bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of low heat rejection diesel engine run on N,N′‐diphenyl‐p‐phenylenediamine antioxidant doped Jatropha methyl ester‐diesel blend
Authors: Pandey Krishna Kumar , Sivalingam Murugan
Published: December 2022

Low heat rejection (LHR) diesel engines help increase engine performance and reduce engine emissions, but they increase air‐polluting nitrogen oxide (NOx) emissions. Different types of antioxidants or additives can be added to fuels to reduce NOx emissions and improve engine performance. In this investigation, N,N′‐diphenyl‐p‐phenylenediamine (DPPD) is used as an antioxidant. Different concentrations of DPPD namely, 500, 1000, 1500, and 2000 ppm are mixed with Jatropha Methyl Ester (JME)‐diesel blend (JME20), and the fuels are tested in an engine fitted with a TBC piston. The piston crown is coated using a mixture of Yttria‐stabilized zirconia (YSZ) and cerium oxide (CeO2) with a coating thickness of 0.3 mm. The novelty of this research work is the comprehensive assessment of the engine characteristics of an LHR diesel engine run on a synthetic antioxidant‐doped biodiesel‐diesel blend. Results indicate that the peak heat release rate (HRR) and the peak cylinder pressure are lesser by about 5.6% and 5.1% for JME20B4, respectively, at maximum engine load, in the coated engine (CE). The nitric oxide (NO), hydrocarbon (HC), and carbon monoxide (CO) emissions are reduced by about 6.5%, 17.4%, and 34.6%, respectively, at full load for the JME20B4 fueled LHR diesel engine. Smoke opacity decreases up to 15.3% in the coated diesel engine fueled with JME20B4 at full load.
A companion to the preclinical common data elements for phenotyping seizures and epilepsy in rodent models. A report of the TASK3‐WG1C: Phenotyping working group of the ILAE/AES joint translational task force
Authors: Barker‐Haliski Melissa , Pitsch Julika , Galanopoulou Aristea S. , Köhling Rüdiger
Published: December 2022

Epilepsy is a heterogeneous disorder characterized by spontaneous seizures and behavioral comorbidities. The underlying mechanisms of seizures and epilepsy across various syndromes lead to diverse clinical presentation and features. Similarly, animal models of epilepsy arise from numerous dissimilar inciting events. Preclinical seizure and epilepsy models can be evoked through many different protocols, leaving the phenotypic reporting subject to diverse interpretations. Serendipity can also play an outsized role in uncovering novel drivers of seizures or epilepsy, with some investigators even stumbling into epilepsy research because of a new genetic cross or unintentional drug effect. The heightened emphasis on rigor and reproducibility in preclinical research, including that which is conducted for epilepsy, underscores the need for standardized phenotyping strategies. To address this goal as part of the TASK3‐WG1C Working Group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Joint Translational Task Force, we developed a case report form (CRF) to describe the common data elements (CDEs) necessary for the phenotyping of seizure‐like behaviors in rodents. This companion manuscript describes the use of the proposed CDEs and CRF for the visual, behavioral phenotyping of seizure‐like behaviors. These phenotyping CDEs and accompanying CRF can be used in parallel with video‐electroencephalography (EEG) studies or as a first visual screen to determine whether a model manifests seizure‐like behaviors before utilizing more specialized diagnostic tests, like video‐EEG. Systematic logging of seizure‐like behaviors may help identify models that could benefit from more specialized diagnostic tests to determine whether these are epileptic seizures, such as video‐EEG.
Prevalence of epilepsy in the rural area of the Bolivian Gran Chaco: Usefulness of telemedicine and impact of awareness campaigns
Authors: Todaro Valeria , Giuliano Loretta , Cicero Calogero Edoardo , Spina Ludovica , Colli Chiara , Cuellar Senovia , Cosmi Francesco , Vilte Estela , Bartoloni Alessandro , Crespo Gómez Elizabeth Blanca , Nicoletti Alessandra
Published: December 2022

Objective

The objective of this study is to estimate the prevalence of epilepsy with Tonic–Clonic (TC) seizures in rural areas of the Bolivian Gran Chaco and to evaluate the usefulness of telemedicine in this context.

Methods

The study was carried out in the Isozo Area, southern‐eastern Bolivia. Twenty‐five rural communities with a population of 8258 inhabitants were included in the survey. Trained community‐health workers administered a validated single screening question to the householders (stage I). A second face‐to‐face questionnaire was administered to each positive subject (stage II). At stage II subjects were also screened using the smartphone app “Epilepsy Diagnosis Aid”. Subjects screened positive at stage II underwent a complete neurological examination to confirm the diagnosis (stage III). Due to the COVID‐19 lockdown, some subjects have been evaluated through a digital platform (Zoom®).

Results

One‐thousand two‐hundred and thirteen interviews were performed at stage I, corresponding to a total screened population of 6692 inhabitants. Thirty‐eight screened positive were identified at stage I and II and of these, 28 people with epilepsy were identified, giving an overall prevalence of 4.2/1000 (95% CI 2.6–5.7). Prevalence rate steeply increased with age reaching a peak of 7.9/1000 in the population aged 20–29 years without significant differences between women and men. For almost 50% of the screened positive subjects, confirmation of epilepsy by a neurologist at stage III was achieved through simple videoconsultation. After a simultaneous awareness campaign, 22 self‐reported PWE requested a consultation and, among them, 11 had a diagnosis of epilepsy confirmed.

Significance

This study shows a prevalence estimate close to those reported for LMIC. Simple videoconsultation and specific apps may be valuable tools in epidemiological research. Awareness campaigns are important allies for a full case identification, particularly in contexts where higher rates of stigma are recorded.
Longitudinal hippocampal diffusion‐weighted imaging and T2 relaxometry demonstrate regional abnormalities which are stable and predict subfield pathology in temporal lobe epilepsy
Authors: Adel Seyed Amir Ali , Treit Sarah , Abd Wahab Wasan , Little Graham , Schmitt Laura , Wilman Alan H. , Beaulieu Christian , Gross Donald W.
Published: December 2022

Objective

High‐resolution (1 mm isotropic) diffusion tensor imaging (DTI) of the hippocampus in temporal lobe epilepsy (TLE) patients has shown patterns of hippocampal subfield diffusion abnormalities, which were consistent with hippocampal sclerosis (HS) subtype on surgical histology. The objectives of this longitudinal imaging study were to determine the stability of focal hippocampus diffusion changes over time in TLE patients, compare diffusion and quantitative T2 abnormalities of the sclerotic hippocampus, and correlate presurgical mean diffusivity (MD) and T2 maps with postsurgical histology.

Methods

Nineteen TLE patients and 19 controls underwent two high‐resolution (1 mm isotropic) DTI and 1.1 × 1.1 × 1 mm3 T2 relaxometry scans (in a subset of 16 TLE patients and 9 controls) of the hippocampus at 3T, with a 2.6 ± 0.8 year inter‐scan interval. Within‐participant hippocampal volume, MD and T2 were compared between the scans. Contralateral hippocampal changes 2.3 ± 1.0 years after surgery and ipsilateral preoperative MD maps versus postoperative subfield histopathology were evaluated in eight patients who underwent surgical resection of the hippocampus.

Results

Reduced volume and elevated MD and T2 of sclerotic hippocampi remained unchanged between longitudinal scans. Focal regions of elevated MD and T2 in bilateral hippocampi of HS TLE were detected consistently at both scans. Regions of high MD and T2 correlated and remained consistent over time. Volume, MD, and T2 remained unchanged in postoperative contralateral hippocampus. Regional elevations of MD identified subfield neuron loss on postsurgical histology with 88% sensitivity and 88% specificity. Focal T2 elevations identified subfield neuron loss with 75% sensitivity and 88% specificity.

Significance

Diffusion and T2 abnormalities in ipsilateral and contralateral hippocampi remained unchanged between the scans suggesting permanent microstructural alterations. MD and T2 demonstrated good sensitivity and specificity to detect hippocampal subfield neuron loss on postsurgical histology, supporting the potential that high‐resolution hippocampal DTI and T2 could be used to diagnose HS subtype before surgery.
Facile fabrication of metal‐organic frameworks with peroxidase‐like activity for the colorimetric detection of Alicyclobacillus acidoterrestris
Authors: Shi Yiheng , Sun Yuhan , Yue Tianli , Yuan Yahong
Published: December 2022

Alicyclobacillus acidoterrestris (A. acidoterrestris), a kind of spore‐forming bacterium, could causes spoilage of fruit juices, which results in pecuniary losses to the industry. Unfortunately, the conventional methods used to identify this bacterium are laborious and complex. In this work, copper‐based metal‐organic frameworks (Cu‐MOFs) with intrinsic peroxidase‐like activity were fabricated by a self‐assembly method. Based on the properties of Cu‐MOFs, a colorimetric assay was developed for the detection of guaiacol, a characteristic metabolite of A. acidoterrestris and chromogenic substrate of peroxidase. Under optimal conditions, an excellent linear relationship was achieved over a range of guaiacol (0.01–0.4 mM), with a limit of detection (LOD) as low as 0.003 mM. This biosensor also showed a satisfactory sensing performance towards guaiacol, allowing the identification of A. acidoterrestris with high selectivity in a real sample. This present study provides a new perspective for the exploration of more sensitive and convenient methods for A. acidoterrestris detection.
Using X‐ray fluorescence to examine ancient Maya granite ground stone in Belize
Authors: Tibbits Tawny L. B. , Peuramaki‐Brown Meaghan M. , Brouwer Burg Marieka , Tibbits Matthew A. , Harrison‐Buck Eleanor
Published: December 2022

While ubiquitous among ancient Maya sites in Mesoamerica, archaeological analysts frequently overlook the interpretive potential of ground stone tools. The ancient Maya often made these heavy, bulky tools of coarse‐grained, heterogeneous materials that are difficult to chemically source, unlike obsidian. This paper describes an application of handheld, energy‐dispersive X‐ray fluorescence (XRF) to provenance ground stone artifacts (tools and architectural blocks) composed of granite: a nonhomogenous, phaneritic stone. We present a multicomponent methodology that independently tested whole‐rock, thin‐sectioned, and powdered samples by petrographic microscope, conventional, lab‐based XRF, and portable XRF units, which yielded comparable results. After establishing distinct geochemical signatures for the three geographically restricted granite plutons in Belize, we devised a field‐based XRF application on a whole rock that could replicate the compositional readings of lab‐based XRF on powdered materials with sufficient accuracy and reliability. We applied this multishot XRF technique to granite ground stone items from a range of ancient Maya sites throughout Belize; we discuss two specific case studies herein. Our results underscore the widespread potential of multishot XRF applications for determining the provenance of coarse‐grained, heterogeneous rock materials. These results can help push the boundaries from one‐dimensional, functional explanations of ground stone items to their social and ideological dimensions, alongside deeper understandings of granite resource management.
Structural brain network lateralization across childhood and adolescence
Authors: Craig Brandon T. , Geeraert Bryce , Kinney‐Lang Eli , Hilderley Alicia J. , Yeates Keith O. , Kirton Adam , Noel Melanie , MacMaster Frank P. , Bray Signe , Barlow Karen M. , Brooks Brian L. , Lebel Catherine , Carlson Helen L.
Published: December 2022

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub‐nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross‐sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right‐handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school‐age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization.
Sexual violence, mental health, and suicidality—Results from a survey in cooperation with idea‐driven organizations and their social media platform followers
Authors: Carlsson Axel C. , Owen Ulrika , Rajan Gita
Published: December 2022

Aims

We specifically aimed to study if individuals who have been subjected to sexual violence more frequently report psychiatric diagnoses and suicide attempts. We also aimed to investigate if individuals who had been sexually violated reported more or less childhood experiences of family environment with alcohol problems, suicide attempts, and domestic violence than those without sexual violations.

Methods

In 2019, the nongovernment organization World of no sexual abuse (WONSA) collected data through a web‐based survey. The survey was shared via websites of idea‐driven organizations working with victims of sexual violence, on social media and through email lists. A total of 4831 individuals participated and 49% answered all questions.

Results

Of the participants exposed to penetrating sexual violence, 49% stated that they had or had been diagnosed with depression, compared with 16% in the group not exposed to sexual violence. Similar findings were found for anxiety: 45% versus 12%; fatigue syndrome 28% versus 9%; post traumatic stress disorder 30% versus <0.1% and suicide attempts, 29% versus 3%. More participants in the group exposed to sexual violence had grown up in families with alcohol problems, suicide attempts, or where they have witnessed violence.

Conclusion

Steps should be taken to adapt the national suicide prevention strategy to the association between sexual violence and suicide attempts, which has been so clearly demonstrated earlier in both international and national studies, and which is again shown in the present study.
Factors influencing plasma donation behavior of COVID‐19 recovered patients in Bangladesh: A pilot study
Authors: Salma Nahid , Hossain Md. Moyazzem , Yasmin Sabina , Alam Muhammad Khairul , Rimon Ahsan Rajvee , Faruque Jobaer , Ali Mohammad
Published: December 2022

Background and Aim

The COVID‐19 pandemic has plagued our lives for more than 2 years, and the preference for convalescent plasma (CP) as a life‐saving treatment since CP has proven as a potential therapeutic option for acute COVID‐19 patients who were suffering from severe disease. It is important to identify which factors are associated with plasma donation. Therefore, this study aimed to assess the associated factors for CP donation to COVID‐19 patients.

Methods

A cross‐sectional study was conducted online from December 21, 2021 to February 15, 2022 to identify different socio‐demographic factors and knowledge related to CP donation. People who recovered from the COVID‐19 infections and those who are willing to participate were included in the study. A total of 60 participants were included in the study. The data were analyzed using descriptive statistics, correlation matrix, and factor analysis.

Results

The analysis results confirm that 41.67% (n = 25) of the participants aged 26–30 years; among the recovered patients, only about 23% (n = 14) of the participants donated plasma. Though 97% (n = 58) of the participants agreed to donate plasma when it will be needed, however, when someone asked to donate plasma then 76.67% (n = 46) of the patients declined it. Findings depict that gender had a weak positive relationship with ever decline in plasma donation at 5% level of significance and the age of the participants inversely related to plasma donation.

Conclusion

Almost all the recovered participants were willing to donate plasma, however, due to a lack of knowledge and misconception, relatively few people actually did. This study reemphasizes the importance of health education to overcome the misconception about plasma donation, which is crucial for the treatment of COVID‐19 infection.
COVID‐19 among health care workers and their impact on the health care system in a teaching hospital in Pakistan: A cross sectional observational study
Authors: Haq Faiz Ul , Rahman Saeed Ur , Imran Muhammad , Romman Muhammad , Shah Asaf , Aslam Zeenaf , Ullah Farman , Madadi Shekiba , Dino Steinmetz Carl Hermann , Cuschieri Sarah
Published: December 2022

Background and Aims

Health care workers (HCWs) are thought to be high‐risk population for acquiring coronavirus disease (COVID‐19). The COVID‐19 emergence has had a profound effect on healthcare system. We sought to investigate the COVID‐19 among HCWs and their effects on the healthcare system.

Methods

A cross sectional observational study was conducted at Timergara teaching hospital. The study included HCWs with positive real time polymerase chain reaction (Q‐PCR) for severe acute respiratory syndrome coronavirus (SARS‐CoV‐2). The study duration was from April to September, 2020. The demographic profile of each recruited subject was collected through structured interview. The patient's admissions to hospital were collected for the 5 months before (October 2019–February 2020) and 5 months after lockdown (March–July 2020).

Results

A total of 72 out of 689 (10%) HCWs were tested positive for SARS‐CoV‐2, of whom 83% were front‐liners. The majority were male (72%), with comorbidities (14%) and no mortality. The structured interview of all participants showed that the healthcare setting was the major possible source of infection (97%). The patient admissions into the hospital were reduced by 42% during lockdown than prelockdown period. The patients admission was significantly decreased in the medical ward during lockdown (60% decrease; p < 0.01) with slightly similar trends in other departments.

Conclusion

In conclusion, we found increased risk of COVID‐19 for front‐line HCWs. Lack of mortality was the favorable outcome. Lack of replacing the infected HCWs possibly explained the marked decrease in hospital admissions, and potential inadequate healthcare delivery during the lockdown. Understanding SARS‐CoV‐2 among HCWs and their impact on health‐care system will be crucial for countries under COVID‐19 crises or in case of future pandemic to deliver proper health services.
COVID‐19 vaccination in children as a global dilemma through an ethical lens: A retrospective review
Authors: Assadi Masoud , Kiani Mehrzad , Shamsi Gooshki Ehsan , Aryanian Zeinab , Afshar Zeinab M. , Hatami Parvaneh
Published: December 2022

Background and Aims

COVID‐19 pandemic led to a need to rapidly vaccinate as many people as possible. Children are an important part of the population with different characteristics which vaccinating them is a matter of great importance as it should be decided considering all aspects and ethics. Here, we present different aspects of COVID vaccination in children including the potential challenges.

Methods

We searched on PubMed, Google Scholar and Scopus in this regard, and all of the relevant papers published until June 28, 2021 were included if we could access their full‐texts.

Results

We found various expert opinions in this regard and tried to summarized them. Saving lives has similar ethical value as preventing evitable adverse event. Accordingly, mandating the children to receive the SARS‐CoV‐2 vaccine, needs risk‐benefit weighing with special consideration of ethical challenges.

Conclusion

Considering the vast range of benefits resulted from pediatric vaccination both for the children and the community, implementing the program in a scientific manner and also with the least financial expenses for the families seems to be reasonable and makes it both ethical and moral.
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

Background and aims

Despite 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.

Methods

A 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.

Results

A 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).

Conclusion

The 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

Hypoxic–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

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 <1% to >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

Background

Transvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) are used for the clinical diagnosis of adenomyosis.

Objectives

To compare the diagnostic accuracy of TVS and MRI for the diagnosis of adenomyosis.

Search Strategy

A search of studies was performed in five databases comparing TVS and MRI for the diagnosis of adenomyosis from January 1990 to May 2022.

Selection Criteria

Studies 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 Analysis

The quality of studies was assessed using the QUADAS‐2 tool. Pooled sensitivity and specificity of both techniques were estimated and compared.

Main Results

Six 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.

Conclusions

MRI 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

Total 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

Mutations 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

Rare 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

Recombinant 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

New 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

There 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

Drug 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

Rare 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

Background

Non‐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.

Objective

We assessed the feasibility of Internet based Emotion Regulation Individual Therapy for Adolescents (ERITA) in psychiatric outpatients aged 13–17 years who engaged in NSSI.

Method

A 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.

Results

We 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.

Conclusion

There 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.
Dental students and recent dental graduates' perceptions of preparedness in treating pediatric patients
Authors: McNutt David E. , Wells Martha H. , DeSchepper Edward J. , Scarbecz Mark
Published: December 2022

Purpose/objectives

To survey potential applicants applying to advanced education in pediatric dental programs and evaluate their preparedness upon graduating from an accredited dental school.

Methods

Attendees of a virtual externship of a University program were recruited to participate in a web‐based survey. The survey collected demographic data, current levels of confidence with various pediatric clinical procedures, predicted confidence with those procedures, and number of procedures completed. Chi‐Square and analysis of variance statistics were performed on resulting data to determine statistical significance.

Results

Fifty‐three participants completed the survey in its entirety (n = 53). Most respondents reported adequate didactic training, mean score of 3.6 (range 0–5) and a moderate to high impact of coronavirus disease 2019 on their overall training with a mean score of 4.9 (range 0–10).

Current dental students reported that they are “not confident at all” (<2.0) for 15/24 (63%) of the procedures. Graduates reported “somewhat confident” (<3.0) for 13/24 (54%) of the categories. Both students and graduates report the lowest levels of confidence for managing dental trauma, invasive treatment of young patients (<4 years of age), and patients with special healthcare needs. Dental students self‐reported the expectation to feel more confident throughout their matriculation; however, their clinical experience was still reported to be limited. Students did not report reaching the level of “confident” for 75% of the procedures.

Conclusion

Dental students and recent dental graduates alike perceive themselves to be under prepared for practice and do not feel confident in performing pediatric dental procedures. This study can provide dental schools, program directors, recent graduates, and dental students with an understanding of areas where they are under prepared and could offer areas where curricula and clinical experiences could be updated or modified.