bluuebunny/crossref_metadata_2025 huggingface dataset:
An Evaluation of Phenolic Compounds, Carotenoids, and Antioxidant Properties in Leaves of South African Cultivars, Peruvian 199062.1 and USA's Beauregard
Authors: Phahlane Charmaine J. , Laurie Sunette M. , Shoko Tinotenda , Manhivi Vimbainashe E. , Sivakumar Dharini
Published: December 2021

In this study, leaves of sweet potato cultivars from South Africa (“Ndou,” “Bophelo,” “Monate,” and “Blesbok”), “Beauregard,” a sweet potato cultivar from the USA, and a Peruvian cultivar “199062. 1” were analyzed using UPLC/QTOF/MS and chemometrics, with the aim of characterizing the locally developed sweet potato cultivars and comparing them with already well-known established varieties on the market. A set of 13 phenolic compounds was identified. A partial least squares discriminant analysis, a hierarchical cluster analysis, and variables importance in projection were used to successfully distinguish sweet potato varieties based on their distinct metabolites. Caffeic acid enabled to distinguish Cluster 1 leaves of varieties (“Beauregard” and “Ndou”) from Cluster 2 (“199062.1,” “Bophelo,” “Monate,” and “Blesbok”). The leaves of “Bophelo” contained the highest concentrations of rutin, quercetin 3-O-galactoside, 3-caffeoylquinic acid (3-CQA), (5-CQA), 1,3 dicaffeoylquinic acid (1,3-diCQA), 1,4-diCQA, and 3,5-diCQA. Furthermore, Bophelo leaves showed the highest antioxidant activities (FRAP 19.69 mM TEACg−1 and IC50 values of (3.51 and 3.43 mg ml−1) for DPPH and ABTS, respectively, compared to the other varieties. Leaves of “Blesbok” contained the highest levels of β-carotene (10.27 mg kg−1) and zeaxanthin (5.02 mg kg−1) on a dry weight basis compared to all other varieties. This study demonstrated that the leaves of local cultivars “Bophelo” and “Blesbok” have the potential to become functional ingredients for food processing.
Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study
Authors: Li Chunyu , Ou Ruwei , Wei Qianqian , Shang Huifang
Published: December 2021

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.

Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.

Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.

Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.
Improved Oxidation Stability of Camellia Oil-in-Water Emulsions Stabilized by the Mixed Monolayer of Soy Protein Isolate/Bamboo Shoot Protein Complexes
Authors: Xi Yuhang , Zhang Aiping , Wang Zhongjiang , Farooq Shahzad , Zhang Cen , Wu Liangru , Zhang Hui
Published: December 2021

The complex of soy protein isolate (SPI)/bamboo shoot protein concentrate (BPC) was developed to stabilize camellia oil-in-water (O/W) emulsions. The surface hydrophobicity of the BPC/SPI complex driven by hydrogen bonds and electrostatic attractions was improved. With the increasing ratio of BPC in the complex, a tighter network layer structure of the complex was formed due to the rearrangement of proteins, and the emulsions showed a progressive enhancement in the gel-like structures. At the SPI/BPC ratio of 2:1, the emulsions had smaller droplet size and lower creaming index of 230 nm and 30%, and the emulsifying activity and stability indices of the emulsions were 803.72 min and 11.85 g/m2, respectively, indicating a better emulsifying activity and stability of emulsions. Meanwhile, the emulsions stabilized by the complex at the ratio of 2:1 showed better storage and antioxidant stability. These findings are expected to develop the application of bamboo shoots in emulsion-based food products such as mayonnaise, salad dressings, and sauces.
Dietary Enteromorpha Polysaccharide Enhances Intestinal Immune Response, Integrity, and Caecal Microbial Activity of Broiler Chickens
Authors: Wassie Teketay , Lu Zhuang , Duan Xinyi , Xie Chunyan , Gebeyew Kefyalew , Yumei Zhang , Yin Yulong , Wu Xin
Published: December 2021

Marine algae polysaccharides have been shown to regulate various biological activities, such as immune modulation, antioxidant, antidiabetic, and hypolipidemic. However, litter is known about the interaction of these polysaccharides with the gut microbiota. This study aimed to evaluate the effects of marine algae Enteromorpha (Ulva) prolifera polysaccharide (EP) supplementation on growth performance, immune response, and caecal microbiota of broiler chickens. A total of 200 1-day-old Ross-308 broiler chickens were randomly divided into two treatment groups with ten replications of ten chickens in each replication. The dietary treatments consisted of the control group (fed basal diet), and EP group (received diet supplemented with 400 mg EP/kg diet). Results showed that chickens fed EP exhibited significantly higher (P < 0.05) body weight and average daily gain than the chicken-fed basal diet. In addition, significantly longer villus height, shorter crypt depth, and higher villus height to crypt depth ratio were observed in the jejunal and ileal tissues of chickens fed EP. EP supplementation upregulated the mRNA expression of NF-κB, TLR4, MyD88, IL-2, IFN-α, and IL-1β in the ileal and jejunal tissues (P < 0.05). Besides, we observed significantly higher (P < 0.05) short-chain volatile fatty acids (SCFAs) levels in the caecal contents of the EP group than in the control group. Furthermore, 16S-rRNA analysis revealed that EP supplementation altered gut microbiota and caused an abundance shift at the phylum and genus level in broiler chicken. Interestingly, we observed an association between microbiota and SCFAs production. Overall, this study demonstrated that supplementation of diet with EP promotes growth performance, improves intestinal immune response and integrity, and modulates the caecal microbiota of broiler chickens. This study highlighted the application of marine algae polysaccharides as an antibiotic alternative for chickens. Furthermore, it provides insight to develop marine algae polysaccharide-based functional food and therapeutic agent.
RAB42 Promotes Glioma Pathogenesis via the VEGF Signaling Pathway
Authors: Liu Baoling , Su Quanping , Xiao Bolian , Zheng Guodong , Zhang Lizhong , Yin Jiawei , Wang Lijuan , Che Fengyuan , Heng Xueyuan
Published: December 2021

Angiogenesis plays an important role in tumor initiation and progression of glioma. Seeking for biomarkers associated with angiogenesis is important in enhancing our understanding of glioma biologically and identifying its new drug targets. RNA-sequencing (RNA-seq) data and matched clinical data were downloaded from the CGGA database. A series of filtering analyses were performed to screen for reliable genes: survival, multivariate Cox, ROC curve filtration, and clinical correlation analyses. After immunohistochemical verification, RAB42 was identified as a reliable gene for further single gene analysis. Afterwards, we performed gene set enrichment analysis (GSEA) and co-expression analysis to establish the related molecular mechanisms and signal pathways in glioma. Finally, the gene functions and the mechanisms were investigated in vitro experiments. A total of 23270 mRNA expression and 1018 glioma samples were included in this study. After the three filtering analyses, we selected ten genes for immunohistochemical verification: KLHDC8A, IKIP, HIST1H2BK, HIST1H2BJ, GNG5, FAM114A1, TMEM71, RAB42, CCDC18, and GAS2L3. Immunostaining demonstrated that RAB42 was significantly expressed on the membrane of glioma tissues but not in normal tissues. These results were verified and validated in GEPIA datasets, and the association between RAB42 with clinical features was also evaluated. Analysis of gene functions indicated that RAB42 activated VEGF signaling pathways and the mechanism was associated with natural killer cell mediated cytotoxicity, JAK-STAT signaling pathway and apoptosis pathways by PI3K/AKT in gliomas. Experiments in vitro suggested that the proliferation and invasion of glioma cells might be inhibited after downregulating of RAB42. And the tumorigenesis promotion of RAB42 may relate to the activation of VEGF signaling pathway. Taken together, this study shows that the overexpression of RAB42 is an independent prognostic factor of adverse prognosis. Its pro-oncogenic mechanism may be associated with the activation of VEGF signaling pathways.
Case Report: Evolution of KIT D816V-Positive Systemic Mastocytosis to Myeloid Neoplasm With PDGFRA Rearrangement Responsive to Imatinib
Authors: Sciumè Mariarita , Ceparano Giusy , Eller-Vainicher Cristina , Fabris Sonia , Lonati Silvia , Croci Giorgio Alberto , Baldini Luca , Grifoni Federica Irene
Published: December 2021

Systemic mastocytosis (SM) is a rare neoplasm resulting from extracutaneous infiltration of clonal mast cells (MC). The clinical features of SM are very heterogenous and treatment should be highly individualized. Up to 40% of all SM cases can be associated with another hematological neoplasm, most frequently myeloproliferative neoplasms. Here, we present a patient with indolent SM who subsequently developed a myeloid neoplasm with PDGFRA rearrangement with complete response to low-dose imatinib. The 63-year-old patient presented with eosinophilia and elevated serum tryptase level. Bone marrow analysis revealed aberrant MCs in aggregates co-expressing CD2/CD25 and KIT D816V mutation (0.01%), and the FIP1L1-PDGFRA fusion gene was not identified. In the absence of ‘B’ and ‘C’ findings, we diagnosed an indolent form of SM. For 2 years after the diagnosis, the absolute eosinophil count progressively increased. Bone marrow evaluation showed myeloid hyperplasia and the FIP1L1-PDGFRA fusion gene was detected. Thus, the diagnosis of myeloid neoplasm with PDGFRA rearrangement was established. The patient was treated with imatinib 100 mg daily and rapidly obtained a complete molecular remission. The clinical, biological, and therapeutic aspects of SM might be challenging, especially when another associated hematological disease is diagnosed. Little is known about the underlying molecular and immunological mechanisms that can promote one entity prevailing over the other one. Currently, the preferred concept of SM pathogenesis is a multimutated neoplasm in which KIT mutations represent a “phenotype modifier” toward SM. Our patient showed an evolution from KIT mutated indolent SM to a myeloid neoplasm with PDGFRA rearrangement; when the eosinophilic component expanded, a regression of the MC counterpart was observed. In conclusion, extensive clinical monitoring associated with molecular testing is essential to better define these rare diseases and consequently their prognosis and treatment.
Association Between Accumulation of Child Maltreatment and Salivary Oxytocin Level Among Japanese Adolescents
Authors: Mizuki Rie , Fujiwara Takeo
Published: December 2021

Background: Child maltreatment is related to oxytocin (OT), which is related to social functioning. It may hamper the OT level to avoid a harmful situation and increase the OT level to adapt to the situation using a tend-and-befriend stress reaction.

Objective: This study aims to examine the association between the accumulation of moderate–severe childhood maltreatment and salivary OT levels in Japanese adolescents.

Participants: We used convenience samples of adolescents living in an institution (n = 31) and those living with their parents (n = 46).

Methods: Child maltreatment experiences were measured with the Childhood Trauma Questionnaire. The salivary OT levels were assessed by enzyme linked immunosorbent assay. A multivariate regression analysis was performed to see the association between the accumulation of child maltreatment types and the salivary OT levels adjusted for covariates (i.e., age, sex, and duration of institutionalization).

Results: Physical abuse was associated with higher OT, while emotional neglect showed an inverse association with OT. OT was the lowest with one maltreatment type group, which was significantly lower than the non-maltreatment group. As the number of maltreatment types increased from one maltreatment type to 2–3 types and to 4–5 types, OT also increased. This U-shaped association between the number of maltreatment types and OT was confirmed with the significant result of a square term of number of maltreatment type in the model (p = 0.012).

Conclusion: We found herein a U-shaped association between the accumulation of child maltreatment and salivary OT levels. Also, different types of maltreatment had varied effects on the salivary OT. Further study is needed to elucidate the non-linear association between child maltreatment and OT levels.
Etiologies of Childhood Hearing Impairment in Schools for the Deaf in Mali
Authors: Yalcouyé Abdoulaye , Traoré Oumou , Taméga Abdoulaye , Maïga Alassane B. , Kané Fousseyni , Oluwole Oluwafemi G. , Guinto Cheick Oumar , Kéita Mohamed , Timbo Samba Karim , DeKock Carmen , Landouré Guida , Wonkam Ambroise
Published: December 2021

Objectives: To identify the etiologies of hearing impairment (HI) in schools for students who are deaf and to use a systematic review to summarize reports on the etiologies and clinical and genetic features of HI in Mali.

Methods: We included individuals with HI that started before the age of 15 years old. Patients were carefully evaluated under standard practices, and pure-tone audiometry was performed where possible. We then searched for articles published on HI in the Malian population from the databases' inception to March 30, 2020.

Results: A total of 117 individuals from two schools for the deaf were included, and a male predominance (sex ratio 1.3; 65/52) was noted. HI was pre-lingual in 82.2% (n = 117), and the median age at diagnosis was 12 years old. The etiologies were environmental in 59.4% (70/117), with meningitis being the leading cause (40%, 20/70), followed by cases with genetic suspicion (29.3%, 21/117). In 11.3% (8/117) of patients, no etiology was identified. Among cases with genetic suspicion, three were syndromic, including two cases of Waardenburg syndrome, while 15 individuals had non-syndromic HI. An autosomal recessive inheritance pattern was observed in 83.3% of families (15/18), and consanguinity was reported in 55.5% (10/18) of putative genetic cases.

Conclusion: This study concludes that environmental factors are the leading causes of HI in Mali. However, genetic causes should be investigated, particularly in the context of a population with a high consanguinity rate.
Recent Advances in Kidney Bioengineering
Authors: Cintron Pregosin Nina , Bronstein Robert , Mallipattu Sandeep K.
Published: December 2021

Kidney disease is an epidemic that affects more than 600 million people worldwide. The socioeconomic impacts of the disease disproportionately affect Hispanic and non-Hispanic Black Americans, making the disease an issue of social inequality. The urgency of this situation has only become worse during the COVID-19 pandemic, as those who are hospitalized for COVID-19 have an increased risk of kidney failure. For researchers, the kidney is a complex organ that is difficult to accurately model and understand. Traditional cell culture models are not adequate for studying the functional intricacies of the kidney, but recent experiments have offered improvements for understanding these systems. Recent progress includes organoid modeling, 3D bioprinting, decellularization, and microfluidics. Here, we offer a review of the most recent advances in kidney bioengineering.
Cross-Sectional Associations Between Wake-Time Movement Compositions and Mental Health in Preschool Children With and Without Motor Coordination Problems
Authors: Brown Denver M. Y. , Kwan Matthew Y. W. , King-Dowling Sara , Cairney John
Published: December 2021

Movement behaviors have been found to be important correlates of health for children and may be particularly important for children with Developmental Coordination Disorder (DCD) who often experience greater mental health problems. To date, however, little research has investigated the daily movement composition of preschool children with Developmental Coordination Disorder (DCD) and/or its association with mental health. The purpose of the current study was to: (1) examine whether differences in movement compositions (i.e., sedentary time, light physical activity, moderate-to-vigorous physical activity) exist between typically developing (TD) preschool-age children and those at risk for DCD (rDCD); and (2) investigate associations between movement compositions and mental health indicators. This cross-sectional study used the baseline cohort data from the Coordination and Activity Tracking in CHildren (CATCH) study. A total of 589 preschool-age children (Mage = 4.94 ± 0.59 years; 57.4% boys) were included in this analysis, of which 288 scored at or below the 16th percentile on the Movement Assessment Battery for Children-2 and were thus classified as rDCD. Wake time movement behaviors were measured using accelerometers and parents completed the Child Behavior Checklist to assess their child's mental health (i.e., internalizing and externalizing problems). Compositional data analysis techniques were used. After adjusting for potential confounders, the results demonstrated similar movement compositions between TD and rDCD children. Among the full sample, findings revealed a significant association between sedentary time and externalizing problems, however, each of the other associations did not reach statistical significance. These results are consistent with emerging evidence demonstrating similar patterns of physical activity and sedentary time among TD children and those classified as rDCD during the preschool years. Although movement behaviors explained little variance in mental health during this period, future research should investigate when movement compositions diverge, and how these changes may impact the mental health of TD children and those classified as rDCD later in childhood.
Adrenal Steroid Metabolism and Blood Pressure in 5- to 7-Year-Old Children Born Preterm as Compared to Peers Born at Term
Authors: Landmann Eva , Brugger Markus , Blank Verena , Wudy Stefan A. , Hartmann Michaela , Strauch Konstantin , Rudloff Silvia
Published: December 2021

Background: Previous studies indicated preterm birth to be a risk factor for hypertension in adolescence and adulthood. However, studies in children investigating the underlying mechanisms are scarce.

Objective: We hypothesized children born preterm to have higher excretion of cortisol and/or androgen metabolites per day concomitantly with higher blood pressure as compared to peers born at term. We thus aimed to compare urinary steroid profiles and blood pressure between 5- to 7-year-old children born preterm and peers born at term. Furthermore, aldosterone precursor excretion per day was compared between both groups.

Methods: Blood pressure was measured in 236 children (preterms n = 116; gestational age 29.8 ± 2.6 (30; 24–33) weeks [mean ± standard deviation (median; range)]) using an automatic oscillometric device. Urinary steroid profiles were determined in 24-h urine samples (preterms n = 109; terms n = 113) using gas chromatographic-mass spectrometric analysis. To assess excretion of cortisol and androgen metabolites per day, major cortisol and androgen metabolites were summed, respectively. To assess aldosterone excretion per day tetrahydrocorticosterone, 5α-tetrahydrocorticosterone, and tetrahydro-11-deydrocorticosterone were summed.

Results: Multiple regression analyses showed prematurity to be associated with systolic but not with diastolic blood pressure. When adjusted for potential confounders (prematurity, gender, age at day of examination, being born small for gestational age, breastfeeding, accelerated weight gain during infancy, family history of cardiovascular disease, parental hypertension, and body mass index) prematurity was shown to be associated with an increase in systolic blood pressure by 2.87 mmHg (95% confidence interval 0.48–5.27; p = 0.02). Cortisol, androgen metabolite, and aldosterone precursor excretion per day were not higher in individuals born preterm. In contrast to our hypothesis, multiple regression analysis showed prematurity to independently decrease cortisol and aldosterone precursor excretion per day (p < 0.001 and 0.04, respectively).

Conclusion: This study provides further evidence for systolic blood pressure to be higher after preterm birth as early as at the age of 5 to 7 years. However, this seems not to be explained by elevated excretion of cortisol and/or androgen metabolites.
Increasing the Focus on Children's Complex and Integrated Care Needs: A Position Paper of the European Academy of Pediatrics
Authors: Brenner Maria , Greene Josephine , Doyle Carmel , Koletzko Berthold , del Torso Stefano , Bambir Ivan , De Guchtenaere Ann , Polychronakis Theofilos , Reali Laura , Hadjipanayis Adamos A.
Published: December 2021

There is wide variation in terminology used to refer to children living with complex needs, across clinical, research and policy settings. It is important to seek to reconcile this variation to support the effective development of programmes of care for this group of children and their families. The European Academy of Pediatrics (EAP) established a multidisciplinary Working Group on Complex Care and the initial work of this group examined how complex care is defined in the literature. A scoping review was conducted which yielded 87 papers with multiple terms found that refer to children living with complex needs. We found that elements of integrated care, an essential component of care delivery to these children, were repeatedly referred to, though it was never specifically incorporated into a term to describe complex care needs. This is essential for practice and policy, to continuously assert the need for integrated care where a complex care need exists. We propose the use of the term Complex and Integrated Care Needs as a suitable term to refer to children with varying levels of complexity who require continuity of care across a variety of health and social care settings.
The Influence of Articulatory Suppression on Reading Among Chinese Children With Developmental Dyslexia: An Eye-Movement Study
Authors: Li Xiuhong , Li Weidong , Liu Buyun , Zhang Jinxin , Ma Jingwen , Xie Chuanbo , Wu Jing , Jing Jin
Published: December 2021

Objective: The study aimed to examine how the phonological loop influences reading ability and processing in Chinese children with developmental dyslexia (DD).

Methods: This study included 30 children with DD and 37 children without DD. Two types of articles (i.e., scenery prose and narrative story) and two conditions (under the conditions of articulatory-suppression and silent reading) were applied. An eye-link II High-Speed Eye Tracker was used to track a series of eye-movement parameters. The data were analyzed by the linear Mixed-Effects model.

Results: Compared with children without DD, Children with DD had lower reading achievement (RA), frequency of saccades (FS) and frequency of fixations (FF), longer reading time (RT) and average fixation duration (AFD), slower reading speed (RS), shorter average saccade amplitude (ASA) and fixation distance (FD), more number of fixations (NF), and number of saccades (NS). There were significant interactions between participant group and articulatory suppression on RT and FD. We also observed interaction effects between article types and articulatory suppression on RA, AFD, ASA, and FS.

Conclusion: Children DD exhibit abnormal phonological loop and eye movements while reading. The role of articulatory suppression on reading varies with the presentation of DD and the article type.
Delayed Presentation and Mortality in Children With Sepsis in a Public Tertiary Care Hospital in Tanzania
Authors: Smith Audrey Marilyn , Sawe Hendry R. , Matthay Michael A. , Murray Brittany Lee , Reynolds Teri , Kortz Teresa Bleakly
Published: December 2021

Background: Over 40% of the global burden of sepsis occurs in children under 5 years of age, making pediatric sepsis the top cause of death for this age group. Prior studies have shown that outcomes in children with sepsis improve by minimizing the time between symptom onset and treatment. This is a challenge in resource-limited settings where access to definitive care is limited.

Methods: A secondary analysis was performed on data from 1,803 patients (28 days−14 years old) who presented to the emergency department (ED) at Muhimbili National Hospital (MNH) from July 1, 2016 to June 30, 2017 with a suspected infection and ≥2 clinical systemic inflammatory response syndrome criteria. The objective of this study was to determine the relationship between delayed presentation to definitive care (>48 h between fever onset and presentation to the ED) and mortality, as well as the association between socioeconomic status (SES) and delayed presentation. Multivariable logistic regression models tested the two relationships of interest. We report both unadjusted and adjusted odds ratios and 95% confidence intervals.

Results: During the study period, 11.3% (n = 203) of children who presented to MNH with sepsis died inhospital. Delayed presentation was more common in non-survivors (n = 90/151, 60%) compared to survivors (n = 614/1,353, 45%) (p ≤ 0.01). Children who had delayed presentation to definitive care, compared to those who did not, had an adjusted odds ratio for mortality of 1.85 (95% CI: 1.17–3.00).

Conclusions: Delayed presentation was an independent risk factor for mortality in this cohort, emphasizing the importance of timely presentation to care for pediatric sepsis patients. Potential interventions include more efficient referral networks and emergency transportation systems to MNH. Additional clinics or hospitals with pediatric critical care may reduce pediatric sepsis mortality in Tanzania, as well as parental education programs for recognizing pediatric sepsis.
The Validity, Reliability, and Feasibility of Measurement Tools Used to Assess Sleep of Pre-school Aged Children: A Systematic Rapid Review
Authors: Phillips Sophie M. , Summerbell Carolyn , Ball Helen L. , Hesketh Kathryn R. , Saxena Sonia , Hillier-Brown Frances C.
Published: December 2021

Background: Sleep of pre-school aged children is important for their health and development, but there are currently no standards for measuring sleep in this age group. We aimed to examine the validity, reliability and feasibility of tools used to assess sleep of pre-school aged children.

Methods: Studies were eligible for inclusion if they examined the validity and/or reliability and/or feasibility of a measurement tool used to examine sleep of pre-school aged children (aged 3–7 years). We systematically searched six electronic databases, grey literature and trial registries. We manually searched topic specific journals, reference and citations of included studies, and reference lists of existing reviews. We extracted data and conducted a risk of bias assessment on the included studies using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist. We used a narrative synthesis to present the results.

Results: Sixteen studies met the inclusion criteria: these explored accelerometers (n = 3) and parental reported tools (n = 13; nine questionnaires, six diaries). Studies assessed construct validity (n = 3), criterion validity (n = 1), convergent validity (n = 13), test-retest reliability (n = 2), internal consistency (n = 4) and feasibility (n = 12). Most studies assessed the convergent validity of questionnaires and diaries compared with accelerometers, but the validity of accelerometers for sleep in this age group is unknown. Of studies with a low risk of bias, one sleep diary was shown to be valid for measuring sleep duration. No measurement tools were appropriate for determining sleep quality. Reporting of reliability and feasibility was minimal.

Discussion: The evidence base in this field is limited, and most studies had high risk of bias. Future research on sleep in pre-school aged children should focus on assessing the validity, reliability and feasibility of accelerometers, which in turn will improve the quality of studies that assess questionnaires and diaries against accelerometers.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021230900; PROSPERO: CRD42021230900.
Clinical Characteristics of Personality and Conduct Disorders in Child Patients With Vasovagal Syncope: A Clinical Case-Control Study
Authors: Wang Tao , Wang Fang , Li Yifei , Shi Xiaoqing , Duan Hongyu , Zhou Kaiyu , Hua Yimin
Published: December 2021

Objective: To analyze the clinical characteristics of abnormal personality and conduct disorders (CDs) in pediatric patients with vasovagal syncope (VVS).

Methods: In this study, we recruited patients diagnosed with VVS at Children's Heart Center from January 2018 to December 2020. Healthy children were recruited as controls. The Eysenck Personality Questionnaire-Child edition (EPQ-C) and Achenbach Child Behavior Checklist (CBCL) were used for the assessment.

Results: One hundred and fifty-one VVS patients and 151 healthy controls were included in this study. Compared with the control group, patients in the VVS group had a higher incidence of abnormal personality and were more prone to suffer from CDs. Moreover, pediatric patients with VVS suffered more events of syncope recurrence if they had CDs.

Conclusion: Abnormal personality and CDs are common clinical characteristics in pediatric patients with VVS.
Cellular Origin(s) of Congenital Diaphragmatic Hernia
Authors: Edel Gabriëla G. , Schaaf Gerben , Wijnen Rene M. H. , Tibboel Dick , Kardon Gabrielle , Rottier Robbert J.
Published: December 2021

Congenital diaphragmatic hernia (CDH) is a structural birth defect characterized by a diaphragmatic defect, lung hypoplasia and structural vascular defects. In spite of recent developments, the pathogenesis of CDH is still poorly understood. CDH is a complex congenital disorder with multifactorial etiology consisting of genetic, cellular and mechanical factors. This review explores the cellular origin of CDH pathogenesis in the diaphragm and lungs and describes recent developments in basic and translational CDH research.
Standardization of Berberis aristata DC and Nigella sativa L. Using HPTLC and GCMS and Their Antineoplasia Activity in 7,12-Dimethylbenz[a]anthracene-Induced Mouse Models
Authors: Mazhar Mohd , Agrawal S S
Published: December 2021

Berberis aristata DC and Nigella sativa L. are officially listed in various Indian Pharmacopoeia and AYUSH official documents. Prescribed for different ailments for proven medicinal activities, they thus became part of polyherbal medications. With reverse pharmacology and scientific validation, more than 30 patents are filed on different formulations of B. aristata and granted. Nigella sativa L. has been broadly studied for its therapeutic potential and wide range of activities against cardiovascular, diabetic, cancer, and life style disorders. Thus, this study is aimed at standardizing B. aristata and N. sativa and their antineoplasia activity in 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mouse models. Molecular docking was done using the Schrodinger program Maestro 9.0. Herbal extracts and essential oil (B. aristata and N. sativa) were standardized and quantified using high-performance thin-layer chromatography (HPTLC) (CAMAG) and gas chromatography–mass spectrometry (GCMS) (Agilent 2010GC System) with validated methods. DMBA was administered orally once a week (1mg/200 µL) to each animal except the normal control. Hematology, histopathology, and immunoassays were performed, and data were analyzed and depicted with GraphPad and SPSS. In molecular docking, thymoquinone showed the highest docking score (9.519, 9.211, and 9.042, respectively) in the active site pockets of IL6 (PDB ID: 4CNI and 5FCU), TNF (PDB ID: 2AZ5), and VEGF (PDB ID: 4KZN). Out of all four target sites, thymoquinone and berberine showed good binding affinity with IL6 (PDB ID: 4CNI) compared to α- and β-pinenes. HPTLC analysis of the hydroalcoholic extract showed the presence of berberine both qualitatively and quantitatively (5.4% berberine), and thymoquinone detected 0.17% in the N. sativa extract. GCMS for essential oil showed 26 compounds including ±pinene. Leukocytes and erythrocytes of N. sativa and B. aristata were analyzed, and significant improvements were recorded (P < 0.05) and graphically presented. Mean survival time was calculated by the Kaplan Meier method (119 days). Immunoassay analyses were conducted, namely, TNF-α and VEGF, and interpreted and marked.
Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System
Authors: Bai Xiaoyin , Jiang Shiyu , Zhou Yangzhong , Zhen Hongnan , Ji Junyi , Li Yi , Ruan Gechong , Yang Yang , Shen Kaini , Wang Luo , Li Guanqiao , Yang Hong
Published: December 2021

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, immune-related adverse events (irAEs) in the gastrointestinal (GI) system commonly occur. In this study, data were obtained from the US Food and Drug Administration adverse event reporting system between July 2014 and December 2020. Colitis, hepatobiliary disorders, and pancreatitis were identified as irAEs in our study. Reporting odds ratio (ROR) with information components (IC) was adopted for disproportionate analysis. A total of 70,330 adverse events were reported during the selected period, 4,075 records of which were associated with ICIs. GI toxicities have been reportedly increased with ICI, with ROR025 of 17.2, 6.7, and 2.3 for colitis, hepatobiliary disorders, and pancreatitis, respectively. The risks of colitis, hepatobiliary disorders, and pancreatitis were higher with anti-CTLA-4 treatment than that with anti-PD-1 (ROR025 2.6, 1.3, and 1.1, respectively) or anti-PD-L1 treatment (ROR025 4.8, 1.3, and 1.3, respectively). Logistic analysis indicated that hepatobiliary disorders and pancreatitis more frequently occurred in female patients (adjusted odds ratio, 1.16 and 1.52; both p < 0.05). Consistently, polytherapy was a strong risk factor for colitis (adjusted odds ratio 2.52, p < 0.001), hepatobiliary disorders (adjusted odds ratio 2.50, p < 0.001), and pancreatitis (adjusted odds ratio 2.29, p < 0.001) according to multivariate logistic analysis. This pharmacovigilance analysis demonstrated an increased risk of all three GI irAEs associated with ICI therapies. The comparative analysis offered supportive insights on selecting GI irAEs for patients treated with ICIs.
Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma
Authors: Raufi Alexander G. , Liguori Nicholas R. , Carlsen Lindsey , Parker Cassandra , Hernandez Borrero Liz , Zhang Shengliang , Tian Xiaobing , Louie Anna , Zhou Lanlan , Seyhan Attila A. , El-Deiry Wafik S.
Published: December 2021

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.
Impact of Non-Persistence on Healthcare Resource Utilization and Costs in Patients With Immune-Mediated Rheumatic Diseases Initiating Subcutaneous TNF-Alpha Inhibitors: A Before-and-After Study
Authors: Carballo Nuria , Garcia-Alzórriz Enric , Ferrández Olivia , Navarrete-Rouco María Eugenia , Durán-Jordà Xavier , Pérez-García Carolina , Monfort Jordi , Cots Francesc , Grau Santiago
Published: December 2021

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are chronic progressive immune-mediated rheumatic diseases (IMRD) that can cause a progressive disability and joint deformation and thus can impact in healthcare resource utilization (HCRU) and costs. The main outcome of the study was to assess the effect of non-persistence to treatment with subcutaneous tumor necrosis factor-alpha inhibitors (SC-TNFis) on HCRU costs in naïve patients with IMRD who started treatment with adalimumab, etanercept, golimumab or certolizumab pegol during 12 months after initiation of treatment. The impact of persistence and non-persistence of SC-TNFis on HCRU costs was compared between 12 months before and 12 months after initiating SC-TNFis. Persistence was defined as the duration of time from initiation to discontinuation of therapy. The study was conducted in an acute care teaching hospital in Barcelona, Spain. Data for the period between 2015 and 2018 were extracted from the hospital cost management control database. HCRU costs comprised outpatient care, outpatient specialized rheumatology care, in-patient care, emergency care, laboratory testing and other non-biological therapies. The study population included 110 naïve SC-TNFis patients, divided into the cohorts of persistent (n = 85) and non-persistent (n = 25) patients. Fifty-six percent of patients were women, with a mean (standard deviation) age of 47.6 (14.8) years. Baseline clinical features and HCRU costs over the 12 months before the index prescription were similar in the two study groups. Before-and-after differences in mean (standard deviation) HCRU costs were significantly higher in the non-persistence group as compared to the persistence group for outpatient rheumatology care (€110.90 [234.56] vs. €20.80 [129.59], p = 0.023), laboratory testing (−€193.99 [195.88] vs. −€241.3 [217.88], p = 0.025), other non-biological drugs (€3849.03 [4046.14] vs. −€10.90 [157.42], p < 0.001) and total costs (€3268.90 [4821.55] vs. −€334.67 (905.44), p < 0.001). Treatment persistence with SC-TNFis may be associated with HCRU cost savings in naïve IMRD patients. Prescribing SC-TNFis with the best long-term persistence is beneficial.
Natural Products for the Prevention and Control of the COVID-19 Pandemic: Sustainable Bioresources
Authors: Singla Rajeev K. , He Xuefei , Chopra Hitesh , Tsagkaris Christos , Shen Li , Kamal Mohammad Amjad , Shen Bairong
Published: December 2021

Background:The world has been unprecedentedly hit by a global pandemic which broke the record of deadly pandemics that faced humanity ever since its existence. Even kids are well-versed in the terminologies and basics of the SARS-CoV-2 virus and COVID-19 now. The vaccination program has been successfully launched in various countries, given that the huge global population of concern is still far behind to be vaccinated. Furthermore, the scarcity of any potential drug against the COVID-19-causing virus forces scientists and clinicians to search for alternative and complementary medicines on a war-footing basis.

Aims and Objectives:The present review aims to cover and analyze the etiology and epidemiology of COVID-19, the role of intestinal microbiota and pro-inflammatory markers, and most importantly, the natural products to combat this deadly SARS-CoV-2 virus.

Methods:A primary literature search was conducted through PubMed and Google Scholar using relevant keywords. Natural products were searched from January 2020 to November 2020. No timeline limit has been imposed on the search for the biological sources of those phytochemicals. Interactive mapping has been done to analyze the multi-modal and multi-target sources.

Results and Discussion:The intestinal microbiota and the pro-inflammatory markers that can serve the prognosis, diagnosis, and treatment of COVID-19 were discussed. The literature search resulted in yielding 70 phytochemicals and ten polyherbal formulations which were scientifically analyzed against the SARS-CoV-2 virus and its targets and found significant. Retrospective analyses led to provide information about 165 biological sources that can also be screened if not done earlier.

Conclusion:The interactive analysis mapping of biological sources with phytochemicals and targets as well as that of phytochemical class with phytochemicals and COVID-19 targets yielded insights into the multitarget and multimodal evidence-based complementary medicines.
Integrated Strategy From In Vitro, In Situ, In Vivo to In Silico for Predicting Active Constituents and Exploring Molecular Mechanisms of Tongfengding Capsule for Treating Gout by Inhibiting Inflammatory Responses
Authors: Yang Wenning , Jiang Xiaoquan , Liu Jingtong , Qi Dongying , Luo Zhiqiang , Yu Guohua , Li Xueyan , Sen Muli , Chen Hongjiao , Liu Wei , Liu Yang , Wang Guopeng
Published: December 2021

The study of screening active constituents from traditional Chinese medicine (TCM) is important for explicating the mechanism of action of TCM and further evaluating the safety and efficacy effectively. However, detecting and identifying the active constituents from complicated biological samples still remain a challenge. Here, a practical, quick, and novel integrated strategy from in vitro, in situ, in vivo to in silico for rapidly screening the active constituents was developed. Firstly, the chemical profile of TCM in vitro was identified using UPLC-Q Exactive-Orbitrap HRMS. Secondly, the in situ intestinal perfusion with venous sampling (IPVS) method was used to investigate the intestinal absorption components. Thirdly, after intragastric administration of the TCM extract, the in vivo absorbed prototype components were detected and identified. Finally, the target network pharmacology approach was applied to explore the potential targets and possible mechanisms of the absorbed components from TCM. The reliability and availability of this approach was demonstrated using Tongfengding capsule (TFDC) as an example of herbal medicine. A total of 141 compounds were detected and identified in TFDC, and among them, 64 components were absorbed into the plasma. Then, a total of 35 absorbed bioactive components and 50 related targets shared commonly by compounds and gout were integrated via target network pharmacology analysis. Ultimately, the effects of the absorbed components on metabolism pathways were verified by experiments. These results demonstrated that this original method may provide a practical tool for screening bioactive compounds from TCM treating particular diseases. Furthermore, it also can clarify the potential mechanism of action of TCM and rationalize the application of TFDC as an effective herbal therapy for gout.
Si-Miao-Yong-An Decoction for Diabetic Retinopathy: A Combined Network Pharmacological and In Vivo Approach
Authors: Du Ao , Xie Yumin , Ouyang Hao , Lu Bin , Jia Wangya , Xu Hong , Ji Lili
Published: December 2021

Si-Miao-Yong-An decoction (SMYAD), a traditional Chinese medicine formula, is mainly used to clear away heat and detoxify and to promote blood circulation and relieve pain. Diabetic retinopathy (DR) is the most common type of microvascular complication caused by diabetes. This study is designed to examine the protective effect of SMYAD against DR and further to reveal the engaged mechanism via integrating network pharmacology and in vivo experimental evidence. Streptozotocin (STZ) was intraperitoneally injected into mice to induce diabetes. The dysfunction of the blood retina barrier (BRB) was observed by conducting Evan’s blue leakage assay, detecting tight junction (TJ) protein expression and counting the number of acellular capillaries in retinas. Our results showed that SMYAD alleviated BRB breakdown in vivo. Network pharmacology results demonstrated that regulating inflammation, immune responses, and angiogenesis might be associated with the efficacy of SMYAD in alleviating DR, in which the tumor necrosis factor (TNF) and hypoxia inducible factor 1 (HIF1) signal pathways were involved. Next, immunofluorescence staining results showed that SMYAD decreased microglia activation in retinas and reduced the enhanced adhesion of leukocytes into retinal vessels. SMYAD reduced the elevated serum TNFα content and retinal TNFα expression. SMYAD abrogated the activation of nuclear factor κB (NFκB) and HIF1α and consequently decreased the enhanced expression of some pro-inflammatory molecules and vascular endothelial growth factor (VEGF) in retinas. These results indicate that SMYAD attenuated DR development through suppressing retinal inflammation and angiogenesis via abrogating NFκB-TNFα and HIF1α-VEGF signal pathways.