitoring Center causality tool) or a Naranjo algorithm tailored to neonates, still does not sufficiently and reliably document causality in neonates. Finally, very recently, a first neonatal severity‐grading tool for neonates has been developed. Following the development of advanced pharmacokinetic approaches and techniques to predict and assess drug exposure, additional efforts are needed to truly and fully assess dose adverse drug events. To further operationalize the recently developed tools on causality and severity, reference databases on a palette of biomarkers and outcome variables and their covariates are an obvious next step. These databases should subsequently be integrated in modeling efforts to truly explore safety outcome, including aspects associated with or caused by drug dose or exposure.
Progress in Drug Development–Pediatric Dose Selection: Workshop Summary
Authors: Wang Jian , van den Anker John N. , Burckart Gilbert J. 
Published: June 2021

AbstractThe "Pediatric Dose Selection" workshop was held in October 2020 and sponsored by the U.S. Food and Drug Administration and the University of Maryland Center for Excellence in Regulatory Science and Innovation. A summary of the presentations in the context of pediatric drug development is summarized in this article.
Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line?
Authors: Johnson Trevor N. , Ke Alice B. 
Published: June 2021

AbstractDeveloping medicines for children is now established in legislation in both the United States and Europe; new drugs require pediatric study or investigation plans as part of their development. Particularly in early age groups, many developmental processes are not reflected by simple scalars such as body weight or body surface area, and even projecting doses based on simple allometric scaling can lead to significant overdoses in certain age groups. Modeling and simulation methodology, including physiologically based modeling, has evolved as part of the drug development toolkit and is being increasingly applied to various aspects of pediatric drug development. Pediatric physiologically based pharmacokinetic (PBPK) models account for the development of organs and the ontogeny of specific enzymes and transporters that determine the age‐related pharmacokinetic profiles. However, when should this approach be used, and when will simpler methods such as allometric scaling suffice in answering specific problems? The aim of this review article is to illustrate the application of allometric scaling and PBPK in pediatric drug development and explore the optimal application of the latter approach with reference to case examples. In reality, allometric scaling included as part of population pharmacokinetic and PBPK approaches are all part of a model‐informed drug development toolkit helping with decision making during the process of drug discovery and development; to that end, they should be viewed as complementary.
Considerations for Drug Dosing in Premature Infants
Authors: van den Anker John , Allegaert Karel 
Published: June 2021

AbstractIn premature infants, effective and safe drug therapy depends on optimal dose selection and requires a thorough understanding of the underlying disease(s) of these fragile infants as well as the pharmacokinetics and pharmacodynamics of the drugs selected to treat their diseases. Differences in gestational and postnatal age or weight are the major determinants of the observed variability in drug disposition and effect in these infants. This article presents an outline on how to translate the results of a population pharmacokinetic/pharmacodynamic study into rational dosing regimens, and how physiologically based pharmacokinetic modeling, electronic health records, and the abundantly available data of vital functions of premature infants during their stay in the neonatal intensive care unit for evaluation of their pharmacotherapy can be used to tailor the most safe and effective dose in these infants.
Developing a self‐assessment tool for dental faculty to map professional growth
Authors: Krupp Michelle M. , Barlow Patrick B. , Kyle Eric J. 
Published: June 2021

AbstractAlthough self‐assessment is a lifelong skill practiced in predoctoral training, the utility of this mechanism is seldom linked to competencies that encompass the broad range of skill sets and roles of an academic dentist. Literature defining faculty competencies and/or roles in medical and dental education is limited in scope focusing primarily on teaching and research. Identifying the broad spectrum of dental faculty skill sets and connecting them to self‐assessment and professional development needs to be explored. Furthermore, a mechanism that can serve as a professional roadmap with identified areas to develop and catapult faculty into a self‐reflection growth process is lacking in dental academia. The purpose of this study was to define the broad spectrum of competencies, or skill sets of an academic dentist and develop a faculty self‐assessment tool grounded in self‐regulation theory to help faculty track and plan professional growth. A mixed‐methods approach including a faculty focus group was used to refine and verify the relevance of pre‐defined faculty roles and skill sets. A self‐assessment instrument was then developed with 31 broad skills and two scales that ascertained faculty interest in developing and development stage for each skill set. The intended utility of the self‐assessment tool is to provide an introspective mechanism to obtain specific information about a wide range of faculty professional growth areas beyond teaching and research. The instrument can also be used to facilitate mentoring and may have implications for determining faculty development programming.
Unrecognized introduction of SARS‐CoV‐2 variants of concern to Central Africa: Import and local transmission of B.1.1.7 in Gabon in the very early stage of the variant spread to the African continent
Authors: Abe Haruka , Ushijima Yuri , Bikangui Rodrigue , Zoa‐Assoumou Samira , Ondo Georgelin Nguema , Manouana Gédéon Prince , More Ayong , Skarwan Emilio , Yali‐Assy‐Oyamli Yoric , Ndeboko Bénédicte , Myrabelle Avome Houechenou Rotimi , Djoba Siawaya Joel Fleury , Lell Bertrand , Adegnika Ayola Akim , Yasuda Jiro 
Published: June 2021

AbstractThe rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variant of concern with higher infectivity has already resulted in the enormous increase in infection cases worldwide. We report an unrecognized introduction of the variant B.1.1.7 in Gabon in December 2020, which was the initial phase of the variant introduction to Africa. The B.1.1.7 variant was also detected in a hospitalized patient in January 2021, indicating a rapid spread of the variant in Gabon since its first detection. Phylogenetic analysis revealed that the detected B.1.1.7 variants originated from the distinct regions, strongly suggesting that the B.1.1.7 variant had been repeatedly introduced to Gabon since December 2020. These results provide insights on the unrecognized risks of infections with variants of concern, and show the necessity to conduct continuous genomic monitoring for immediate alert and control of novel SARS‐CoV‐2 variant infections.
Estimation and removal of spurious echo artifacts in single‐voxel MRS using sensitivity encoding
Authors: Berrington Adam , Považan Michal , Barker Peter B. 
Published: June 2021

PurposeIn localized MRS, spurious echo artifacts commonly occur when unsuppressed signal outside the volume of interest is excited and refocused. In the spectral domain, these signals often overlap with metabolite resonances and hinder accurate quantification. Because the artifacts originate from regions separate from the target MRS voxel, this work proposes that sensitivity encoding based on receive‐coil sensitivity profiles may be used to separate these signal contributions.MethodsNumerical simulations were performed to explore the effect of sensitivity‐encoded separation for unknown artifact regions. An imaging‐based approach was developed to identify regions that may contribute to spurious echo artifacts, and tested for sensitivity‐based unfolding of signal on six data sets from three brain regions. Spectral data reconstructed using the proposed method (“ERASE”) were compared with the standard coil combination.ResultsThe method was able to fully unfold artifact signals if regions were known a priori. Mismatch between estimated and true artifact regions reduced the efficiency of removal, yet metabolite signals were unaffected. Water suppression imaging was able to identify regions of unsuppressed signal, and ERASE (from up to eight regions) led to visible removal of artifacts relative to standard reconstruction. Fitting errors across major metabolites were also lower; for example, Cramér–Rao lower bounds of myo‐inositol were 13.7% versus 17.5% for ERASE versus standard reconstruction, respectively.ConclusionThe ERASE reconstruction tool was demonstrated to reduce spurious echo artifacts in single‐voxel MRS. This tool may be incorporated into standard workflows to improve spectral quality when hardware limitations or other factors result in out‐of‐voxel signal contamination.
Single‐shot pseudo‐centric EPI for magnetization‐prepared imaging
Authors: Lee Hyun‐Soo , Hwang Seon‐Ha , Park Jaeseok , Park Sung‐Hong 
Published: June 2021

PurposeTo implement a single‐shot centric‐reordered EPI (1sh‐CenEPI), which reduces TE significantly, thus enabling to improve SNR for magnetization‐prepared imaging.MethodsWe proposed a 1sh‐CenEPI in which grouped oscillating readout gradients, phase‐encoding blips within each group, and big phase‐encoding jumps between two consecutive groups are incorporated to encode whole k‐space from the center to the edges in a single shot. The concept was tested on phantoms and human brains at 3 T. In addition, the proposed reordering scheme was applied to pseudo‐continuous arterial spin labeling for evaluating the efficiency of the centric reordering in magnetization‐prepared imaging.ResultsThe proposed 1sh‐CenEPI reduced TE from 50 ms to 1.4 ms for gradient‐echo EPI, and from 100 ms to 7 ms for spin‐echo EPI, while the elongation of readout duration was below 10% of the whole readout duration in most cases. The 1sh‐CenEPI images exhibited no distinct geometric distortion both in phantom and human brain, comparable to the conventional two‐shot center‐out EPI. In pseudo‐continuous arterial spin labeling results, 3‐fold temporal SNR increase and 2‐fold spatial SNR increase in the perfusion‐weighted images were achieved with 1sh‐CenEPI compared with the conventional linear ordering, whereas the cerebral blood flow values were consistent with previous studies.ConclusionThe proposed 1sh‐CenEPI significantly reduced TE while maintaining similar readout window and providing images comparable to the conventional linear and multishot center‐out EPI images. It can be a qualified candidate as a new readout for various magnetization‐prepared imaging techniques.
Drivers of mechanical performance variance in 3D‐printed fused filament fabrication parts: An Onyx FR case study
Authors: Ma Christine , Faust Jessica , Roy‐Mayhew Joseph D. 
Published: June 2021

AbstractEffects on mechanical properties of user‐controlled and user‐uncontrolled factors in a 3D printing system were investigated using a flame retardant carbon fiber reinforced nylon filament. Moisture and print orientation, both user controllable elements, dominated mechanical property variation. Dry samples exhibited tensile (flexural) strength 2.4 (2.1) times greater than that of wet samples, while ZX samples were measured to have about half the tensile strength of XY and XZ samples. User‐uncontrolled factors including material to material variation and printer to printer variation were found to have minor impact (<5%) on part tensile strength. Reinforcing the part with 21 vol% continuous fiber lowers the moisture induced variance from 13% to 2% in addition to increasing the measured strength by about 10× (to 451 MPa).
Prospective study of diagnostic accuracy in the detection of high‐grade prostate cancer in biopsy‐naïve patients with clinical suspicion of prostate cancer who underwent the Select MDx test
Authors: Lendínez‐Cano Guillermo , Ojeda‐Claro Ana Victoria , Gómez‐Gómez Enrique , Morales Jimenez Pedro , Flores Martin José , Dominguez Juan Francisco , Amores Javier , Cozar Jose Manuel , Bachiller Jaime , Juárez Alvaro , Linares Ramón , Garcia Galisteo Emilio , Alvarez Ossorio Jose Luis , Requena Tapia Maria José , Moreno Jimenez Juan , Medina Lopez Rafael Antonio ,   AEU‐PIEM/2018/000 Investigators
Published: June 2021

AbstractObjectivesThis study aimed to externally validate the diagnostic accuracy of the Select MDx test for Significant prostate cancer (Sig PCa) (ISUP > 1), in a contemporaneous, prospective, multicenter cohort with a prostate‐specific antigen (PSA) between 3 and 10 ng/ml and a non‐suspicious digital rectal examination.Methods and ParticipantsFor all enrolled patients, the Select Mdx test, the risk calculator ERSPC3 + DRE, and a prostatic magnetic resonance imaging (MRI) were carried out. Subsequently, a systematic 12‐core trans‐rectal biopsy and a targeted biopsy, in the case of a prostate imaging–reporting and data system (PIRADS) > 2 lesion (max three lesions), were performed. To assess the accuracy of the Select MDx test in the detection of clinically Sig PCa, the test sensitivity was evaluated. Secondary objectives were specificity, negative predictive value (NPV), positive predictive value (PPV), and area under the curve (AUC). A direct comparison with the ERSPC + DRE risk calculator and MRI were also performed. We also studied the predictive ability to diagnose Sig PCa from the combination of the Select MDx test with MRI using clinical decision‐curve analysis.ResultsThere were 163 patients enrolled after meeting the inclusion criteria and study protocol. The Select MDx test showed a sensitivity of 76.9% (95% CI, 63.2–87.5), 49.6% specificity (95% CI, 39.9–59.2), 82.09% (95% CI, 70.8–90.4) NPV, and 41.67% (95% CI, 31.7–52.2) PPV for the diagnosis of Sig PCa. COR analysis was also performed, which showed an AUC of 0.63 (95% CI, 0.56–0.71). There were no differences in the accuracy of Select MDx, ERSPC + DRE, or MRI. The combination of Select MDX + MRI showed the highest impact in the decision‐curve analysis, with an NPV of 93%.ConclusionOur study showed a worse performance for the SelectMdx test than previously reported, within a cohort of patients with a PSA 3–10 ng/ml and a normal DRE, with results similar to those from ERSPC + DRE RC and MRI, but with an improvement in the usual PSA pathway. A combination of the Select Mdx test and MRI could improve accuracy, but studies specifically evaluating this scenario with a cost‐effective analysis are needed.
Using physiologically‐based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet
Authors: Sun Lei , Barter Zoe , von Moltke Lisa , Rowland Yeo Karen 
Published: June 2021

AbstractA combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically‐based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once‐daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady‐state total systemic exposures by 1.1‐, 1.5‐, and 1.6‐fold, respectively, for olanzapine, and by 1.2‐, 1.9‐, and 2.3‐fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.
Terminal sliding mode‐based tracking control with error transformation for underwater vehicles
Authors: Liu Xing , Zhang Mingjun , Rogers Eric , Wang Yujia , Yao Feng 
Published: June 2021

AbstractOcean currents and waves can cause the initial position of an underwater vehicle to deviate from the initial state of the desired trajectory. For such cases, this paper investigates the finite‐time tracking control problem for a vehicle in the presence of large initial tracking errors and external disturbances. A continuous finite‐time tracking control scheme is developed for this scenario based on an improved nonsingular terminal sliding mode surface modified by a piecewise function. Compared to the alternative approaches, a method based on error transformation is added to the sliding mode surface, resulting in improved tracking accuracy in the steady state. Then, to reduce the effect of large initial tracking error on the control input signals, an exponential decay function about the initial location of the vehicle is developed to obtain the control law by combining it with a strictly generalized saturation function. In contrast to alternative approaches, a nonlinear structure is used to counteract the approximation error of the neural network used in the modeling of the dynamics. Moreover, it is shown that the tracking error converges to a small neighborhood of zero in a fixed time. Finally, the new control scheme's effectiveness is verified by simulation studies on an underwater vehicle model and the results compared to other existing control designs.
Understanding of Strain‐Induced Electronic Structure Changes in Metal‐Based Electrocatalysts: Using Pd@Pt Core‐Shell Nanocrystals as an Ideal Platform
Authors: Xue Shuyan , Chen Guanyu , Li Fan , Zhao Yunhao , Zeng Qingwen , Peng Jiaheng , Shi Fenglei , Zhang Wencong , Wang Yizhe , Wu Jianbo , Che Renchao 
Published: June 2021

AbstractWhile metal‐based electrocatalysts have garnered extensive attention owing to the large variety of enzyme‐mimic properties, the search for such highly‐efficient catalysts still relies on empirical explorations, owing to the lack of predictive indicators as well as the ambiguity of structure‐activity relationships. Notably, surface electronic structures play a crucial role in metal‐based catalysts yet remain unexplored in enzyme‐mimics. Herein, the authors investigate the electronic structure as a possible indicator of electrocatalytic activities of H2O2 decomposition and glucose oxidation using Pd@Pt core‐shell nanocrystals as a well‐defined platform. The electron densities of the Pd@Pt are modulated with the correlation of strain through precise control of surface orientation and the number of atomic layers. The close relationships between the electrocatalytic activities and the surface charge accumulation are found, in which the increase of the electron accumulation can enhance both the enzyme‐mimic activities. As a result, the Pd@Pt3L icosahedra with compressive strain in Pt shells exhibit the highest electrocatalytic activities for H2O2 decomposition and glucose oxidation. Such systematic and comprehensive study provides the structure‐activity relationships and paves a new way for the rational design of metal‐based electrocatalysts. Especially, the charge accumulation degrees may serve as a general performance indicator for metal‐based catalysts.
Reactivity and Selectivity Principles in Native Protein Bioconjugation
Authors: Adakkattil Ramesh , Thakur Kalyani , Rai Vishal 
Published: June 2021

AbstractAre chemical methods capable of precisely engineering the native proteins? Is it possible to develop platforms that can empower the regulation of chemoselectivity, site‐selectivity, modularity, protein‐specificity, and site‐specificity? This account delineates our research journey in the last ten years on the developments revolving around these questions. It will range from the realization of chemoselective and site‐selective labeling of reactivity hotspots to modular linchpin directed modification (LDM®) platform and site‐specific Gly‐tag® technology. Also, we outline a few biotechnology tools, including Maspecter®, that accelerated the detailed analysis of the bioconjugates and rendered a powerful toolbox for homogeneous antibody‐drug conjugates (ADCs).