bluuebunny/crossref_metadata_2025_split huggingface dataset:
Awareness of sports‐related dental emergencies and prevention practices among Libyan contact sports coaches: A cross‐sectional study
Authors: Elareibi Iman , Fakron Sarah , Gaber Amal , Lambert Martijn , El Tantawi Maha , Arheiam Arheiam 
Published: December 2022

AbstractBackground and aimsDespite the high incidence rate of dental trauma and its possible devastating physical and psychological consequences on children, little is known about sport‐related dental trauma and its prevention and management among Libyan sports coaches. The present study aimed to assess the knowledge and attitude of Benghazi contact sports coaches regarding sport‐related dental trauma and its prevention and management.MethodsA cross‐sectional study design was used. Two hundred and thirty‐one contact sports coaches were recruited from different public and private youth sports centers across Benghazi. The data were collected using a self‐administered questionnaire translated into Arabic and piloted to evaluate its validity and clarity. In addition, Mann–Whitney U, Kruskal–Wallis, and χ2 tests were used to check associations between the variables.ResultsA total of 151 contact sports coaches returned a completed questionnaire; the majority of coaches (74%) have seen orofacial injuries during their coaching career, whereas less than half of them (47%) personally experienced these injuries. Only one participant said he would preserve the tooth in milk, and four indicated that they would replant it. Most coaches (89.4%) knew what a mouthguard is, but 53.6% would recommend its use, and these were more likely to have previously used mouthguards (p ≤ 0.001). About 41.1% received previous training on TDIs‐related emergencies. Higher knowledge scores were observed among coaches who previously received training (p = 0.023).ConclusionThe findings of this study indicate low awareness of how to manage and prevent orofacial injuries among Libyan contact sports coaches, even though they commonly encounter these injuries and believe in mouthguards' effectiveness. Previous training on managing emergencies and experience appeared to influence the coaches' knowledge. Training coaches on preventing TDIs and their early management in sports fields should be an implemented policy and a prerequisite to obtaining a training license.
Protective effect of isoflurane preconditioning on neurological function in rats with HIE
Authors: Fei‐Sun Yi , Huang Miao , Qin Hao‐Yue , Campos de SouzaHan Senio , Xue Han , Wang Yu‐Ying , Wang Yi‐Bo 
Published: December 2022

AbstractHypoxic–ischemic encephalopathy (HIE) is an important cause of neonatal death and disability, which can lead to long‐term neurological and motor dysfunction. Currently, inhalation anesthetics are widely used in surgery, and some studies have found that isoflurane (ISO) may have a positive effect on neuroprotection. In this paper, we investigated whether ISO pretreatment has a neuroprotective effect on the neurological function of HIE rats. Here, 7‐day‐old neonatal rats were randomly divided into a sham group, a hypoxic–ischemic (HI) group, and an ISO pretreatment (pretreatment) group. The pretreatment group was pretreated with 2% ISO for 1 h, followed by the HI group to establish an HI animal model. The HI‑induced neurological injury was evaluated by Zea‑Longa scores and triphenyltetrazolium (TTC) staining. Neuronal number and histomorphological changes were observed with Nissl staining and Hematoxylin–eosin (HE) staining. In addition, motor learning memory function was evaluated by the Morris water maze (MWM), the Y‐maze, and the rotarod tests. HI induced severe neurological dysfunction, brain infarction, and cell apoptosis as well as obvious neuron loss in neonatal rats. In the MWM, the rats in the pretreatment group showed a decrease in escape latency (p = 0.042), indicating that pretreatment with ISO could improve the learning ability of HI rats. The results of Nissl staining showed that in the HI group, there was an irregular arrangement of neurons and nuclear fixation; however, the cell damage was significantly reduced and the total number of neurons was increased after ISO pretreatment (p < 0.001). In conclusion, ISO pretreatment improved cognitive function and attenuated HI‐induced reduction of Nissl‐positive cells and spatial memory impairment, suggesting that pretreatment with ISO before HI modeling could reduce neuronal cell death in the hippocampus after HI.
Critical review of the OSPAR risk-based approach for offshore-produced water discharges
Authors: Nielsen Ann F. , Baun Anders , Andersen Simon I. , Skjolding Lars M. 
Published: December 2022

Abstract
The management of produced water (PW) discharges from offshore oil and gas installations in the North Atlantic is under the auspices of OSPAR (Oslo/Paris convention for Protection of the Marine Environment of the North-East Atlantic). In 2010, OSPAR introduced the risk-based approach (RBA) for PW management. The RBA includes a hazard assessment estimating PW ecotoxicity using two approaches: whole-effluent toxicity (WET) and substance-based (SB). Set against the framework of the WET and SB approach, we conducted a literature review on the magnitude and cause of PW ecotoxicity, respectively, and on the challenges of estimating these. A large variability in the reported magnitude of PW WET was found, with EC50 or LC50 values ranging from &lt;1% to &gt;100%, and a median of 11% (n = 301). Across the literature, metals, hydrocarbons, and production chemicals were identified as causing ecotoxicity. However, this review reveals how knowledge gaps on PW composition and high sample and species dependency of PW ecotoxicity make clear identification and generalization difficult. It also highlights how limitations regarding the availability and reliability of ecotoxicity data result in large uncertainties in the subsequent risk estimates, which is not adequately reflected in the RBA output (e.g., environmental impact factors). Thus, it is recommended to increase the focus on improving ecotoxicity data quality before further use in the RBA, and that WET should play a more pronounced role in the testing strategy. To increase the reliability of the SB approach, more attention should be paid to the actual composition of PW. Bioassay-directed chemical analysis, combining outcomes of WET and SB in toxicity identification evaluations, may hold the key to identifying drivers of ecotoxicity in PW. Finally, an uncertainty appraisal must be an integrated part of all reporting of risk estimates in the RBA, to avoid mitigation actions based on uncertainties rather than reliable ecotoxicity estimations. Integr Environ Assess Manag 2023;19:1172–1187. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
Transvaginal ultrasound versus magnetic resonance imaging for diagnosing adenomyosis: A systematic review and head‐to‐head meta‐analysis
Authors: Alcázar Juan Luis , Vara Julio , Usandizaga Claudia , Ajossa Silvia , Pascual María Á. , Guerriero Stefano 
Published: December 2022

AbstractBackgroundTransvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) are used for the clinical diagnosis of adenomyosis.ObjectivesTo compare the diagnostic accuracy of TVS and MRI for the diagnosis of adenomyosis.Search StrategyA search of studies was performed in five databases comparing TVS and MRI for the diagnosis of adenomyosis from January 1990 to May 2022.Selection CriteriaStudies were eligible if they reported on the use of TVS and MRI in the same set of patients. The reference standard must be pathology (hysterectomy).Data Collection and AnalysisThe quality of studies was assessed using the QUADAS‐2 tool. Pooled sensitivity and specificity of both techniques were estimated and compared.Main ResultsSix studies comprising 595 women were included. The risk of bias of patient selection was high in three studies. The risk of bias for index tests and reference test was low. Pooled estimated sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for TVS were 75%, 81%, 3.9, and 0.31, respectively. These figures for MRI were 69%, 80%, 3.5, and 0.39, respectively. No statistically significant differences were found (p = 0.7509). Heterogeneity was high.ConclusionsMRI and TVS have similar performances for the diagnosis of adenomyosis.
Dual‐analgesic loadedUHMWPEexhibits synergistic antibacterial effects againstStaphylococci
Authors: Gil Dmitry , Hugard Shannon , Borodinov Nikolay , Ovchinnikova Olga S. , Muratoglu Orhun K. , Bedair Hany , Oral Ebru 
Published: December 2022

AbstractTotal joint arthroplasty is one of the most common surgeries in the United States, with almost a million procedures performed annually. Periprosthetic joint infections (PJI) remain the most devastating complications associated with total joint replacement. Effective antibacterial prophylaxis after primary arthroplasty could substantially reduce incidence rate of PJI. In the present study we propose to provide post‐arthroplasty prophylaxis via dual‐analgesic loaded ultra‐high molecular weight polyethylene (UHMWPE). Our approach is based on previous studies that showed pronounced antibacterial activity of analgesic‐ and NSAID‐loaded UHMWPE againstStaphylococci. Here, we prepared bupivacaine/tolfenamic acid‐loaded UHMWPE and assessed its antibacterial activity againstStaphylococcus aureusandStaphylococcus epidermidis. Dual‐drug loaded UHMWPE yielded an additional 1–2 log reduction of bacteria, when compared with single‐drug loaded UHMWPE. Analysis of the drug elution kinetics suggested that the observed increase in antibacterial activity is due to the increased tolfenamic acid elution from dual‐drug loaded UHMWPE. We showed that the increased fractal dimension of the drug domains in UHMWPE could be associated with increased drug elution, leading to higher antibacterial activity. Dual‐analgesic loaded UHMWPE proposed here can be used as part of multi‐modal antibacterial prophylaxis and promises substantial reduction in post‐arthroplasty mortality and morbidity.
Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice
Authors: Ahmad Mubashir , Stirmlinger Nadine , Jan Irfana , Stifel Ulrich , Lee Sooyeon , Weingandt Marcel , Kelp Ulrike , Bockmann Jürgen , Ignatius Anita , Böckers Tobias M. , Tuckermann Jan 
Published: December 2022

ABSTRACTMutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2−/−) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)‐derived osteoblasts from a loss‐of‐function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Natural History and Real‐World Data in Rare Diseases: Applications, Limitations, and Future Perspectives
Authors: Liu Jing , Barrett Jeffrey S. , Leonardi Efthimia T. , Lee Lucy , Roychoudhury Satrajit , Chen Yong , Trifillis Panayiota 
Published: December 2022

AbstractRare diseases represent a highly heterogeneous group of disorders with high phenotypic and genotypic diversity within individual conditions. Due to the small numbers of people affected, there are unique challenges in understanding rare diseases and drug development for these conditions, including patient identification and recruitment, trial design, and costs. Natural history data and real‐world data (RWD) play significant roles in defining and characterizing disease progression, final patient populations, novel biomarkers, genetic relationships, and treatment effects. This review provides an introduction to rare diseases, natural history data, RWD, and real‐world evidence, the respective sources and applications of these data in several rare diseases. Considerations for data quality and limitations when using natural history and RWD are also elaborated. Opportunities are highlighted for cross‐sector collaboration, standardized and high‐quality data collection using new technologies, and more comprehensive evidence generation using quantitative approaches such as disease progression modeling, artificial intelligence, and machine learning. Advanced statistical approaches to integrate natural history data and RWD to further disease understanding and guide more efficient clinical study design and data analysis in drug development in rare diseases are also discussed.
Clinical Pharmacology Considerations on Recombinant Adeno‐Associated Virus–Based Gene Therapy
Authors: Sun Kefeng , Liao Michael Z. 
Published: December 2022

AbstractRecombinant adeno‐associated virus (AAV) is currently the most widely used platform for in vivo gene therapy. Clinical pharmacology is a central field for AAV gene therapy, represented by the pillars of pharmacokinetics, pharmacodynamics/efficacy, and safety. In this review, we provide a comprehensive summary of clinical pharmacology considerations for recombinant AAV. The main topics covered are biodistribution and shedding, dose–exposure–response relationship, safety, immune and stress response, and clinical dose selection strategies. We highlight how the cumulative knowledge of AAV gene therapy could help with guiding clinical trial design and assessing and mitigating risks, as well as planning and executing pharmacokinetic/pharmacodynamic /safety data analyses. In addition, we discuss the major gaps and areas of growth in clinical pharmacology understanding of recombinant AAV. These include the mechanisms of the durability of treatment response and variability in biodistribution, transduction, and immunogenicity, as well as a potential influence on AAV's safety and efficacy profiles by drug product characteristics and patient intrinsic/extrinsic factors.
Immunogenicity Considerations for Therapeutic Modalities Used in Rare Diseases
Authors: Fathallah Anas M. , Oldfield Philip , Fiedler‐Kelly Jill , Ramadan Abdulraouf 
Published: December 2022

AbstractNew therapeutic modalities carry with them great promise for the treatment of rare diseases. They also present unique development challenges including immunogenicity, which can impact the safety and efficacy of those new modalities. In this review, an overview of the basic function of the immune system and its possible interaction with new therapeutic modalities is presented. A juxtaposition of immunogenicity in the rare disease space versus traditional clinical programs is hereby being proposed. A clinical pharmacology viewpoint of immunogenicity, proposed approaches to account for immunogenicity in clinical data, bioanalytical considerations, and effects of route of administration and production changes on immunogenicity are discussed.
Overview of Clinical Pharmacology Packages of New Drug Applications Approved for the Treatment of Rare Diseases
Authors: Qosa Hisham , Hassan Hazem E. , Younis Islam R. 
Published: December 2022

AbstractThere are more than 7000 rare diseases affecting approximately 30 million people in the United States. More than 90% of these diseases lack approved therapies. Several challenges face the development of “orphan drugs”, such as the small populations of patients, high development costs, and long development timelines. This study evaluates clinical pharmacology assessments conducted during the development of drugs to treat rare diseases approved by the United States Food and Drug Administration in 2020 and 2021. Thirty‐nine new drug applications (NDAs) have been identified and the associated regulatory reviews, approved labels, and approval letters were reviewed. Approximately, 95%, 74%, and 77% of these submissions contained at least one type of drug–drug interaction, the effect of organ impairment (hepatic and renal) on drug exposure, and QT liability assessment, respectively. Modeling and simulation approaches were utilized to address many clinical pharmacology questions, with population pharmacokinetic analyses used extensively in the evaluation of the effect of organ impairment on drug exposure and with physiologically based pharmacokinetic analyses used mainly in assessing drug interaction risks. In general, the clinical pharmacology packages in the NDAs of orphan drugs are not optimal and more work is needed to obtain a complete clinical pharmacology package at the time of initial approval to ensure the safe and effective use of these drugs across the spectrum of the target patient population. This study provides insights into the clinical pharmacology studies needed for drugs to treat rare diseases and would help both the regulators and drug developers to identify challenges and opportunities in conducting clinical pharmacology assessments for drugs developed to treat rare diseases.
Regulatory Framework for Drug Development in Rare Diseases
Authors: Korth‐Bradley Joan M. 
Published: December 2022

AbstractDrug development is a highly regulated industry. Therapeutic options for rare diseases must meet the same high standards for the demonstration of safety and efficacy as do those for more common diseases. The approval of the Orphan Drug Act in 1983 has resulted in many more resources for preclinical research, the standardization of patient registries, and the use of real‐world data, among other measures, that, along with the advances in drug development, has resulted in the approval of therapies for some of the most unusual diseases. Increased attention to the diagnosis and treatment of rare diseases has also accelerated the development of gene therapies that may offer significant amelioration and even cures for such diseases in the near future. Rare diseases disproportionately affect children, with severe and debilitating effects. Few effective treatments are available for most rare diseases. To avoid the unnecessary waste of data collected in studies of these patients, and to promote efficient drug development, there is a growing collaboration among patient communities, investigators, clinicians, sponsors, and regulatory authorities. All interested parties are working together to identify the most appropriate research questions and move quickly to make available safe and effective treatments. This article is a survey of the most commonly used regulatory remedies that have been put in place to serve as a framework for drug development in rare diseases.
Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein
Authors: Lee Lucy , Gollen Rakesh , Fathallah Anas M. , Gao Lan , Patil Shivakumar 
Published: December 2022

AbstractRare diseases are frequently caused by inherited ‘monogenic’ defects. Treatment interventions that target a specific genetic location or that replaces a specific protein provide rational therapeutic approaches. The current review discusses innovative targeted therapies that act or modulate at the level of DNA, RNA, or protein. They include DNA gene editing, small interference RNA (siRNA), antisense oligonucleotide (ASO), small molecule RNA splicing modifier, and bispecific antibody. With limited numbers of patients, testing multiple dose levels and regimens prior to making an informed dose decision remains one of the major challenges in rare disease drug development. Clinical pharmacology strategically bridges the gap to support drug development and regulatory approvals. Pharmacokinetic drug exposures are driven by absorption, distribution, metabolism, elimination, and in some cases immunogenicity. Drug responses are measured by pharmacodynamic biomarkers that are linked to either short‐ or long‐term clinical outcomes. Understanding the drug exposure–response relationship lies at the heart of bridging the gap that enables a dose decision by balancing effectiveness and safety. Furthermore, and importantly, understanding the influence of intrinsic and extrinsic factors on drug pharmacokinetics enables dose adjustment decisions based on drug exposures. Case examples include the identification of doses and regimens without a formal dose‐finding study, the support of new doses and regimens without conducting additional studies, and the extrapolation of adult drug–drug interaction (DDI) studies to pediatrics without performing a pediatric DDI study. With increasing discoveries of innovative treatment modalities, the responsibility of clinical pharmacologists is expected to grow and enhance the development of novel treatments for rare diseases.
Internet based intervention (Emotion Regulation Individual Therapy for Adolescents) as add‐on to treatment as usual versus treatment as usual for non‐suicidal self‐injury in adolescent outpatients: The TEENS randomised feasibility trial
Authors: Morthorst Britt , Olsen Markus Harboe , Jakobsen Janus Christian , Lindschou Jane , Gluud Christian , Heinrichsen Michella , Møhl Bo , Rubæk Lotte , Ojala Olivia , Hellner Clara , Bjureberg Johan , Pagsberg Anne Katrine 
Published: December 2022

AbstractBackgroundNon‐suicidal self‐injury (NSSI) is common in adolescents receiving psychiatric treatment and is a significant risk factor for suicidal behavior. There are few randomised clinical trials assessing interventions for NSSI in youth, and knowledge about internet‐delivered interventions is limited.ObjectiveWe assessed the feasibility of Internet based Emotion Regulation Individual Therapy for Adolescents (ERITA) in psychiatric outpatients aged 13–17 years who engaged in NSSI.MethodA randomised clinical feasibility trial with a parallel group design. Non‐suicidal self‐injury engaging patients were recruited from Child and Adolescent Mental Health Outpatient Services in the Capital Region of Denmark from May to October 2020. ERITA was provided as add‐on to treatment as usual (TAU). ERITA is a therapist‐guided, internet‐based program of emotion regulation and skills training involving a parent. The control intervention was TAU. Feasibility outcomes were the proportion who completed follow‐up interviews at end of intervention; proportion of eligible patients who participated in the trial; proportion of participants completing ERITA. We further investigated relevant exploratory outcomes, including adverse risk‐related events.ResultsWe included 30 adolescent participants, 15 in each group (ERITA vs. Treatment as usual). 90% (95% CI, 72%–97%) of the participants completed post‐treatment interviews; 54% (95% CI, 40%–67%) of the eligible participants were included and randomised; and 87% (95% CI, 58%–98%) of the participants completed at least six out of 11 ERITA modules. We identified no difference for the primary exploratory clinical outcome of NSSI between the two groups.ConclusionThere are few randomised clinical trials assessing interventions for NSSI in youth, and knowledge about internet‐delivered interventions is limited. Based on our results we conclude that a large‐scale trial seems feasible and warranted.