bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective randomized controlled trial measuring satisfaction and parents stress after GOMCO and Plastibell infant circumcision
Authors: Alsowayan Ossamah Saleh , Zahrani Abdullah Mousa Al , Basalelah Jumanah Hamad , Madi Maha Khalid Al , Humam Abdullah Abdlz. Al , Otaibi Aali Naif Al , AlKhamis Abdulmalik Abdulaziz , Fadaak Kamel Hussien , Suhaibani Shaheed Saleh Al , Darawany Hamed Mohamed El
Published: April 2023

Purpose:
To compare the physician and parental satisfactions between the two types of circumcision maneuvers used in our units, GOMCO and Plastibell circumcision.
Methodology:
This study was performed from 2019 to 2021. A total of 190 children were circumcised either by Gomco or plastibell procedure. Each child was evaluated during the procedure, immediately after the operation, and 1, 2, and 3 weeks after the procedure. Data were collected, statistically analyzed using SPSS version 25.
Results:
A total of 190 children underwent circumcision from 2019 to 2021. 98/190 children (51.6%) underwent circumcision by GOMCO, while 92/190 (48.4%) underwent circumcision by Plastibell. Bleeding was significantly higher in plastibell method, while excess skin was significantly higher in GOMCO method (p-value 0.048). Physician evaluation results show no significant difference between both methods in late physician evaluation. 23/92 (28%) of parents were not satisfied after Plastibell circumcision, compared to 8/98 (8.2%) of parents who were not satisfied with the results of Gomco circumcision (P value 0.002).
Conclusion:
Gomco needs a longer operative time, and Plastibell circumcision is less preferable by parents. There is no significant difference in physician satisfaction between the two procedures, but parents are less satisfied with Plastibell circumcision.
Study on Wear Analysis of Ni-20Al2O3 HVOF Micron Layers Using Artificial Neural Network Technique
Authors: Singh Jashanpreet , Singh Ranvijay , Vasudev Hitesh , Ubaidullah Mohd
Published: April 2023

The paper presents the study of the erosion performance of stainless steel SS316L grade. The micron layers of Ni-20Al2O3 powder were sprayed on the surface SS316L by utilizing a high-velocity oxygen–fuel (HVOF) thermal spraying process. Wear experiments were performed in a slurry pot tester (Ducom TR-41) at different speeds varying from 600 to 1500 rpm. During the experiments, the sand was used to erode the coated surface of SS316L. Multi-sized slurry having a solid concentration lies in the range of 30-60% (by weight) was prepared to perform the wear experiments. A neural network technique was implemented to predict the erosion data by training 75% of the total data. Results show that the microhardness of bare and Ni-20Al2O3 HVOF coated SS316L was tested as 196±21 and 393.32±17 VHN respectively. The current ANN model yielded an R-value that was 0.98871 for training, 0.97209 for validation, and 0.96264 for testing accordingly. It was determined that the total R-value of the model was 0.98153. The ANN’s performance evaluated based on the mean squared error (MSE) was determined as 0.0176, 0.00265, and 0.00334 respectively for the training, validation, and testing.
Long-term 10-Year Comparison of Girls with Congenital Adrenal Hyperplasia Who Underwent Early and Late Feminizing Genitoplasty
Authors: Erginel Basak , Ozdemir Banu , Karadeniz Meltem , Poyrazoğlu Sukran , Keskin Erbug , Soysal Feryal Gun
Published: April 2023

Objectives: The appropriate time to perform feminizing genitoplasty in patients with congenital adrenal hyperplasia (CAH) with the 46, XX genotype is still debatable. The aim of our study was to evaluate the relationship between age at surgery and surgical success in patients who had feminizing genitoplasty due to CAH in our clinic.
Methods: Our clinic retrospectively analyzed 14 patients with CAH and 46, XX genotypes with feminizing genitoplasty (clitoroplasty + vaginoplasty) between 2005 and 2022. The patients were divided into two groups. The mean follow-up time was 10 years.
Results: . Group 1 consisted of seven girls (n = 7/14) who has operations before the age of 2 years (mean 11.7 months). Group 2 consisted of seven girls (n = 7/14) who had operation after the age of 2 years (mean 53 months). There was no statistically significant difference between those operated on before and after two years in terms of anatomical assessments, overall cosmetic results and parent satisfaction except the need for additional intervention (P=0.049). When parent satisfaction was compared with additional surgical intervention, as expected, parents’ satisfaction increased as major surgical intervention decreased. This was statistically significant (p = 0.007). The main source of dissatisfaction was repeated surgery among the parents.
Conclusions: The possibility of this additional surgical intervention increases, and patient satisfaction decreases in patients below the age of 2 years. The corrective surgeries can be deffered until the gender identity of the patient matures and the patient autonomy in deciding whether this surgery should occur.
A novel hybrid wavelength division multiplexing integrated NG PON-VLC systems based TWDM/OCDMA for green smart building applications
Authors: Kumari Meet , Hayal Mohammed R. , Elsayed Ebrahim E. , Nurhidayat Irfan , Shah Mohd Asif
Published: April 2023

Green and smart buildings (SBs) are promising solutions to the fast-growing and ongoing urbanization around the globe and are the composition of huge services. The SB can acquire a tremendous amount of information and perform proper handling of many broadcasting residents accordingly. With the abrupt increase in the high-quality data transmission demands over long reach for the large number of connected residents in SBs, conventional data transmission techniques are inadequate to provide adequate services. Thus, in this paper, to improve the intelligence and reliability of SBs with high overall efficiency, cost-effectiveness, and security, a hybrid passive optical network (PON) and visible light communication (VLC) indoor broadcasting system is proposed. The bidirectional hybrid PON-VLC consists of integrated time and wavelength division multiplexing (TWDM) and wavelength division multiplexing (WDM) with optical code division multiplexing (OCDMA) PON with red green blue employed light emitting diodes (RGB LEDs) based VLC system. Seven OCDMA codes are utilized in the proposed work at a 10/2.5Gbps per channel transmission rate over hybrid fiber-VLC channels to strengthen the system performance. The simulation results show that the modified new zero cross-correlation (MNZCC) code outperforms other codes and provides a faithful 100km fiber length and 5m VLC range for 200 active residents. Moreover, VLC distance can be incremented up to 10m wireless range by increasing the received aperture diameter of 25cm. Also, the numerical analysis, as well as comparative performance, depicts the superiority of PON-VLC under the impact of impairments and noise in fiber-VLC link-based SBs.
Symptom guided multimodal neuroimage fusion patterns in children with attention-deficit/hyperactivity disorder and its potential “brain structure-function-cognition-behavior” pathological pathways
Authors: Feng Yuan , Zhi Dongmei , Zhu Yu , Guo Xiaojie , Luo Xiangsheng , Dang Chen , Liu Lu , Sui Jing , Sun Li
Published: April 2023

The “brain-cognition-behavior” process is an important pathological pathway in children with attention-deficit/hyperactivity disorder (ADHD). Symptom guided multimodal neuroimaging fusion can capture behaviorally relevant and intrinsically linked structural and functional features, which can help to construct a systematic model of the pathology. Analyzing the multimodal neuroimage fusion pattern and exploring how these brain features affect executive function (EF) and leads to behavioral impairment is the focus of this study. Based on gray matter volume (GMV) and fractional amplitude of low frequency fluctuation (fALFF) for 152 ADHD and 102 healthy controls (HC), the total symptom score (TO) was set as a reference to identify co-varying components. Based on the correlation between the identified co-varying components and EF, further mediation analysis was used to explore the relationship between brain image features, EF and clinical symptoms. This study found that the abnormalities of GMV and fALFF in ADHD are mainly located in the default mode network (DMN) and prefrontal-striatal-cerebellar circuits, respectively. GMV in ADHD influences the TO through Metacognition Index, while fALFF in HC mediates the TO through behavior regulation index (BRI). Further analysis revealed that GMV in HC influences fALFF, which further modulates BRI and subsequently affects hyperactivity-impulsivity score. To conclude, structural brain abnormalities in the DMN in ADHD may affect local brain function in the prefrontal-striatal-cerebellar circuit, making it difficult to regulate EF in terms of inhibit, shift, and emotional control, and ultimately leading to hyperactive-impulsive behavior.
Severity assessment in melioidosis pneumonia: what is the most appropriate score or factor?
Authors: Nguyen-Ho Lam , Hoang-Thi Hong-Linh , Le-Thuong Vu , Duong-Minh Ngoc , Dang-Vu Thong , Le-Phuong Mai , Truong-Thien Phu , Tran-Van Ngoc
Published: April 2023

Background and objective
Pneumonia induced by Burkholderia pseudomallei is a common clinical entity of melioidosis. Along with the development of melioidosis rapid tests, prognostic assessment for melioidosis pneumonia (MP) patients at admission is essential. Our study aims to evaluate the validity of the mortality prognostic score for acute melioidosis and pneumonic scores in predicting MP patients.
Methods
A prospective study was conducted from the late 2019 to the early 2022 at the respiratory department of the largest hospital in Southern Vietnam.
Results
Of 66 MP patients, mean age 51.17 ± 11.02, male/female ratio 57/9, and 89.39% presented with acute pulmonary melioidosis. The rate of need for intensive respiratory or vasopressor support (IRVS) was 34.8% and the mortality at discharged time was 25.80%. The areas under ROC curve (AUCs) of PSI, CURB-65, and SMART-COP in predicting the IRVS need were 0.813 (p < 0.001), 0.868 (p < 0.001), and 0.910 (p < 0.001), respectively. The AUCs of PSI, CURB-65, SMART-COP, and the mortality score of acute melioidosis in predicting the death outcome were 0.698 (p = 0.017), 0.797 (p < 0.001), 0.797 (p < 0.001), and 0.663 (p = 0.047), respectively. The sensitivity, specificity, and positive likelihood ratio for CURB-65 score ≥ 2 in predicting the IRVS need and the mortality were 69.57% and 70.59%, 90.70% and 83.67%, 7.48 and 11.53, respectively.
Conclusions
MP could present mild to severe clinical scenario with high mortality among severe MP cases. The simple CURB-65 score could be useful in predicting severe MP.
A Systematic Review of the Literature on the Development of New Concepts from the Perspective of Promoting Patient-Centered Care
Authors: Gupta Atantra Das
Published: April 2023

Background: The concept of the patient as an organization is gaining traction in digital healthcare. This concept places the patient in the driver's position, empowering them to manage their health and wellness and make care decisions. It also encourages healthcare providers to collaborate with patients more closely, allowing for a more proactive, individualized approach to healthcare. In addition, this concept contributes to creating an environment in which patients and providers can utilize data-driven technologies such as AI and machine learning to enhance healthcare outcomes.
Objective: Establishing the concept of patient as an organization in health-care.
Design: Analysis of the concept through different patient attributes & existing concepts.
Data Sources: The literature was searched using electronic databases including PubMed, ScienceDirect, Scopus, Google Scholar, with no date limitation. Any quantitative or qualitative studies published in English, which were focused on patient’s attributes & various concepts were included in the study.
Review methods: Walker and Avant’s strategy for concept analysis was used. The patient attributes and the attributes regarded as concepts are studied.
Results: A total of 40 articles were included. Different attributes and existing concepts like engagement, trust, advocacy, acuity, health literacy. cultural competence, self-efficacy, self-care, resilience and social support are explored.
Attributes like age, gender, medical history, lifestyle factors, socioeconomic status, ethnicity, and culture were studied as antecedents. The consequences of Patient as an Organization were also identified, including those pertaining to care recipients, care providers.
Conclusion: A theoretical definition and a conceptual model of new concept has been developed. The attributes as antecedents, and consequences of the said concept has been identified to script a new paradigm of patient-based healthcare model.
Correlations between miR-223/mTOR/S6K pathway and RA activity and antibody levels
Authors: Jiang Zhen , Liu Juan , Bai Wen-hua
Published: April 2023

Objective: To investigate the expression levels of miR-223 and mTOR/S6K pathways in synovial tissues of rheumatoid arthritis (RA) and their correlation with disease activity and antibody levels.
Methods: 17 hospitalized patients with moderate to severe disease RA were selected. During the same period, 9 patients hospitalized for knee osteoarthritis (OA) operation were involved. The synovial tissue of the knees was obtained under the guidance of ultrasound in RA group and obtained by orthopedic surgeons in OA group. The expression levels of mTOR, S6K, RPS6 mRNAs and miR-223 level in the synovial tissue were detected by QRT-PCR. The differences of miR-223 level and the mRNA levels of mTOR, S6K and RPS6 between the two groups were analyzed. The correlations between the level of miR-223 and the mRNA levels of mTOR, S6K and RPS6 were analyzed and the correlations between miR-223 level, the levels of mTOR, S6K, RPS6 mRNA and anti-CCP antibody and disease activity indicators were also analyzed in RA group.
Results: The miR-223 level in RA group was significantly increased compared with OA group (P<0.05), and the mRNA levels of S6K and RPS6 in RA group were significantly decreased compared with OA group (P<0.05). The miR-223 level in RA group was negatively correlated with the mRNA levels of S6K and RPS6 (P<0.05), but there was no significant correlation between miR-223 level and the level of mTOR mRNA (P>0.05). The levels of miR-223 and mTOR mRNA in RA group were negatively correlated with the serum anti-CCP antibody level (P<0.05), and the level of RPS6 mRNA was positively correlated with the anti-CCP antibody level (P<0.05). The miR-223 level in RA group was positively correlated with the serum CRP level (P<0.05). RPS6 mRNA level was negatively correlated with CRP level (P<0.05).
Conclusion: Abnormal miR-223/mTOR/S6K pathway exists in the synovial tissue of RA knee joints, which is correlated with the levels of anti-CCP antibody and CRP, indicating the direction for further research on the pathogenesis of RA.
Pulmonary parenchymal segmentation based on CT images of lungs in a highland population
Authors: Zhang Lijun , Dong Jianmin , Ye Kai , Wang Yinghan
Published: April 2023

In response to the more complex characterization of lung CT image data in the highland population, the problem of left and right lung adhesions, gross contours and blurred borders that are very likely to arise during lung parenchymal segmentation, we propose a new network structure based on U-Net for lung parenchyma segmentation in highland population. First, we introduce residual block, which replaced ordinary convolution with residual convolution in the encoding stage to improve the speed of network convergence and accuracy; Then, the Augmented Attention Module (AAM) is introduced in the skip connection part to enhance the feature of the lung parenchyma contour information; Finally, considering the processing efficiency of the network, we reduce the depth of the network model to 4 layers. After that, we verify the effectiveness of our method on the public dataset LUNA16, and the segmentation results show that the selected evaluation indicators are improved to varying degrees. This shows that our proposed method has a good effect on the segmentation of lung parenchyma. Finally, applying our method to lung CT image segmentation in a highland population gives some advantages over other existing methods.
Development and validation of a nomogram for predicting metabolic-associated fatty liver disease in the Chinese physical examination population
Authors: Zhou Bingqian , Gong Ni , Huang Xinjuan , Zhu Jingchi , Qin Chunxiang , He Qingnan
Published: April 2023

Aim We aim to develop and validate a nomogram including readily available clinical and laboratory indicators to predict the risk of MAFLD in the Chinese physical examination population.Methods The annual physical examination data of Chinese adults from 2016 to 2020 were retrospectively analyzed. We extracted the clinical data of 138 664 subjects and randomized participants to the development and validation groups (7:3). Significant predictors associated with MAFLD were identified by using univariate and random forest, and the nomogram was constructed to predict the risk of MAFLD based on a Lasso-Logistic model. Receiver operating characteristic curve analysis, calibration curves, and decision curve analysis were used to verify the discrimination, calibration, and clinical practicability of the nomogram, respectively.Results Ten variables were selected to establish the nomogram for predicting MAFLD risk: sex, age, waist circumference, uric acid, BMI, WHR, SBP, FPG, TG, and ALT. The nomogram built on the non-overfitting multivariable model showed good prediction of discrimination (AUC 0.914, 95% CI: 0.911–0.917), calibration, and clinical utility.Conclusions This nomogram can be used as a quick screening tool to assess MAFLD risk and identify individuals at high risk of MAFLD, thus contributing to the improved management of MAFLD.
Optimal placement of ureteral access sheath in retrograde intrarenal surgery
Authors: Chen Yujun , Cheng Xiaofeng , Yang Heng , Deng Wen , Chen Luyao , Zhou Xiaocheng , Wang Gongxian
Published: April 2023

Purpose: To explore the optimal location of ureteral access sheath (UAS) in retrograde intrarenal lithotripsy (RIRS).
Materials and methods: RIRS model was built by AutoCAD 2011 software, and imported COMSOL 5.6 software to computer simulation. An RIRS model was constructed in vitro to analyze the distribution pattern of stone fragments, and compare the weight of stone fragments carried out by the irrigation fluid when the UAS is in different positions.
Results: Computer simulation showed that the highest flow of irrigation fluid was in the channel of flexible ureteroscopy (f-URS) and in the lumen of UAS. From the f-URS to the renal collection system and then to the UAS, the velocity of irrigation fluid changes gradually from high-flow to low-flow and then to high-flow. When the f-URS and the UAS are at the same level, the irrigation fluid is always at a state of high flow during the process from f-URS to UAS. When the f-URS and the UAS are at the same level, it can increase the local intrarenal pressure (IRP) at the front of f-URS. The stone fragments are mainly sediment in the low-flow region of irrigation fluid. More stone fragments could follow the irrigation fluid out of the body when the tip of f-URS and the tip of UAS are at the same level (P＜0.001).
Conclusions: The UAS should be brought closer to the stone in RIRS. And more stone fragments can be taken out of the body by the effect of irrigation fluid.
Agreement between the Multi-Beat Analysis algorithm for cardiac output estimation and 2D echocardiography in the ICU
Authors: Saseedharan Sanjith , Thingna Aalia , Pawar Komal , Kadam Vaijayant
Published: April 2023

Background Cardiac output (CO) and stroke volume (SV) monitoring are cornerstones of hemodynamic management in patients at risk of shock. The multi-beat analysis (MBA) method provides continuous estimates of CO and SV by analysis of a patient’s arterial blood pressure waveform. In this study we assessed the agreement of CO and SV between 2D echocardiography (CO-ECHO and SV-ECHO) and the multi-beat analysis (MBA) method via the Argos monitor (CO-MON and SV-MON).Methods Fifty patients with a wide range of diagnoses were prospectively enrolled in the ICU in this observational, method comparison study. One set of paired, simultaneous measurements was recorded for each patient.Results for the 50 included data points in the study the mean difference between CO-ECHO and CO-MON was − 0.05 ± 0.58 L/min with limits of agreement from − 1.18 to + 1.08 L/min and a percentage error of 21.5%. The mean difference between SV-ECHO and SV-MON was − 0.9 ± 6.6 mL with limits of agreement from − 13.9 to + 12.0 mL and a percentage error of 22.8%.Conclusion Accuracy of the MBA method was clinically acceptable as compared to 2D echocardiography.
Non-Local EPR Correlations using Quaternion Spin
Authors: Sanctuary Bryan
Published: April 2023

A statistical simulation is presented which reproduces the correlation obtained from EPR coincidence experiments without non-local connectivity. We suggest that spin carries two complementary properties. In addition to the spin polarization, we identify spin coherence. This spin attribute is anti-symmetric and generates the helicity. In addition this spin has structure formed from two orthogonal magnetic moments. From these, a resonance spin results from their coupling in free flight. Upon encountering a filter, the resonance spin 1 decouples back into two independent spins of ½, with one aligning with the filter and the other randomizing.
The process of decoupling the resonance spin is responsible for the quantum correlation which results in the observe violation of Bell's Inequalities. The polarized states give a CHSH value of 2 while the resonance spin give a CHSH value of 1. Coherence can only be formulated by the existence of a bivector which gives a spin the same geometric structure as a photon.
Although this work is not about Bell's theorem, we note that there are no hidden variables (HV). The only local variable is the angle that orients a spin on the Bloch sphere, first identified in the 1920's. The new features introduced are changing the spin symmetry from SU(2) to the quaternion group, Q8, and the introduction of a bivector into spin which leads to an element of reality which is anti-Hermitian. The calculations use standard spin algebra, and properties of quaternions.
March 28, 2023
Precise isolation of high-quality RNA from leaves and storage roots of cassava (Manihot esculenta) for gene expression studies.
Authors: Reuben-Kalu Jane Ijeoma , Eswaran Kokiladevi , Muthurajan Raveendran , Doraiswamy Uma , Venkatasamy Balasubramani , Shanmugam Kavitha P.
Published: April 2023

The isolation of RNA from leaves and storage roots of cassava (Manihot esculenta) is a challenging one, due to the presence of large amounts of polyphenolic compounds, polysaccharides, and tuber proteins. RNA with high quality and intact integrity is vital for gene expression studies. We hereby report a precise, reproducible, and less cumbersome technique for isolating high-quality RNA from leaves and storage roots of cassava with minimal contamination from polyphenols, polysaccharides, and other secondary metabolites, using affordable reagents. This protocol functions without guanidinium salts in the extraction buffer. The presence of guanidinium salts usually leads to the formation of agglomerates during the extraction of RNA from plant tissues with high starch contents. RNA was isolated from leaves and storage roots of 10 different casava genotypes which yielded between 1576.1 to 2861.9 µg/ml for RNA isolated from the leaf tissues and 2761.2 to 3873.5 µg/ml for RNA isolated from the storage roots. The A260:A280 ratios of the total RNA were more than 2.0 for both leaf and storage root samples, indicating minimal contamination from polysaccharides and polyphenols. The RNA samples recorded intact integrity, as demonstrated by clear 28 S and 18 S rRNA bands observed on agarose gel electrophoresis. The RIN values ranged between 7.2 to 8.0. Also, the RNA samples were successfully used for transcriptome sequencing. The present method which yielded high-quality and transcriptionally competent RNA samples is suitable for use in gene expression studies and downstream applications in molecular breeding of cassava and related root/tuber crops.
Effect of glucocorticoids on the development of COVID-19-associated pulmonary aspergillosis: a meta-analysis of 21 studies and 5174 patients
Authors: Hashim Zia , Nath Alok , Khan Ajmal , Gupta Mansi , Kumar Anup , Chatterjee Riksoam , Dhiman Radha Krishan , Hoenigl Martin , Tripathy Naresh Kumar
Published: April 2023

Objective:
COVID-19-associated pulmonary aspergillosis (CAPA) remains a high mortality mycotic infection throughout the pandemic, and glucocorticoids (GCs) may be its root cause. We aimed to evaluate the effect of systemic GC treatment on the development of CAPA.
Methods: We systematically searched the PubMed, Google Scholar, Scopus, and Embase databases to collect eligible studies published until December 31, 2022. The pooled outcome of CAPA development was calculated as the log odds ratio (LOR) with 95% confidence intervals (CI) using a random effect model.
Results: A total of 21 studies with 5174 patients were included. Of these, 20 studies with 4675 patients consisting of 2565 treated with GC but without other immunomodulators (GC group) and 2110 treated without GC and other immunomodulators (controls) were analyzed. The pooled LOR of CAPA development was higher for the GC group than for the control group (0.54; 95% CI: 0.22, 0.86; p<0.01). In the subgroups, the pooled LOR was higher for high-dose GC (0.90; 95% CI: 0.17, 1.62: p=0.01) and dexamethasone (0.71; 95% CI: 0.35, 1.07; p<0.01)-treated patients, but there was no significant difference for low-dose GC (0.41; 95% CI: -0.07, 0.89; p=0.09)- and non-dexamethasone GC (0.21; 95% CI: -0.36, 0.79; p=0.47)-treated patients versus controls.
Conclusion: GC treatment increased the risk of CAPA development, and the risk was associated with the use of high-dose GC or dexamethasone therapy.
Ensino híbrido de música: a experiência do projeto “Musicarte”
Authors: VIEIRA JUNIOR Luis Antonio Braga , LISBOA Richarlison Freitas
Published: April 2023

O artigo apresenta o relato de um projeto de extensão de ensino híbrido de música, intitulado “Musicarte: Curso de Formação Musical”, realizado na cidade de Tucuruí. O projeto ofereceu 80 vagas divididas em duas turmas de musicalização, com carga horária total de 80 horas. São descritos os recursos produzidos especificamente para o curso, tais como videoaulas, treinos de percepção rítmica e melódica e exercícios teóricos. Também são explicitadas as ferramentas tecnológicas e as atividades pedagógicas do projeto, concluindo com reflexões que emergiram desta experiência de ensino híbrido de música. Implicaçõespara a educação musical no formato híbrido são discutidas ao término do artigo.
Surveillance Approaches for Regulatory Science
Authors: Dai Susie Y.
Published: April 2023

The essential function of a regulatory agency is to enforce laws enacted by the government and regulations established by the agency. For example, the US Food and Drug Administration (FDA) is charged with protecting public health by the regulation of food; pharmaceuticals, both over-the-counter and prescription; dietary supplements; medical devices; animal feeds; and veterinary medications. The effective regulation requires fit-for-purpose surveillance activities. Designing surveillance activities based on scientific theory and management through a science-based approach provides a repeatable and verifiable framework for iteratively gathering and analyzing data, and developing increasingly effective risk-mitigation techniques to support regulatory programs.https://doi.org/10.21423/jrs-v04n01pi (DOI assigned 7/23/2019)
Selective Safety Data Collection in Clinical Studies of Oncology Drugs for Marketing Approval in the United States
Authors: Sekine Nobuyuki , Aruga Atsushi
Published: April 2023

Optimization of data collection is a key issue in clinical studies of oncology drugs because it affects the workload and financial burden of the clinical infrastructure. Focusing on oncology drugs, which produce many low-grade as well as serious adverse reactions, we investigated the use of selective safety data collection in the pivotal clinical studies for marketing approval in the United States. Drug labels were examined to find clinical studies that evaluated adverse events with limited data, and found ten drugs approved between 2004 and 2015 whose pivotal studies used selective rather than comprehensive safety data collection. Only three were in accordance with the 2001 FDA Guidance for Industry, "Cancer Drug and Biological Products -- Clinical Data in Marketing Applications", which suggests such selectivity when targeting a similar population to the initial approval. Two selective studies were applied to a drug's initial approval. Three adopted the Guidance criteria for safety data collection of only noting grade 4-5 hematologic and 3-5 non-hematologic toxicities.No major problems caused by this approach were found in the description of medical reviews, approval letters and post-marketing revisions to the boxed warnings on labels issued by the FDA. Selective safety data collection can be an efficient approach to streamlining the procedure of clinical studies and should be considered for use in pivotal clinical studies for oncology drugs.https://doi.org/10.21423/jrs-v05n02p036 (DOI assigned 3/11/2019)
A Simple Procedure for Determination of Aminocyclopyrachlor and Aminopyralid in Soil, Corn Meal, and Soy Meal using Liquid Chromatography/Tandem Mass Spectrometry
Authors: Baumhover Nicholas J. , Larabee-Zierath David , Vargo John D. , Spak David R. , Netzband Derek , Dai Susie Y.
Published: April 2023

An analytical method has been developed that efficiently extracts aminocyclopyrachlor and aminopyralid from a variety of matrices including soil, soy meal, and corn meal without the need of time-consuming matrix cleanup steps such as solid phase extraction. Following extraction, the samples are analyzed by positive mode LC-ESI-MS/MS. Spiking studies were conducted at low- and intermediate-concentrations to determine the method detection limit as well as to evaluate the accuracy and precision of the method. Generally, aminocyclopyrachlor and aminopyralid recoveries were acceptable following extraction from soil, soy meal, and corn meal.https://doi.org/10.21423/jrs-v06n02p001 (DOI assigned 1/24/2019)
Challenges in the Development of drugs for Systemic Lupus Erythematosus: A Regulatory Perspective
Authors: Del Vecchio Alfred M. , Chevrier Marc R. , Elias Drew R. , O'Dowd Liza C. , Paxson Bethany K. , Rose Shawn M. , Shields-Tuttle Kimberly A. , Vermeulen Rob
Published: April 2023

Systemic lupus erythematosus (SLE) is a debilitating disease that affects at least 5 million people worldwide. Currently, there are limited approved treatment options for patients with SLE, and a great need remains for therapies to achieve important treatment goals such as reductions in flares, prevention of organ damage, clinical low disease activity or remission. The purpose of this article is to review the current health authority guidance for the development of drugs to treat SLE and discuss some of the challenges in the development of drugs for SLE from a regulatory perspective. Given the substantial number of failed late-stage clinical trials in this indication despite the inclusion of large numbers of subjects, reviewing the regulatory guidance and complexities surrounding the development of drugs for the treatment of SLE is crucial to understand the complexities of the disease itself and the challenges and limitations to conducting successful trials evaluating the impact of treatment of new agents in SLE. As only one new drug (belimumab, trade name BENLYSTA®) with a novel mechanism of action has been approved over the last six decades, the prescribing information for belimumab will be reviewed in the context of the guidance.https://doi.org/10.21423/jrs-v07delvecchio
An Approach for Predicting Mainstream Cigarette Smoke Harmful and Potentially Harmful Constituent (HPHC) Yields
Authors: Hannel Thaddaeus , Pithawalla Yezdi B. , Morton Michael J. , Wang Jingzhu , Gannon Thomas J. , Wagner Karl A. , Jupe Richard , Rostami Ali A.
Published: April 2023

To ensure quality, consistency, and supply of cigarette products, a manufacturer may change materials, which can affect its product portfolio. Rather than testing each product individually to determine the effect of a change, designed experiments can be conducted using a subset of products, and statistical modeling can be performed to determine the harmful and potentially harmful constituent (HPHC) yields for the remaining products. To demonstrate this, we selected 30 representative cigarette products covering a wide range of tobacco blends, ingredients, and design parameters from a manufacturer's portfolio. Sets of cigarette products used papers produced with one type of manufacturing technology (control products) and two additional cigarette papers (changed products). The physical characteristics of the changed products' papers were similar to the control products but were manufactured using alternative methods, which could lead to differences in their chemical composition. The experiment was controlled to minimize variations among products, manufacturing, and testing. Linear regression was used to model the relationship between HPHC yields of the tested products. Twelve randomly selected products were used for validation by comparing predicted to measured yields. Model predictions were robust; differences between measured and predicted values were within standard repeatability limits, demonstrating the feasibility of this approach.https://doi.org/10.21423/jrs-v07hannel
Regulatory Science Transparency: Assessment Of Environmental Protection Agency’s Proposed Rule on Strengthening Transparency in Regulatory Science
Authors: Moghissi A. Alan , Calderone Richard A. , Jaeger Lisa M. , Real Lismary , Alessa Yousef , Alsharif Mansour , Debrah Henry , Garrison Destini , Ginigeme Anita , Lamoureux Bralen , Li Yanzhuo , Lin Yuhan , Ogletree Camden , Shadid Hadeel , Sohail Saher , Sohail Soha , Persaud Misti , Ephraim Natalie , Oh Joohye , Pan Tianze , Trippe Lauren
Published: April 2023

In its proposed rule, Strengthening Transparency in Regulatory Science, the Environmental Protection Agency (EPA) requires transparency in certain areas of regulatory science. The proposed rule mandates public access to the details of studies that address dose response and models. This paper is the result of a study conducted by graduate students at Georgetown University. The study relied upon a specific process for selecting a small number from an exceptionally large number of responses to study the subject. The evaluation of the responses was largely based on Best Available Regulatory Science (BARS) and Metrics for Evaluation of Regulatory Science Claims derived from BARS. The results of the study indicate that opposition to the EPA's proposed rule is largely based on the claim that its implementation would eliminate key studies that contain confidential data from consideration during the regulatory process. Although the proposed rule would allow exemptions from the public access requirements, there is opposition to making exemptions available at the discretion of the EPA Administrator. The study concluded that a regulatory science process called "controlled transparency" would be a reasonable solution to compliance with transparency requirements while protecting confidential information.https://doi.org/10.21423/jrs-v07moghissi
Multi-laboratory evaluation of staphylococcal enterotoxin detection by the RIDASCREEN® SE A, B, C, D, E ELISA kit
Authors: McCallum Kristina , Phillips Robert
Published: April 2023

The RIDASCREEN® SE A, B, C, D, E kit was evaluated for use as a secondary test for the detection of staphylococcal enterotoxins in meat matrices  Seven state agriculture and public health laboratories participated in the study. The study demonstrated that the kit is able to detect each of the five serotypes in hot dogs, breaded chicken nuggets, bologna, and ready-to-eat barbeque meat. Staphylococcal enterotoxins were detected at a minimum of 1.0 ng/g in all matrices and at levels as low as 0.375 ng/g in some matrices. While cross-reaction between some serotypes is seen, false negative and false positive results were minimally observed. When used along with the BioMerieux VIDAS® SET2 automated immunoassay test, this kit provides a secondary assay to use as confirmation for the presence of staphylococcal enterotoxins in a meat sample.https://doi.org/10.21423/jrs-v07p001
Core and Supplementary Studies to Assess the Safety of Genetically Modified (GM) Plants Used for Food and Feed
Authors: Brune Phil , Chakravarthy Suma , Graser Gerson , Mathesius Carey A. , McClain Scott , S. Petrick Jay , Sauve-Ciencewicki Alaina , Schafer Barry , Silvanovich Andre , Brink Kent , Burgin Kristina , Bushey Dean , L. Cheever Matthew , Edrington Thomas , Fu Huihua , Habex Veerle , Herman Rod A. , Islamovic Emir , Lipscomb Elizabeth A. , Motyka Shawn , Privalle Laura , Ranjan Rakesh , Roper Jason , Song Ping , Tilton Gregory , Zhang John , Waters Stephen , Ramos Adela , Hendrickson Culler Angela , Hunst Penny , Gast Rachel , Mahadeo Debbie , Goodwin Laurie
Published: April 2023

Genetically modified (GM) plants used for food and feed have an established history of safe use over more than 25 years of their commercialization. Developers and regulatory authorities have accumulated extensive experience in evaluating their safety over time. The studies required for the safety assessment of GM plants used for food and feed should now be re-defined to leverage this experience and increased scientific knowledge. This paper, a companion paper for Waters et al. also published in this issue, presents a systematic approach for the safety assessment of newly expressed proteins (NEPs) in GM plants by evaluating the two components of risk: hazard and exposure. Although the paper focuses on NEPs, the principles presented could also apply to other expression products that do not result in a NEP. A set of core studies is recommended, along with supplementary studies, if needed, to evaluate whether the GM plant poses risk. Core studies include molecular and protein characterization and hazard identification encompassing toxicity and allergenicity. In the absence of hazard, core studies are sufficient to conclude that GM plants are as safe as their conventional counterparts. Depending on the GM trait and intended use, supplementary studies should be performed to characterize hazard and exposure when a hazard is identified. Problem formulation should be used to identify hypothesis-driven supplementary studies. Acute toxicity studies, compositional assessment, and dietary exposure assessment are recommended to be hypothesis-driven supplementary studies. Further discussion on the current food and feed safety assessment landscape for GM plants and the use of problem formulation as a tool for identifying supplementary studies can be found in the companion paper [62].

doi: 10.21423/jrs-v09i1brune
Stacked Trait Products Are As Safe As Non-Genetically Modified (GM) Products Developed By Conventional Breeding Practices
Authors: Goodwin Laurie , Hunst Penny , Burzio Luis , Rowe Laura , Money Stephanie , Chakravarthy Suma
Published: April 2023

International safety assessments and independent publications conclude that stacking genetically modified (GM) traits (events) through conventional breeding poses no greater risk to food or feed safety than stacking multiple non-GM traits by conventional breeding. Stacked trait products are not substantially different from their conventional comparator or their GM parent plants. Additional safety assessment of a stacked trait product produced by conventional breeding should not be required unless there is a plausible and testable hypothesis for interaction of the traits. However, the different approaches employed for the regulation of stacked trait products between countries results in asynchronous approvals, increasing the potential for trade flow disruptions, and adds to the regulatory burden for product developers. Considering their proven safety and benefit over the past 20+ years, regulatory authorities in some countries do not regulate stacked trait products, while others have simplified the approval process based on experience and sound science, reducing or eliminating the need for additional regulatory oversight. Countries that choose to regulate stacked trait products should consider integrating the more than 20 years of safety assessment experience, history of safe use, and global regulatory experience, in their approach to reduce redundancy, simplify regulations, and minimize the likelihood for trade disruption.

doi: 10.21423/jrs-v09i1goodwin
Regulatory Assessment of Off-Target Changes and Spurious DNA Insertions in Gene-Edited Organisms for Agri-Food Use
Authors: Lema Martin
Published: April 2023

Worldwide, an increasing number of regulatory systems have begun to consider applications for the authorization of activities involving gene-edited organisms for agri-food use. Although a handful of countries have made advances in establishing regulatory criteria and gathering practical experience in this regard, there is still a general need for regulatory cooperation concerning capacity building and development of harmonized criteria. Consequently, many biotechnology regulators need to quickly become more acquainted with the numerous technological possibilities enclosed under the concept of "gene editing", and to incorporate criteria for their regulatory assessment. This article contains a simplified introduction to the state of the art in genome editing, described from a regulatory perspective. In particular, two issues of higher practical importance are covered in detail, namely, off-target effects and unintended DNA insertions. The detailed review of current evidence regarding those issues serves as the basis for proposing concrete regulatory criteria to address them.

doi: 10.21423/jrs-v09i1lema
Recommendations for Science-Based Safety Assessment of Genetically Modified (GM) Plants for Food and Feed Uses
Authors: Waters Stephen , Ramos Adela , Hendrickson Culler Angela , Hunst Penny , Zeph Lawrence , Gast Rachel , Mahadeo Debbie , Sottosanto Jordan , Huber Scott , Shan Guomin , Chakravarthy Suma , Goodwin Laurie
Published: April 2023

Since the commercial introduction of genetically modified (GM) plants in agriculture over two decades ago, technology developers and regulatory authorities have gained significant experience in assessing their safety based on assessing potential impact to humans, animals and the environment.  Over 3500 independent regulatory agency reviews have positively concluded on the safety of GM plants for food and feed. Yet, divergent and increased regulatory requirements have led to delayed and asynchronous approvals, and have restricted access to innovative products for farmers and consumers. With accumulated knowledge from safety assessments conducted so far, an enhanced understanding of plant genomes, and a history of safe use, it is time to re-evaluate the current approaches to the regulation of GM plants used for food and feed.  A stepwise approach using weight-of-evidence should be sufficient for the safety assessment of newly expressed proteins in GM plants.  A set of core studies including molecular characterization, expression and characterization of the newly expressed proteins (or other expression product), and safety assessment of the introduced protein are appropriate to characterize the product and assess safety.  Using data from core studies, and employing a “problem formulation” approach, the need for supplementary hypothesis-driven or case-by-case studies can be determined.  Employing this approach for the evaluation of GM plants will remove regulatory data requirements that do not provide value to the safety assessment and provide a consistent framework for global regulation.

doi: 10.21423/jrs-v09i1waters
Setting a Structured Food and Feed Laboratory Testing Capacity in the Arab Region
Authors: Godefroy Samuel
Published: April 2023

Food and feed analysis is a key component in the healthy function and performance of a food control system. Sound decision making relies upon accurate food and feed test results, such as robust scientific data, to inform the risk analysis process: the foundation for establishing responsible regulatory measures. This paper presents efforts presently underway in the Arab region to structure the operation of food and feed testing laboratories and to coordinate sanitary and phytosanitary measures, as a means to stimulate intra-regional trade of food and agri-food commodities. It examines previous experiences undertaken to frame such collaborative action in food and feed testing in the European Union (EU), and, more recently in South East Asia. In addition, the outputs of a survey conducted among key opinion leaders, actors of accreditation bodies, and food competent authorities with regard to current assets and challenges faced by food and feed regulatory testing in the Arab region are discussed. Lastly, a path forward is proposed to shape the development of Arab regional Reference Laboratories, and requirements are recommended to achieve a common policy direction and criteria for the designation of such Reference Laboratories. A regional approach is introduced to promote the integration of food regulatory systems in the region, to strengthen the performance, and to enhance the reliability of food and feed testing in priority areas, with the aim to better characterize the food safety and quality realities in the Arab region.
https://doi.org/10.21423/jrs-v09i2godefroy
Repercussions of politicized regulation exemplified by compulsory new TC1507-maize 90-day rat feeding study
Authors: Roper Jason , Carlson Anne , Podevin Nancy , Wang Yiwei , Mathesius Carey , Herman Rod
Published: April 2023

Politicized and prescriptive regulation of genetically modified (GM) crops has unintended adverse effects, including misdirected resources and reduced benefits.  In the case of animal testing, this suboptimal use of resources includes the needless sacrifice of animals.  Whole-food animal feeding studies are generally of negligible value in the risk assessment of GM crops, a position that was affirmed by the European Food Safety Authority (EFSA).  Contrary to EFSA’s 2011 position, in 2013, the European Commission directed that 90-day rat studies be conducted for new GM events.  As no EFSA guidance was available for hypothesis-free 90-day rat feeding studies, EFSA interpreted this as a mandate to develop a prescriptive study design.  Recently, EFSA has retroactively required 90-day rat studies be completed under new study guidelines for previously approved component single events as part of the approval of breeding stacks.  Having been unable to secure a derogation (exemption) from EFSA, a new compulsory 90-day rat study was conducted with TC1507 maize to support a breeding-stack submission.  As previously shown, TC1507 maize does not adversely affect rats.  This politically driven additional animal testing is risk disproportionate, at odds with European and international standards for animal welfare, and provides no scientific value to the safety assessment for GM breeding stacks.